Donovan Hair Clinic, Whistler, BC, Canada
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: Jeff Donovan has received honoraria from Pfizer, maker of abrocitinib, tofacitinib and ritlecitinib.

Abstract:
Oral Janus kinase (JAK) inhibitors now have a position as first-line agents for treating advanced alopecia areata. Oral JAK inhibitors are considerably more effective than topical JAK inhibitors, although topical agents may still have a valuable role for specific subgroups of patients. The US FDA approval of baricitinib in 2022 was an important milestone. Numerous JAK inhibitors are now being intensely studied for use in alopecia areata and several additional medications may also become approved in the near future. Accumulating clinical trial data points to a generally good safety profile for JAK inhibitors when used for patients with alopecia areata. However, long-term data pertaining to the safety and efficacy in this patient population are lacking.

Keywords: alopecia areata, cytokines, hair loss, Janus kinase inhibitors, JAK inhibition

Introduction

The treatment of advanced forms of alopecia areata (AA) is more challenging than the milder forms and patients with advanced AA often require systemic therapy in order to regrow hair. Since the introduction of Janus kinase (JAK) inhibitors to the world over a decade ago, these agents have risen to the top of the treatment ladder to become a bona fide first-line therapeutic option for severe AA.¹ The US FDA approval of baricitinib on June 13, 2022 marked an important new chapter in the field of AA.²

The Janus Kinase (JAK) Pathway

The JAK pathway is an intracellular signaling pathway that mediates the effects of many different pro-inflammatory signaling molecules.³ The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway consists of three main components: 1) the cell surface receptor, 2) the intracellular JAK and 3) the downstream regulatory signals of JAKs known as STAT. There are four members of the JAK family: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Current JAK inhibitor medications block one, two, three or all of the JAK enzymes. JAK1, JAK3 and TYK2 have a role in mediating signals in a wide range of inflammatory disorders. JAK2 not only mediates signals related to inflammation but also mediates signals for a range of inflammatory cytokines that involve hematopoiesis. Newer JAK inhibitors that lack the ability to inhibit JAK2 are of particular interest as they may have fewer hematologic side effects.

Clinical Studies of JAK Inhibitors: Pre-FDA Approval Era

Initial studies in 2014 using mouse models of AA revealed that JAK-STAT signaling had a key role in the development of autoreactive CD8+ T-cells targeting the hair follicle.⁴ These studies also confirmed that use of JAK inhibitors promoted hair regrowth in affected animals and more revolutionary – also in humans affected by AA. Three patients with AA treated with oral ruxolitinib experienced near complete hair growth after 5 months of treatment.⁴

In 2014, a second JAK inhibitor, tofacitinib, was reported to be helpful for treating AA in humans.⁵ A patient presenting with both plaque psoriasis and advanced AA exhibited complete regrowth of scalp hair after 3 months of treatment and full regrowth of all body hair after 8 months of treatment.⁵

Since 2014, there have been many case reports, retrospective case series, open label trials and randomized control trials (RCT) reporting the benefits of JAK inhibitors for some, but not all, patients with various types of AA. Most of the larger RCTs have studied JAK inhibitors for patients with severe AA (currently defined as ≥50% scalp hair loss).

Meta-analyses Confirm Efficacy of JAK Inhibitors

In 2019, Phan and Sebaratnam performed a systematic review and meta-analysis examining the benefits of JAK inhibitors for treating AA.⁶ Studies of tofacitinib, ruxolitinib and baricitinib from 30 studies and 289 patients were included in the analysis. A good response was defined as 50-100% hair growth and a partial response was defined as 5-50% hair growth. The proportion of patients achieving a good response was 45.7% and the proportion of patients with partial responses was 21.4% The mean time to initial hair growth was 2.2 ± 6.7 months. Children and adults treated with JAK inhibitors appeared to benefit in a similar manner.

More recently, Yan et al.⁷ performed another systematic review and meta-analysis. They included 14 studies (5 RCTs and 9 non-RCTs) from 1845 patients. A good response was defined as the achievement of Severity of Alopecia Tool score of 50% improvement (SALT50) and a complete response was defined as a SALT90 (90% improvement in SALT score compared with baseline). The SALT is the severity of alopecia tool score and ranges from 100 in the case of complete hair loss to 0 in the case of complete hair regrowth.

In the RCT data examining baricitinib and the experimental JAK inhibitors brepocitinib and ritlecitinib, oral JAK inhibitors were found to have a better response rate compared to controls, although topical JAKs did not perform better than controls. When evaluating the non-RCT data involving tofacitinib and ruxolitinib, pooled data showed a good response in 63% of patients using oral JAKs and in 28% of those using topical JAKs. Overall, the Yan et al. study suggested that oral JAK inhibitors can be expected to help patients reduce SALT scores by an average of 30-50%.⁷ It appears that all of the currently studied JAK inhibitors are fairly similar in effectiveness although this may change as more data accumulates and newer JAK inhibitors are studied. Data on JAK inhibitors also showed that many patients lose hair again when they reduce or stop treatment. Many studies have shown that relapses occur within 3 months after stopping treatment.^6,8,9-11

The FDA Approval of Baricitinib

Orally administered baricitinib is a reversible and selective JAK1 and JAK2 inhibitor. The FDA approval of baricitinib on June 13, 2022 marked an important landmark date in the field of AA.

It was the pivotal phase 3 trials of baricitinib that ultimately supported the drug’s FDA approval.¹² The two trials, termed BRAVE-AA1 and BRAVE-AA2, included 654 and 546 patients, respectively. Each trial randomly assigned patients with severe AA to daily treatments consisting of either placebo, 2 mg or 4 mg of baricitinib, with the primary outcome being the percentage of patients achieving a SALT score of ≤20. The average baseline SALT score in these studies was approximately 85 indicating that a large proportion of patients with advanced AA were included in these trials. After 36 weeks of treatment, the primary outcome was achieved by 35.9-38.8% of patients in the 4 mg group, 19.4-22.8% in the 2 mg group, and 3.3-6.2% of placebo patients.

Extended follow-up data from patients in the BRAVE-AA1 and BRAVE-AA2 trials using continuous therapy through 52 weeks (1 year) showed that the 4 mg group had 36.6-40.9% of patients achieve a SALT score of ≤20, while the 2 mg group had 21.1-24.4%.¹³

Longer Term Baricitinib Data

Senna et al.¹⁴ recently presented longer term data on the efficacy of baricitinib in patients with severe AA following 104 weeks (2 years) of continuous therapy. Several findings are particularly important to note. First, some patients were not able to maintain their good 52 week results and lost hair between weeks 52 and 104. About 10-20% of patients who met the SALT ≤20 cut off at week 52 experienced slight hair loss in the second year of treatment. These patients did not meet the SALT ≤20 cut off at week 104 despite meeting the target at week 52. Therefore, good results are not maintained in all AA patients treated with baricitinib.

Second, a small proportion of patients experience good regrowth in the first 4-10 months after starting baricitinib and then lose some amount of hair as the 1 year mark approaches.¹⁴ These patients are called “mixed responders”. Mixed responders are more likely to be patients that have a longer duration of AA and more likely to have more severe hair loss at the start of treatment. It is evident from these results that a small proportion of patients with severe AA or longer duration AA will experience confusing and frustrating periods of hair regrowth followed by hair loss while using baricitinib. About 40% of mixed responders end up growing back hair and achieving a SALT ≤20 score at week 104, but 60% of mixed responders do not achieve this density again. Therefore, not all AA patients who experience hair loss after a period of good regrowth will recapture their hair density even with a longer duration of treatment.

Third, the 104 week data showed that further improvements in eyebrow and eyelash density can be expected from week 52 to week 104.¹⁴ Patients with AA using baricitinib can be advised that the eyebrow and eyelash density they achieve at week 52 are not necessarily representative of the final density they will achieve.

Baricitinib was generally well-tolerated in the BRAVE-AA1 and BRAVE-AA2 trials. In data recently presented by King and colleagues,¹⁵ there were no new safety signals with the 104 week data. Among 1303 patients with alopecia studied on 2 mg and 4 mg doses to date (with a mean 1.6 years of evaluation), serious adverse events occurred in 5% of patients. Serious infections occurred in 1.2% of patients. One case of a major cardiac adverse event (MACE), 1 deep vein thrombosis/pulmonary embolism (DVT/TE), 2 nonmelanoma skin cancers, 5 malignancies other than non-melanoma skin cancer (including B cell lymphoma, breast cancer, chronic lymphocytic leukemia, malignant melanoma and melanoma in situ) and 1 case of gastrointestinal perforation were documented in the trials, but were adjudicated to be unrelated to the study drug. There was 1 DVT that was felt to be related to the drug. There were no deaths.

Overall, COVID-19, upper respiratory tract infections (URTI), headache, acne, urinary tract infections (UTI) and increases in creatinine phosphokinase (CPK) were the most commonly reported adverse events. Extended study data showed that 18% of patients receiving 4 mg had elevation of low-density lipoprotein (LDL) cholesterol, 5% had elevation of CPK, 2.3% had elevated alanine aminotransferase (ALT) and herpes zoster occurred in 1.6%.¹⁵

Baricitinib is now marketed in the US under the trade name Olumiant™. The recommended dosage is 2 mg once-daily. Patients are recommended to increase the dosage to 4 mg once-daily if treatment response is not adequate. For patients with nearly complete or complete scalp hair loss, the recommended starting dose is 4 mg once-daily rather than 2 mg once-daily.

New Directions with Baricitinib

The FDA approval of baricitinib marks the beginning, rather than the end, of rigorous study for the use of this medication in patients with AA. In the years to come, the number of patients using these medications will dramatically increase. In addition to better understanding the long-term risks and benefits, we will also gain further insight if any particular patient subgroup can actually reduce the dose of the JAK inhibitor once full regrowth is achieved.

Despite the well-known risk of hair loss when doses of JAK inhibitors are reduced and despite the possibility that some patients with AA who do lose hair do not regrow hair back when they increase the dose again, the baricitinib product monograph indicates that patients using 4 mg “reduce the dose to 2 mg once-daily when an adequate response has been achieved.” This may be poor advice for some patients with AA. Various JAK inhibitor studies, for example, have suggested that patients who decrease their JAK inhibitor dose and then experience hair loss are not always able to regrow back hair to the exact same high density after restarting treatment.¹⁶ This also appears to be the case for patients using baricitinib. For example, King and colleagues¹⁷ recently evaluated the effect of reducing baricitinib from 4 mg to 2 mg in patients who achieved a SALT ≤20 cut off score at week 52. About one-half of patients (52.4%) who reduced from 4 mg to 2 mg were able to maintain a SALT ≤20 density. However, the remaining 47.6% of patients lost hair and no longer maintained sufficient hair density to meet the SALT ≤20 cut off. The risk of hair loss seems too great to follow the recommendations of the product monograph in every patient.

Furthermore, it is clear that reducing the baricitinib dose with a plan to simply resume the 4 mg dose if hair loss occurs, does not come with a guarantee that the patient will eventually get their hair back again. Recent studies in 7 patients who lost hair following a baricitinib dose reduction showed that 5 patients (71.4%) were able to regrow hair and once again achieve a SALT ≤20 after 36 more weeks of follow up.¹⁷ Two of the 7 patients (28.6%), however, did not get back to the SALT ≤20 density they once had.

More studies are needed before universally recommending dose reductions in all patients once full hair regrowth is achieved. It is possible that the recommendations for dose reductions found in the current baricitinib product monograph will be modified over time. If not, it is possible that they may be ignored if the standard of practice among hair loss experts ultimately moves in the direction of maintaining a large proportion of patients on a 4 mg dose once full regrowth occurs.

Finally, it is possible that the definition of severe AA may change over time. As reviewed above, baricitinib received FDA approval for patients with severe AA, defined as patients with ≥50% loss of scalp hair. It is increasingly recognized, however, that using scalp hair coverage alone to define “severe” AA is inadequate and excludes a large proportion of patients who fit a more encompassing definition of what constitutes severe AA.¹⁸ A recent expert focus group proposed that one must consider not only the hair density but the pattern of hair loss, location of hair loss, nail involvement, duration, quality of life and prior treatment responses in determining if someone should best be classified as having severe AA. It is possible that the criteria to more broadly define severe AA, and therefore the formal indications for drug approval, could change over time.

Possible New JAK Inhibitor Approvals in the Future

Although the FDA has approved baricitinib for the treatment of advanced AA, a number of new JAK inhibitor drug approvals are possible in the near future, including ritlecitinib and deuruxolitinib.

Ritlecitinib

Ritlecitinib is the first in a new class of kinase inhibitors that have high selectivity for Janus kinase 3 (JAK3) and members of the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family.

The randomized, double-blind ALLEGRO phase 2b/3 study addressed the use ritlecitinib in 718 patients ≥12 years of age with severe AA.¹⁹ Patients were randomized to receive ritlecitinib 50 mg, 30 mg, 10 mg or placebo (with or without 1 month of initial treatment with once-daily ritlecitinib 200 mg, 50 mg, 30 mg, 10 mg or placebo). The primary endpoint was the proportion of patients achieving a SALT score ≤20 at week 24. The study showed statistically greater proportions of patients treated with ritlecitinib 30 mg and 50 mg (with or without a loading dose) achieving this study endpoint compared to placebo. Overall, approximately 22-31% of patents achieved this target at week 24. By week 48 of the study, approximately 35-40% of patients in the higher dosing groups achieved a SALT ≤20.

Ritlecitinib was found to be well tolerated by both adult and adolescent patients. Adverse events (AEs) were experienced by 82% of patients and serious AEs by 2% of patients – with similar rates across the active treatment groups. The most common AEs seen in the ALLEGRO studies were nasopharyngitis, headache, herpes zoster and URTI. There were no MACE, deaths or opportunistic infections. There was one case of pulmonary embolism and two cases of breast cancers in the ritlecitinib 50 mg group. The case of pulmonary embolism and one of the cases of breast cancer were not felt to be related to ritlecitinib treatment. The other case of breast cancer, however, was felt to be related to treatment – this was a 58 year-old female participant diagnosed with breast cancer on day 198.

Both the FDA and European Medicines Agency are reviewing the application for formal approval of ritlecitinib and a decision is expected in 2023.

Deuruxolitinib

Deuruxolitinib (formerly CTP-543) selectively inhibits JAK1 and JAK2. THRIVE-AA1 was a randomized, muliticenter double-blind, placebo-controlled clinical trial involving 706 adult patients aged 18-65 years with severe AA.²⁰ THRIVE-AA2 was similar in design with 517 patients.²¹ Patients were randomized to receive either 8 mg twice-daily or 12 mg twice-daily of deuruxolitinib or placebo for 24 weeks. The primary endpoint was the percentage of patients achieving a SALT score of ≤20 at 24 weeks.

In THRIVE-AA1, the proportion of patients achieving a SALT score of ≤20 at week 24 was 41.5% in the 12 mg twice-daily dose group and 29.6% in the 8 mg twice-daily dose group, compared to 0.8% of patients in the placebo group. The treatment difference for both dose groups, relative to placebo, was statistically significant. In the THRIVE-AA2, the proportion of patients achieving a SALT score of ≤20 at week 24 was 38.3% in the 12 mg twice-daily dose group and 33.0% in the 8 mg twice-daily dose group, compared to 0.8% of patients in the placebo group. The most common side effects were headache, acne, URTI, increased creatine kinase levels, COVID-19 infection and nasopharyngitis.

In early May 2023, the FDA intervened in the clinical trials of deuruxolitinib.²² Specifically, the FDA halted use of deuruxolitinib 12 mg twice-daily in clinical trials on account of a trial participant developing a pulmonary embolism while receiving deuruxolitinib 12 mg twice-daily. The individual was participating in one of the deuruxolitinib long-term open label extension studies. The company recently stated that clinical trial participants receiving 12 mg twice-daily were switched to 8 mg twice-daily.²² Given that there have been no thrombotic events reported to date for 8 mg twice-daily dosing, the FDA has not placed this regimen on hold and clinical trials of the 8 mg twice-daily dose are continuing.

The company developing deuruxolitinib reports that it also intends to utilize this data from the THRIVE-AA1 and THRIVE-AA2 trials as the basis of a New Drug Application submission to the FDA in 2023.

New JAK Inhibitor Clinical Trials and Studies

In the last 8 years, we have progressed from studies of tofacitinib, ruxolitinib and baricitinib to trials that also include ritlecitinib, deuruxolitinib and a variety of other JAK inhibitors. A large number of registered clinical trials of various JAK inhibitors are currently underway (Table 1).

New case reports of selective JAK inhibitors to treat AA are increasingly reported in the literature (Table 2). These JAK inhibitors were developed with the goal to more precisely induce inhibition of JAK pathway components and reduce unwanted AEs. The main benefit of the selective JAK inhibitors is avoiding JAK2 inhibition and the hematologic side effects that come from JAK2 inhibition.

The JAK1 selective inhibitors abrocitinib and upadacitinib were both FDA approved in 2022 for the treatment of moderate to severe atopic dermatitis. Findings are now emerging in case reports of benefits in the treatment of AA.^23-32 Filgotinib, approved in Europe and Japan for treating rheumatoid arthritis, has also recently been reported to help AA.³³ The TYK2 selective inhibitor deucravacitinib is Health Canada and FDA approved for psoriasis and will soon enter a trial for AA. A summary of several JAK inhibitors and their study in AA is summarized in Table 2.

Topical JAK Inhibitors

Topical JAK inhibitors have been studied for off label use in adults and children and for various sites including scalp, eyebrows and eyelashes. Studies pertaining to the benefits of topical JAK inhibitors for treating scalp AA are inconsistent. Some studies suggest a benefit whereas others do not. Even the vehicle selected by the pharmacy to compound the JAK inhibitor can have a dramatic effect on patient outcomes. This only adds to the challenges of fully studying the benefits of topical JAK inhibitors.³⁴

Two recent meta-analyses demonstrated that topical JAK inhibitors are far less effective than oral JAK inhibitors for treating scalp AA.^6,7 The 2022 meta-analysis by Yan et al.⁷ found there was no significant difference in efficacy outcomes between topical JAK inhibitors and placebo when RCT studies were examined. When examining the non-RCT studies, the authors found that topical JAK inhibitors induced minimal hair regrowth but the authors felt that the improvement was too little to be clinically meaningful or to be distinguished from the spontaneous remission and placebo effect. Topical JAK inhibitors may be of more benefit in treating eyebrow loss or eyelash loss than scalp hair loss, although more detailed studies are needed.

JAK Inhibitors for Treatment of Pediatric AA

There are no FDA approved treatments for children with AA and the current FDA approval of baricitinib does not extend to include children or adolescents. New clinical trials are increasingly opting to include adolescents in their study population (Table 1).

Children and adolescents appear to respond to JAK inhibitor treatment just as well as adults.⁶ A meta-analysis by Chen et al.³⁴ examined 10 pediatric studies and 69 patients, reporting 68.5% of patients overall were considered good responders and 7.7% were partial responders. Similar to what is seen in adults, the use of oral JAK inhibitors was linked to a much better response than topical medications. Behrangi et al.³⁵ also published a systematic review and meta-analysis of topical and oral tofacitinib use in pediatric patients. They included observational studies from 59 patients ranging in age from 4-19 years. The meta-analysis showed good/complete response by 55% and 41% experienced partial response. Oral administration was significantly more efficacious than topical application. Even though topical JAK inhibitors seem less effective than oral JAK inhibitors in children, more studies are needed to better define how well they work.

Options for Patients Who Do Not Respond Well to JAK Inhibitors

About 25-30% of patients with advanced AA respond extremely well to JAK inhibitor therapy. However, a significant proportion of patients with severe AA are not able to achieve full regrowth with any of our currently available JAK inhibitors. It remains to be elucidated why some patients do not benefit to the same degree from JAK inhibitors and why others seem to be complete nonresponders. Although patients with extremely long duration of disease (especially more than 10 years) and patients with more advanced disease (alopecia totalis/universalis vs. localized) have lower response rates to JAK inhibitors, other factors are not well understood.

In prior years, the strategy to address poor responses has been to increase the dose of the JAK inhibitor.³⁶ However, data showing an increased risk of thrombosis as well as other side effects with tofacitinib 10 mg twice-daily compared to 5 mg twice-daily has dramatically reduced the tendency of clinicians to use higher doses of JAK inhibitors.

Some studies have suggested that if a patient fails one JAK inhibitor, it can still be worthwhile to switch to another JAK inhibitor drug.³⁷ Finally, it will be important to understand why some patients initially respond to JAK inhibitors and then lose benefits over time. Our current AA clinical trials are not long enough in duration to adequately understand the phenomenon of waning treatment responses. The 104 week baricitinib extension studies discussed above reminds us that there is a significant proportion of patients (i.e., 10-20%) who experience waning of results over time.¹⁴

Long-term Safety

Studies of JAK inhibitors in patients with AA generally point to good safety of these agents. It would appear that the prevalence of specific side effects are fairly similar among various JAK inhibitors when used by AA patients. This may change over time as studies with greater numbers of patients and longer duration are conducted.

The 2019 meta-analysis by Phan et al.⁶ reported JAK inhibitor side effects included URTI (18.2%), UTI (2.2%), lipid abnormalities (11.8%) leucopenia (1%) and transaminitis (1.6%). A 2022 metaanalysis by Yan et al.⁷ reported generally good safety from use of these agents. In RCTs examining the use of baricitinib, ritlecitinib and brepocitinib, there was no significant difference between JAK inhibitors and placebo in the risk of experiencing treatmentemergent AEs, serious AEs, URTI, headache or nasopharyngitis. However, acne was approximately three times more common with baricitinib than with placebo. Yan et al.⁷ showed the highest risk was observed for URTI (37.05%), followed by diarrhea (19.65%), acne (9.31%), UTI (6.98%), headache (6.33%) and folliculitis (4.48%).

The ORAL Surveillance Study

Recent published results from the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance trial have affected the entire JAK inhibitor prescribing community.³⁸

The ORAL Surveillance trial was a randomized trial evaluating the safety and efficacy of tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor in patients with rheumatoid arthritis who were ≥50 years of age and had at least one additional cardiovascular (CV) risk factor. The primary endpoints of the study were the risk of MACE (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) and cancer. A 33% increase in MACE and 48% increase in cancer was noted in tofacitinib users compared to TNF inhibitors.³⁸

On account of these findings, the FDA has placed new boxed warnings on certain JAK inhibitors used in inflammatory conditions including baricitinib, upadacitinib and tofacitinib and abrocitinib. The boxed warning includes information about the risk for serious infections, mortality, cancer, CV events and thrombosis.

Whether or not the findings from the ORAL Surveillance trial of rheumatoid arthritis patients are directly applicable to patients with AA and whether these findings are broadly applicable to all JAK inhibitors is still unknown.

There is a tremendous amount of work ahead to address all the safety issues related to JAK inhibitors. However, the news for patients with AA appears to be reasonably good based on the short duration clinical studies that have been performed to date. Studies lasting many years, rather than many months, will ultimately be needed. The data from the 104 week baricitinib trials¹⁴ are a step in the right direction to understanding the long-term effects of JAK inhibitors specifically in AA patients.

Conclusion

JAK inhibitors are now a first-line treatment option for patients with advanced AA. This is supported by a several studies including an ever increasing number of well-designed randomized, placebo-controlled trials. Baricitinib represents the first of what will likely be many JAK inhibitors that will be used to treat severe AA. Oral JAK inhibitors are superior to topical JAK inhibitors but a role for topical JAK inhibitors in the management of some aspects of AA treatment (eyebrows, eyelashes, pediatric AA) cannot be excluded. There are still many issues we do not fully understand including the long-term safety and efficacy of JAK inhibitors. Appropriate patient assessment and counselling will not only help identify individuals who may benefit most from these medications but will also help exclude those who may be at risk for side effects (Table 3). These issues will be important for us all to follow in the future.

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¹Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada;
³Skin Investigation Network of Canada (SkIN Canada), Toronto, ON, Canada; ⁴Dalhousie University, Halifax, NS, Canada; ⁵Probity Medical Research, Waterloo, ON, Canada

Conflict of interest: Nadia Kashetsky reports no conflicts of interest. Irina Turchin was a consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Novartis, Pfizer, Sanofi, UCB.

Abstract:
As systemic administration of Janus kinase-inhibitors is associated with safety concerns, local alternatives, such as topical ruxolitinib, have been developed. This review summarizes utilization of topical ruxolitinib in dermatology. A literature search was performed of studies reporting topical use of ruxolitinib in dermatologic conditions. Twenty-four articles were included, representing 2618 patients. Results show improvement with topical ruxolitinib formulations in atopic dermatitis, vitiligo, psoriasis, and lichen planus. Results are conflicting in alopecia areata. Minimal bioavailability and low rates of mild-to-moderate treatment-related adverse events support a favorable safety profile and higher tolerability of topical ruxolitinib compared to oral Janus kinase-inhibitors.

Keywords: ruxolitinib, topical, Opzelura™, Janus kinase-inhibitors, JAK-inhibitors, vitiligo, atopic dermatitis, eczema, psoriasis, alopecia areata, lichen planus

Introduction

Immune-mediated skin conditions are common and cause significant morbidity and healthcare utilization.^1,2 Treatment of these conditions was previously focused on symptom management and nonspecific immunosuppression, however, recent advances in understanding the pathogenesis of immunologic disease has led to novel therapeutic targets.^2,3

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, shown to be vital in downstream signaling of inflammatory cytokines, is amongst these novel therapeutic targets, for which JAK-inhibitors have been developed.^4-6 JAK-dependent cytokines are important in the immunopathology of diverse immune-mediated skin diseases, leading to the utilization of JAK-inhibitors in dermatology.^4,6 However, as systemic administration of JAK-inhibitors are associated with safety concerns, local alternatives, such as topical ruxolitinib (RUX), have been developed.^7,8 Topical 1.5% RUX cream was US FDA approved for AD in September 2021 and nonsegmental vitiligo in July 2022.⁹

Although several systematic reviews have described the utilization of JAK-inhibitors in dermatology, a summary of topical RUX in dermatology is lacking.^10-12 Accordingly, this review comprehensively summarizes the available data on efficacy and safety outcomes of topical RUX in dermatological conditions.

Methods

A literature search was performed of studies reporting topical RUX utilization in dermatologic conditions (Figure 1).

Results

Twenty-five articles were included in this review, representing 2618 patients (Table 1). Articles reported data on topical RUX use in atopic dermatitis (AD, n=8), vitiligo (n=6), alopecia areata (AA, n=5), psoriasis (n=2), and lichen planus (LP), necrobiosis lipoidica, discoid lupus erythematosus, and seborrheic dermatitis (n=1 each).

Efficacy

Atopic Dermatitis

A 4-week, phase I, open-label, maximum-use trial investigated efficacy of RUX cream in patients with AD, aged 12-65 years, disease duration ≥2 years, Investigator’s Global Assessment (IGA) score ≥2, and ≥25% body surface area (BSA) involvement (n=41).^13,14 Patients applied 1.5% RUX cream twice-daily (BID) for 4 weeks. An extension period to week 8 was completed by 37 patients. IGA treatment success (an IGA score of 0/1 with a ≥2-grade improvement from baseline) was reported in 20% of patients at day 15, 35.9% of patients at day 28, and 56.8% of patients at day 56. Mean standard deviation (SD) BSA decreased from 38.1% (16.3%) at baseline to 6.5% (8.2%) at day 28 and 3.1% (5.4%) at day 56; 79.5% and 94.6% of patients achieved ≥75% improvement in Eczema Area and Severity Index (EASI-75) at day 28 and day 56; and 82.6% and 90.5% of patients achieved ≥4-point improvement in the itch Numerical Rating Scale (NRS) at days 28 and 56, respectively. The mean daily application amount of RUX cream over the first 4 weeks was 20.2 g compared to 5.4 g in the phase III studies.^13,14

An 8-week, phase II, randomized study with vehicle control and active control (0.1% triamcinolone acetonide cream) investigated efficacy of RUX cream in patients with AD, aged 18-70 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=307).¹⁵ Patients were randomly assigned to 1.5% RUX cream BID (n=50), 1.5% daily (n=52), 0.5% daily (n=51), 0.15% daily (n=51), 0.1% triamcinolone BID for 4 weeks then vehicle for 4 weeks (n=51), or vehicle BID (n=52). Mean percentage change in EASI score from baseline at week 4 was 71.6% versus 15.5% for 1.5% RUX cream BID versus vehicle (P<0.0001). At week 4, IGA response defined as a patient achieving an IGA score of 0 to 1, with 2 or more points improvement from baseline was achieved by 38% of patients in the RUX 1.5% arm compared to 25.5% of patients in the 0.1% triamcinolone arm.

Within 36 hours after the first 1.5% RUX cream application BID, itch NRS was significantly reduced compared to vehicle (-1.8 versus -0.2, P<0.0001), and significantly more patients achieved minimally clinically important difference (42.5% versus 13.6%, P<0.01).¹⁶ Within 2 weeks, all RUX cream regimens decreased itch NRS and achieved significant improvements in quality of life as measured by Skindex-16.¹⁶

Two, 8-week, phase III, randomized, double-blind, vehicle-controlled studies of identical study design, investigated efficacy of RUX cream in patients with AD, aged ≥12 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=631/n=618 in Study 1/2).^17,18 Patients were randomized to apply 1.5% RUX cream BID (n=253/n=246), 0.75% BID (n=252/n=248), or vehicle cream BID (n=126/n=124). IGA treatment success at week 8 was achieved by significantly more patients in both Study 1 and Study 2 with 1.5% RUX cream (53.8%/51.3%) and 0.75% RUX cream (50.0%/39.0%) compared to vehicle (15.1%/7.6%, all P<0.0001).

Pooled data demonstrated significant rapid itch reduction within 12 hours of 1.5%/0.75% RUX cream application (-0.5/-0.4, versus -0.1 for vehicle; both P<0.02).¹⁹ At 36 hours, a ≥4-point itch NRS improvement was achieved by significantly more patients with 1.5%/0.75% RUX cream (11.2%/8.9%, versus 2.1% for vehicle; both P<0.005),¹⁹ and significantly more patients achieved an itch free state versus vehicle.²⁰

At week 8, significant impact on work productivity and activity impairment were achieved.²¹ Estimated incremental annual indirect cost savings for patients were US$5302/US$4228 for 1.5%/0.75% RUX cream.²¹

Long-term safety and efficacy of 1.5% and 0.75% RUX cream was further investigated in the long-term extension of the phase III studies.²² Patients initially randomized to twice-daily 0.75%/1.5% cream were maintained in their assigned arms for 44 weeks, and patients randomized to vehicle were re-assigned at week 8 to either RUX cream strength. At week 52 of as-needed treatment, 74.1%-77.8% of patients had IGA0/1, and a mean affected BSA was low (1.4%-1.8%).

Vitiligo

A 20-week, phase II, open-label proof-of-concept study investigated efficacy of RUX cream in patients with vitiligo, ≥18 years, with ≥1% BSA (n=11).²³ Patients applied 1.5% RUX cream BID for 20 weeks.²³ Mean improvement in Vitiligo Area Scoring Index (VASI) at week 20 was significant (23%, P=0.02). An extension of this study included 8 patients without previous response, and showed significant overall mean improvement from baseline at 52 weeks (37.6%, P=0.011).²⁴

A 52-week, phase II, randomized, double-blind, dose-ranging study investigated the efficacy of RUX cream in patients with vitiligo, aged 18-75 years, 0.5% facial BSA, and ≥3% non-facial BSA (n=157).^25,26 Patients were randomly assigned to 1.5% RUX cream BID (n=33), 1.5% daily (n=30), 0.5% daily (n=31), 0.15% daily (n=31), or vehicle cream BID (n=32). A ≥50% improvement in facial Vitiligo Area Scoring Index (F-VASI50) at week 24, was achieved by 50%/45% of patients with 1.5% RUX daily/BID versus 3% with vehicle (P<0.001/P=0.001). In patients who received 1.5% RUX cream BID in this trial, a sub-analysis indicated a larger proportion of F-VASI50 responders were aged ≤50 years, women, had baseline ≤1.5% facial BSA, disease duration >20 years, and received previous phototherapy.²⁷ All body areas had repigmentation, including difficult to treat acral areas.²⁷

Following the double-blind period of this phase II study, an open-label phase assessed the efficacy of RUX cream with narrowband ultraviolet B (NB-UVB) (n=19).²⁸ At week 104, overall mean improvement was 50.1% for F-VASI and 29.5% for total body VASI (T-VASI) versus the last visit before adding NB-UVB.

Two 24-week, phase III, double-blind, vehicle-controlled trials of identical study design investigated the efficacy of RUX cream in patients with vitiligo, aged ≥12 years, ≤10% BSA, ≥0.5% facial BSA, and ≥3% non-facial BSA (n=330/n=344 in Study 1/2).^29,30 Patients were randomized to apply 1.5% RUX cream BID (n=221/n=229) or vehicle cream BID (n=109/n=115) for 24 weeks. At week 24, F-VASI75 was achieved by 29.8%/30.9% of patients in the RUX cream arms compared to vehicle (7.4%/11.4%, P<0.001).

Alopecia Areata

A 28-week, phase I, prospective, double-blind, placebo controlled, pilot study investigated the efficacy of 1% RUX ointment, 2% tofacitinib ointment, 0.05% clobetasol dipropionate ointment, and vehicle in patients with alopecia areata (AA) (n=16).³¹ All 4 ointments were applied to designated areas BID. Partial regrowth was achieved in 5/6/10/2 patients treated with 1% RUX/2% tofacitinib/0.05% clobetasol dipropionate/vehicle.

A phase II, 2-part, double-blind, randomized, vehicle-controlled study, investigated the efficacy of RUX cream in patients with AA, aged 18-70 years, Severity of Alopecia Tool (SALT) score 25%-99% (Part A: n=12; Part B: n=78).³² In Part A patients applied 1.5% RUX cream BID for 24 weeks. A ≥50% improvement in SALT (SALT50) was achieved by 50% of patients at week 24. In Part B patients were randomized to 1.5% RUX cream BID (n=39) or vehicle BID (n=39) for 24 weeks. Percentage of patients achieving SALT50 between RUX cream and vehicle at week 24 was not significant (12.8% versus 12.8%, P=0.99).

Moreover, 4 case reports utilizing RUX cream in patients with AA demonstrate conflicting results. A teenaged female had marked improvement with 0.6% RUX cream BID for 12 weeks,³³ whereas a 66-year-old female who exhibited lack of improvement with 0.6% RUX cream daily for 8 weeks, increased to BID for 6 weeks.³⁴ Finally, 2 patients, a 17-year-old female, and 4-year-old male, showed partial and no regrowth, with 1% RUX in a liposomal base BID for 18 months, and 2% RUX in a liposomal base BID then 1% tofacitinib liposomal base BID for 3 months, respectively.³⁵

Psoriasis

A 4-week, phase II, double-blind, vehicle or active comparator study assessed efficacy of RUX cream in patients with stable and active plaque psoriasis, aged 18-75 years, <20% BSA (n=29).³⁶ Patients were randomized to 0.5% or 1.0% RUX cream daily, 1.5% RUX BID, vehicle daily or BID, 0.005% calcipotriene cream BID, or 0.05% betamethasone dipropionate cream BID for 4 weeks. At 4 weeks, mean total lesion score decreased by 53%/54% for 1.0% RUX daily/1.5% RUX BID versus vehicle (32%, P=0.033/P=0.056).

A 4-week, phase II, open-label, multicenter, cohort, doseescalation study evaluated efficacy of RUX cream in patients with stable and active psoriasis, aged 12-65 years (n=25).³⁷ Patients applied 1.0% or 1.5% RUX cream daily or BID for 4 weeks to 2%-20% BSA. In all cohorts, at 4 weeks, mean total lesion scores decreased and PGA scores improved.

Other

An 8-week, phase II, single-arm, open-label trial investigated the efficacy of RUX cream in patients with biopsy proven lichen planus (LP), aged ≥18 years, ≤20% BSA and ≥4 lesions (n=12).³⁸ Patients applied 1.5% RUX cream BID for 8 weeks. At week 4, lesion count significantly decreased by a median of 50 lesions (P<0.001); and mean modified Composite Assessment of Index Lesion Severity of index versus control lesions decreased significantly by a mean of 7.6 points (P=0.016).

A 19-year-old female with refractory necrobiosis lipoidica showed marked improvement with 1.5% RUX cream BID for 3 months.³⁹ A 28-year-old female with discoid lupus erythematosus exhibited improvement of scalp lesions with 1.5% RUX cream daily for 2 months.⁴⁰ A 74-year-old male with seborrheic dermatitis and rosacea showed complete and partial response, respectively, with 1.5% RUX cream BID for 2 weeks.⁴¹

Safety and Tolerability

Bioavailability of RUX cream was limited.^{13,14,25,36,37,42,43} The highest strength average steady-state trough plasma concentrations were well below clinically relevant systemic pharmacological activity, remaining below the half-maximal inhibitory concentration of JAK-mediated myelosuppression.^{13,14,25,36,37,42,43}

No serious treatment related adverse events (TRAE) were reported across all topical RUX data. Mild-to-moderate TRAE were reported in minority of patients, most commonly including application-site pain, pruritus, acne, erythema, and hyperpigmentation. Rare treatment-emergent adverse events included increase in aspartate aminotransferase and alanine aminotransferase, leukopenia, hemoglobin decrease, mild reticulocytosis, dyspnea, abnormal taste, and transient hypoaesthesia of the fingertips.

Discussion

This review summarizes the utilization of topical RUX in dermatological conditions. Results show improvement with topical RUX formulations in AD, vitiligo, psoriasis, and LP. Results are conflicting in AA. Minimal bioavailability and low rates of mild-to-moderate TRAEs support higher tolerability of topical RUX as compared to oral JAK-inhibitors.

RUX is a targeted inhibitor of JAK1/2, selectively interrupting effects of the cytokines which signal through JAK1/2 proteins.⁴⁴ AD pathogenesis involves JAK1/2 mediated cytokines interleukin (IL)-4, IL-13, IL-31, and IL-33.^6,45 Vitiligo and AA, both involve JAK1/2 mediated interferon (IFN)-gamma and IL-15 in their pathogenesis.⁶ IFN-gamma is also important in the pathogenesis of LP and psoriasis.^4,6,38 Psoriasis pathogenesis also has shown involvement of other JAK1/2 mediated cytokines including IL-6, IL-21, IL-22, and IL-23.^4,6

Conclusion

Available clinical trial data support the efficacy of topical RUX in AD, vitiligo, psoriasis, and LP with a favorable safety profile and tolerability compared to oral JAK-inhibitors suggesting that topical RUX is a promising new therapy in dermatology.

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¹Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
²Section of Dermatology, Department of Internal Medicine, Carilion Clinic, Roanoke, VA, USA

Conflict of interest:
Mr. Svoboda, Dr. Johnson, and Dr. Phillips have no conflicts of interest to disclose

Abstract:
Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, represent a new class of medication that have broad potential to treat dermatologic disease. Currently, the only FDA-approved dermatologic indication for this class of medications is psoriatic arthritis; however, their utility in treating other immune-mediated skin conditions including atopic dermatitis, vitiligo, alopecia areata, and systemic and cutaneous lupus is actively being investigated. Overall, these drugs appear to be well-tolerated and have a safety profile similar to that of other biologics commonly used in dermatologic practice, although an increased risk of thromboembolism has been associated. While risk of mild infection and herpes zoster appears to be increased regardless of JAK selectivity, risk of thrombosis and malignancy based on the subtype of JAK inhibition remains to be seen. Certainly, safety concerns warrant further investigation; however, early data from ongoing clinical trials offer promise for the broad utility of these medications within future dermatologic practice.

Key Words:
Janus kinase inhibitors, JAK inhibitors, jakinibs, baricitinib, ruxolitinib, tofacitinib, dermatologic applications, adverse effects

Background

Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, are a class of medication that offers promise for a number of immunologically driven conditions. Originally developed for the treatment of hematologic diseases, jakinibs have demonstrated efficacy in various autoimmune and autoinflammatory disorders.^1-3 Currently FDA-approved jakinibs include tofacitinib (Xeljanz^®) for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, baricitinib (Olumiant^®) for rheumatoid arthritis, and ruxolitinib (Jakafi^®) for myelofibrosis and polycythemia vera.²

As their name implies, JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes, of which there are four presently identified – JAK1, JAK2, JAK3, and TYK2. These JAK enzymes are tyrosine kinases that play a critical role in mediating the signal transduction of cytokines, particularly those that bind to and activate the type 1 and type 2 cytokine receptors on the surface of cells. More specifically, the phosphorylation of these cytokine receptors by Janus kinases leads to recruitment of Signal Transducer and Activation of Transcription (STAT) proteins which modulate gene expression. It is the immunoregulatory role of cytokines and the aberrant production of cytokines observed in many autoimmune disorders that makes interruption of the JAK-STAT signaling pathway an attractive therapeutic strategy.^1-3

The first JAK inhibitor to reach clinical trials was tofacitinib, an antagonist of JAK1 and JAK3 primarily.¹ It was granted initial approval in 2012 for the treatment of rheumatoid arthritis in patients who had an inadequate response to methotrexate, and since entering into commercial use, its approval has been extended to treatment-resistant psoriatic arthritis and moderate-to-severe active ulcerative colitis as well.^1,2 Other first generation jakinibs that have demonstrated clinical efficacy for these conditions among others include ruxolitinib and baricitinib; however, these agents differ in that their selectivity is for both JAK1 and JAK2.^2,4-7

Due to the variable activity and, in some cases, limited efficacy of the commercially available JAK inhibitors, 2nd generation agents with novel selectivity for Janus kinases are being developed and investigated.^1-3 Unfortunately, the exact relationship between inhibition of specific Janus kinase enzymes and therapeutic effect on target diseases is currently unknown.^1-3,6,8 However, as our understanding of the specific JAK/STAT pathways involved in the pathogenesis of dermatologic disease evolves, selective targeting of Janus kinases may allow for improved treatment precision and avoidance of adverse off-target effects.

Clinical Applications in Dermatology

Within dermatology, JAK inhibitors have been most extensively studied in psoriasis and psoriatic arthritis and have demonstrated clinical efficacy for these patients.⁶ However, their utility in treating other autoimmune/autoinflammatory skin conditions including atopic dermatitis, alopecia areata, vitiligo, and systemic lupus erythematosus is actively being investigated in clinical trials with various 1st and 2nd generation jakinibs (Table 1).

Psoriasis and Psoriatic Arthritis

Excessive activation of the JAK1/JAK2/STAT1 and JAK1/ TYK2/STAT3 pathways – and resultant amplification of proinflammatory genes – triggered by interferon (IFN)-gamma and interleukin (IL)-22, respectively, has been implicated in the pathogenesis of psoriasis.⁹ Therefore, inhibition and subsequent blockade of these overactive signaling pathways represents an attractive therapeutic target. Out of all the jakinibs, tofacitinib has been most widely studied in psoriasis and is currently the only jakinib with FDA-approval for the treatment of psoriatic arthritis.^6,10 This regulatory approval for this indication was granted in 2017 after statistically significant improvements in the American College of Rheumatology 20 (ACR20) assessment were observed in two phase III trials.^11,12 Subsequently, phase III trials demonstrated both 5 mg and 10 mg twice daily tofacitinib to be more effective than placebo in achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI 75), with improvement seen in a dose-dependent manner (46.0, 59.6, and 11.4%, respectively for OPT Pivotal 2).^12,13 These doses also provided significant improvements in nail psoriasis and were sustained for up to 52 weeks.^11-13 Moreover, a phase III noninferiority trial found the 10 mg twice daily dose of tofacitinib to be noninferior to etanercept, 50 mg subcutaneously twice per week, with a similar side effect profile.¹⁴ Unfortunately, a topical tofacitinib 2% ointment did not demonstrate improvement over placebo after a 12 week phase II trial in patients with mild-to-moderate psoriasis.¹⁵

Several other jakinibs have also shown promising early results. Phase II trials of baricitinib, filgotinib, itacitinib, and BMS- 986165 have all have yielded improved outcomes in the PASI 75 and Physician’s Global Assessment when compared to placebo.^16-18 Also, a phase II trial of topical ruxolitinib 1.5% cream was found to be efficacious in reducing the area of psoriatic plaques. However, it was only as effective as standard of care topical calcipotriene and betamethasone dipropionate.¹⁹ Results from ongoing clinical trials of upadacitinib and brepocitinib (PF-06700841) are eagerly awaited. Head-to-head randomized controlled trials comparing the efficacy between jakinibs and existing treatments for psoriasis or psoriatic arthritis have not been conducted.

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions and is driven by barrier dysfunction and abnormal immune activation predominantly of T helper (Th) 2 and Th22 cells, but to a lesser degree Th1 and Th17 subtypes as well.²⁰ JAK inhibition may, therefore, be a viable therapeutic approach as the JAK-STAT pathway underlies the activation of these T helper subsets.²⁰ Both oral and topical formulations of JAK inhibitors have been shown to decrease AD severity and symptoms.²⁰ In 2015, Levy et al. demonstrated efficacy of oral tofacitinib in six patients with moderate-to-severe, recalcitrant AD, noting that overall disease severity decreased by approximately 55% as judged by the SCORing Atopic Dermatitis (SCORAD) index. Additionally, patients had even greater average reductions in sleep loss and pruritus scores.²¹ Though encouraging, this study was inadequately powered to allow for major conclusions about the efficacy of oral JAK inhibitors in treating AD. In 2016, a phase II placebo-controlled trial showed significant improvement in the Eczema Area and Severity Index (EASI) score after 4 weeks of topical tofacitinib in 69 patients.¹⁶ While evidence for the clinical efficacy of JAK inhibitors for A still remains limited at this time, the literature is anticipated to rapidly expand as several phase II and III trials with oral and topical JAK inhibitors are ongoing and near completion. Current agents under investigation include baricitinib, upadacitinib, ruxolitinib (topical), brepocitinib (topical), and abrocitinib (PF-04965842).²⁰

Alopecia Areata

Alopecia areata (AA) is an autoimmune disease of the hair follicle characterized by patchy hair loss of the scalp, and, in some patients, has potential to progress to total scalp hair loss (alopecia totalis) and total body hair loss (alopecia universalis). Numerous case reports have documented the efficacy of oral and topical jakinibs for AA; however, clinical trials thus far have been limited.^6,22-26 A phase I, placebo-controlled, double-blind study in patients with alopecia universalis found significant hair regrowth with two topical JAK inhibitors, 2% tofacitinib and 1% ruxolitinib after 28 weeks. However, only about half of patients responded to the medication, and the response rate was inferior to topical clobetasol.²⁷ In contrast to the topical formulations, an open-label clinical trial comparing the efficacy of oral tofacitinib and ruxolitinib in 75 patients with severe AA found that both medications induced remarkable hair regrowth at the end of 6 months, with a mean change in the Severity of the Alopecia Tool (SALT) score of 93.8 ± 3.25 in the ruxolitinib group and 95.2 ± 2.69 in the tofacitinib group.²⁶ There was no statistically significant difference between the groups regarding hair regrowth at the end of the 6-month treatment, and relapse rate at the end of the 3-month follow-up was the same for both medications. While both drugs were well tolerated with no serious adverse effects reported, approximately two-thirds of cases experienced relapse after drug discontinuation.²⁶

Vitiligo

Numerous case reports, case series, and open-label studies have documented the efficacy of both oral and topical JAK inhibitors for vitiligo, an acquired depigmenting disorder caused by autoimmune destruction of melanocytes.^28-31 In a phase II open-label study of 11 patients, application of ruxolitinib 1.5% cream for 20 weeks resulted in significant improvement in the overall Vitiligo Area Scoring Index (VASI) with facial vitiligo demonstrating the best response.³⁰ Follow-up of five patients at 6 months after treatment cessation revealed that all had maintained their response. While reports of cases employing oral tofacitinib and ruxolitinib documented significant repigmentation during medication administration, both also noted regression within weeks after treatment discontinuation.^28,31 Clinical trials of topical ruxolitinib and two 2nd generation oral jakinibs, brepocitinib and PF-06651600, are currently underway.

Systemic Lupus Erythematosus

Inhibition of JAK2/3 has shown promise in animal models of lupus dermatitis and nephritis.³² While clinical studies are limited, one randomized phase II trial of oral baricitinib 4 mg reported modest efficacy for arthritis and rash severity after 24 weeks in patients with active systemic lupus erythematosus (SLE) who were not adequately controlled despite standard of care therapy.³³ Unfortunately, these improvements were only observed with the 4 mg and not the 2 mg dose. While these preliminary results are promising, data from ongoing trials of 2nd generation jakinibs will help ascertain effectiveness of this drug class for cutaneous lupus.³² To date, there have been no published reports assessing the efficacy of JAK inhibitors in specifically treating subacute and chronic forms of cutaneous lupus erythematosus.

Lichen Planopilaris

As is the case for AA, upregulation of interferons and JAK signaling play an etiologic role in lichen planopilaris (LPP), an inflammatory cicatricial alopecia. A retrospective study found that eight out of ten patients with recalcitrant LPP had clinically measurable improvement after treatment with oral tofacitinib 5 mg twice or three times daily for 2 to 19 months.³⁴ There was a greater than 50% mean reduction of LPP activity index in the eight patients that did observe a benefit. The only adverse effect reported was a 10-pound weight gain in one patient after treatment for 12 months.³⁴

Other Dermatologic Diseases

Evidence from case reports suggests that JAK inhibitors may provide benefit for patients with treatment-refractory or rare diseases without effective therapies such as cutaneous sarcoidosis, dermatomyositis, pemphigus, hidradenitis suppurativa, chronic mucocutaneous candidiasis, hypereosinophilic syndrome, polyarteritis nodosa, mastocytosis, and severe chronic actinic dermatitis.^35-40

Adverse Effects and Safety Considerations

The relatively broad and nonspecific anti-inflammatory and immunosuppressive properties of jakinibs, which allow for their potential efficacy across many indications, are mirrored in the wide array of potential adverse effects seen across this drug class. The primary safety concerns surrounding their use include the risk of infection, malignancy, and thromboembolic events. Nevertheless, jakinibs currently appear to have an acceptable safety profile comparable to that of the biologics already being used to treat many of the same conditions.^10,41 The majority of this safety data originates from clinical trials of tofacitinib and baricitinib in patients with rheumatoid arthritis.

Infection

The most commonly reported adverse events for those taking JAK inhibitors are mild upper respiratory infections and nasopharyngitis. For patients on tofacitinib, these mild infections occur at rates of approximately 10% or less.^6,20,42,43 There is also an increased risk of serious bacterial, fungal, mycobacterial, and viral infections, occurring at rates of 2.6 to 3.6 events per 100 patient-years for those on tofacitinib.²⁹ More specifically, the rates of tuberculosis and non-disseminated herpes zoster is 0.2 and 3.8 to 5.2 events per 100 patient-years, respectively.^43-45 Fortunately, the risk of tuberculosis is extremely low, especially for individuals residing in nonendemic areas. One study found that 21 out of 26 new tuberculosis cases in 5671 patients taking tofacitinib, occurred in countries with a high prevalence of tuberculosis.⁴⁵ Additionally, of 263 patients with latent tuberculosis, none developed active tuberculosis when they took tofacitinib and isoniazid concurrently.⁴⁵

The safety profile of baricitinib appears similar to that of tofacitinib with mild infection, namely nasopharyngitis, being the most common adverse event. In a 24-week, phase II study of 301 patients, only 1% developed a serious infection, but all recovered and continued with the study.⁴⁶ In a 52-week, phase II study of 142 patients, herpes zoster occurred in 11 patients and tuberculosis occurred in none.^46,47 Clinical trials of the 2nd generation jakinibs are reporting similar, if not improved, rates of infection to the 1st generation drugs.⁴⁸ However, phase IV studies and head-to-head trials between jakinibs will be required to establish any differences in risk.

Although the rates of herpes zoster in those taking jakinibs are similar to those of other biologic disease-modifying antirheumatic drugs, immunization with the recombinant zoster vaccine prior to initiating treatment may reduce the risk of this infection. While it is not specifically approved for patients using JAK inhibitors, it has been studied in individuals who are immunocompromised and found to be both safe and efficacious.¹⁰

Malignancy

There is concern about the theoretical increased risk for developing cancer with the use of jakinibs as a result of blocking the action of interferons and natural killer cells, which play an important role in tumor surveillance. While there have been reports of lymphoma and other malignancies associated with tofacitinib and baricitinib, multiple large studies have failed to demonstrate an increased risk of malignancy, with a mean follow-up of 3.5 years.^6,42,44,49 Moreover, a 128-week open-label extension study of tofacitinib did not show any cases of malignancy with prolonged treatment.⁵⁰ Yet, one study of myelofibrosis patients did find a slightly higher rate of aggressive B cell lymphoma in those treated with ruxolitinib. In response to this association, a bioinformatics study evaluating gene expression data from numerous lymphoma cell lines discovered that ruxolitinib can increase the pathological expression of transcription factors important in lymphoma genesis.⁵¹ Consequently, longer-term studies are necessary to further assess the correlation between jakinib therapy and cancer risk. Quantification of these risks based on dosage, duration of treatment, subtype of JAK inhibition, and disease type should be explored.

Thromboembolism

While the potential risks for infection and malignancy have been the primary safety considerations surrounding the use of jakinibs, more recently, concern for increased risk for thromboembolic events has arisen. In July 2019, the FDA issued a black box warning for the 10 mg, twice-daily dose of tofacitinib after a post-market safety review of the FDA’s Adverse Event Reporting System (FAERS) noted an increased rate of pulmonary thrombosis (OR = 2.46, [95% CI = 1.55-3.91]), though not pulmonary embolism (PE) or deep venous thrombosis (DVT), in patients with rheumatoid arthritis.⁵² However, a 2019 systematic review comparing complications associated with 5 mg versus 10 mg tofacitinib twice daily for the treatment of various autoimmune diseases found no difference in the rate of any serious adverse events at the end of the 3- and 6-month follow-up periods.⁵³ To date, approval of the 10 mg dose of tofacitinib is limited to those with treatment-refractory ulcerative colitis.

Baricitinib also has a black box warning denoting the risk for thromboembolic events, as clinical studies have observed an increased incidence of DVT and PE compared to placebo.⁵⁴ However, this risk of thromboembolic events appears to be quite low as it is estimated to be approximately five events per 1000 patient-years for the 4 mg daily dose in patients with RA. For non-RA patients, this risk is estimated to be even less, with one to four events per 1000 patient-years.⁵⁴ It should be noted that patients with RA also carry increased risk for thromboembolic events independent of JAK inhibitor therapy, although marginally increased risk has also been observed in patients with psoriatic arthritis and ulcerative colitis taking tofacitinib.^55,56

Nevertheless, this entire class of medication has come under closer scrutiny in light of these findings. Therefore, future trials of JAK inhibitors should ensure accurate and detailed documentation of any thromboembolic events that occur. Additionally, given the low incidence of thromboembolic events, large observational studies will likely be required to arrive at more definitive conclusions. Furthermore, it is crucial to differentiate whether these thromboembolic risks are attributable to JAK inhibitors or to the disease process itself and its comorbidities.

Lab Abnormalities

JAK inhibitors have also been associated with various laboratory abnormalities including anemia, neutropenia, and thrombocytopenia.^{8,43,44,47,57} These effects may be a consequence of JAK2 inhibition as erythropoietin and colony stimulating factor act through this pathway. Elevations in liver transaminases, high- and low-density lipoproteins, creatinine, and creatine phosphokinase may also be observed.^47,50,58 Importantly, many of these effects have been found to be dose-dependent, and all were reversible upon treatment discontinuation.^53,57,58 Also, long-term use does not appear to progressively worsen these abnormalities, and few patients discontinue treatment as a result of them.^47,50,53 Furthermore, a meta-analysis assessing the cardiovascular risks associated with the hyperlipidemia seen in psoriasis patients treated with baricitinib, found that there was no increased risk of major adverse cardiovascular events for these patients.⁵⁸

Discussion

JAK inhibitors appear to be a viable treatment option for a number of dermatologic conditions. With good oral bioavailability and lack of immunogenicity, they address some of the limitations of biologics. For most patients, jakinibs seem to be well-tolerated as discontinuation rates for safety issues are less than 10%.⁵⁹ The vast majority of adverse events are related to infection, but ensuring that patients are up to date on their immunizations can mitigate this risk to some degree. In particular, live-attenuated vaccines should be administered prior to initiation of therapy, as these should generally be avoided while taking JAK inhibitors. Historically, the live-attenuated zoster immunization was particularly important to administer prior to starting JAK inhibitor therapy; however, with the advent of the killed zoster vaccine (Shingrix), this is less of a concern. Moreover, closely monitoring patients for signs of infection and checking their complete blood count, liver transaminases, creatinine, and creatine phosphokinase may help prevent associated complications.⁶⁰

Nevertheless, additional research is needed to assess long-term efficacy and safety. While the increased risk of malignancy and thromboembolism attributable to JAK inhibitors appears to be quite low, large observational studies will likely be required to obtain a more accurate risk assessment.⁵⁴ Although it is not yet fully understood how selective inhibition of the JAK subtypes may affect the safety profile of these medications, it seems plausible that adverse effects may be influenced by the level and type of JAK inhibition. Head-to-head trials of these various 1st and 2nd generation jakinibs at varying dosages and durations of treatment are necessary to elucidate these risk differences, if any. Given the number of jakinibs in development and currently being tested in randomized trials for both dermatologic and non-dermatologic diseases, we remain optimistic regarding the benefit-risk profile of this class of medication.

Conclusion

Although the only dermatologic condition that is currently approved for treatment with a JAK inhibitor is psoriatic arthritis, their potential applications within dermatology are numerous. These drugs appear to be well-tolerated and have a safety profile relatively similar to that of biologics, excepting the increased risk of thromboembolism, and superior to many disease-modifying anti-rheumatic drugs. Moreover, these drugs seem to have a large overlap in their safety profiles despite differences in JAK selectivity. While risk of mild infection and herpes zoster appears to be increased regardless of JAK selectivity, risk of thrombosis and malignancy based on the subtype of JAK inhibition remains to be seen. Furthermore, thromboembolic and oncologic risk may also be dependent on a number of others factors including dosage, duration of treatment, concurrent treatments, disease type and severity, and comorbidities. While these significant safety concerns certainly warrant further investigation, ongoing clinical trials offer promise for the widespread application of these medications within future dermatologic practice.

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Conflict of interest:
Dr. Emer has been a consultant for Regen Lab and Eclipse.

Abstract
Platelet-rich plasma (PRP) is an autologous serum containing high concentrations of platelets and growth factors. PRP continues to evolve as an important treatment modality with many applications in dermatology, particularly in the areas of hair restoration, skin rejuvenation, acne scars, dermal augmentation, and striae distensae. Furthermore, combining PRP with laser therapies, microneedling, dermal fillers, and autologous fat grafting produces synergistic effects, leading to improved aesthetic results. Future studies should standardize PRP treatment protocols for specific indications. PRP holds considerable promise in dermatology with therapeutic applications continuing to expand.

Key Words:
acne scars, aesthetic, androgenic alopecia, autologous fat grafting, cosmetic, dermal fillers, dermatology, facial rejuvenation, fractional laser resurfacing, hair restoration, microneedling, platelet rich plasma, PRP, rhytids

Introduction

Platelet-rich plasma (PRP) is an ever-expanding treatment modality that continues to demonstrate considerable promise in the field of dermatology. PRP has long been used in the medical fields of cardiac surgery, oral surgery, orthopedics, and facial plastic surgery, and it continues to develop as a versatile therapy in dermatology. PRP is an autologous serum containing high concentrations of platelets and growth factors.¹ Alpha granules within the platelets are responsible for promoting stem cell regeneration and soft tissue remodeling.² Many fundamental growth factors are contained within the PRP alpha granules, such as platelet-derived growth factors (aa, bb, ab), vascular endothelial growth factor, epithelial growth factor, transforming growth factor beta, and insulin-like growth factor.³ Mitogenesis and differentiation of monocytes, fibroblasts, stem cells, keratinocytes, and endothelial cells occur as a result of PRP alpha granule growth factors.² These growth factors are also known to induce cell proliferation, angiogenesis, and chemotaxis, as well as contain serotonin, dopamine, histamine, adenosine, and calcium, which increase membrane permeability.^2-4

The use of PRP results in improved cosmetic dermatologic outcomes through angiogenesis, neocollagenesis, and adipogenesis.² Applications for hair restoration and skin rejuvenation remain the most highly-supported indications for PRP in aesthetic dermatology (Table 1). Moreover, the use of PRP when combined with other treatment modalities, such dermal fillers, lasers, and other devices demonstrates significant improvements in skin appearance, texture, and tone. There is also emerging potential for the use of PRP with augmented fat injections to enhance fat survival (Figure 1). Although few clinical trials have been performed on the numerous above-mentioned therapeutic options, physicians note enhanced results with treatments combined with PRP versus solo treatment. PRP shows promising uses in the field of dermatology, and more studies are needed to test its validity alone or in combinations for enhancing outcomes.

Harvesting Platelet-Rich Plasma

There are many commercially available PRP systems and kits, and protocols vary according to brand name and treatment indication (Table 2). Traditionally accepted preparations involve initial venipuncture to obtain 10 to 22 mL of whole blood, which is combined with an anticoagulant agent. Centrifugation then separates the whole blood sample into three layers: red blood cells (RBCs), platelet-poor plasma (PPP), and the of-interest PRP layer. Subsequent centrifugations isolate and harvest the PRP layer, while discarding the RBCs and PPP. The now concentrated PRP pellet may be treated with calcium chloride or thrombin to activate the platelets (many harvesting systems do not require activation), releasing alpha granules and growth factors. For the most common dermatological uses, activation is not required, as a more viscous substance (once activated) is better suited for wound healing, post-surgical healing, and orthopedic uses. Activation of growth factors occurs within 10 minutes, with nearly 100% activation occurring within 1 hour.⁵ Some cosmeceutical brands have started to create “customized” skin care products that allow patients’ PRP to be added to a base formulation to complete a bespoke growth factor anti-aging skin care product. However, it is not yet known for how long the activated growth factors remain viable. It is thought that changes in pH and temperature may affect the viability of PRP within a few hours after collection. Current US Food and Drug Administration (FDA) guidelines also indicate that platelets should not be used beyond 5 days after collection, due to bacterial contamination during venipuncture. Nevertheless, patient demand for such autologous customized skin care products remains high.

Commercially Available PRP Harvesting Systems

Eclipse PRP® (Eclipse)

Magellan® (Isto Biologics)

PurePRP® (EmCyte)

RegenKit® (Regen Lab)

Selphyl® PRFM (UBS Aesthetics)

Table 2: Commercially available platelet-rich plasma harvesting systems commonly used in dermatology.

Platelet-Rich Plasma Subtype Families

Platelet concentrations vary per harvest protocol; a platelet count of 1 million/mL is widely accepted as the necessary PRP platelet concentration for therapeutic efficacy.⁶ Moreover, PRP contains plasma at concentrations 2 to 8 times greater than unaltered whole blood.² PRP preparations have been classified into four subtypes: pure platelet-rich plasma (P-PRP), leukocyte platelet-rich plasma (L-PRP), pure platelet-rich fibrin matrix (P-PRFM), and Leukocyte and platelet-rich fibrin matrix (L-PRFM). Aesthetic dermatology indications predominantly use the pure PRP preparation with minimal leukocyte collection.³ The P-PRFM preparation has a lower platelet concentration and includes fibrin. The fibrin matrix created in P-PRFM binds and traps growth factors, releasing them more slowly over several days. This preparation may be used for fat grafting procedures, as it allows for sustained, prolonged release of growth factors within the grafted tissues.⁷

Hair Restoration

PRP has demonstrated significant improvements in hair growth when treating androgenic alopecia (AGA) (Figure 2). PRP growth factors promote hair regrowth by stimulating stem cell differentiation of hair follicles, inducing and prolonging the proliferative anagen phase of hair follicles, as well as activating anti-apoptotic pathways and promoting angiogenesis to increase perifollicular vascularization and the survival of dermal papilla fibroblasts.^2,8-10

A wide array of studies indicates that PRP is a promising treatment for thinning hair.² Both male and female pattern hair loss, as well as alopecia areata, can be improved with PRP. Injections of PRP may be combined with progesterone, dalteparin microparticles, or CD34+ cells. PRP administered with progesterone naturally inhibits 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). DHT damages hair follicles and is culpable in genetic hair loss. Progesterone inhibits 5-alpha reductase and thus DHT, which allows hair growth to recover. PRP with dalteparin induced significant increases in hair diameter and proliferation of collagen fibers and fibroblasts, along with thickened epithelium and hair follicles due to increased angiogenesis.¹¹ Using CD34+ cells with PRP showed significant improvement in hair thickness and overall presentation.¹²

While some studies reveal minimal improvement in hair restoration, it is hypothesized that inadequate treatment protocols have been used. Studies using an insufficient number of treatments lacked substantial improvements.² Multiple continued treatments with PRP is necessary for significant aesthetic improvement of increased hair density. It is thought that three injections per year is the minimum frequency in order to observe any clinically beneficial result. In clinical practice, most physicians commence with a series of monthly injections until improvement is seen, then continuing with maintenance therapies every 2 to 3 months indefinitely. More research is needed nevertheless to determine proper frequency, dosing, and maintenance. Furthermore, combining PRP injections with other hair restoration treatments, such as finasteride (male patients), minoxidil, low-level light therapy, and spironolactone (female patients), may enhance the overall efficacy. PRP injections may also improve the outcome of hair transplantation and may soon be part of the pre-treatment and post-treatment maintenance protocols. In clinical practice, the author (JE) has found substantial improvement with the use of ACell® (naturally-occurring urinary bladder matrix epithelial basement membrane; MicroMatrix®) and/or human exosomes (placental mesenchymal stem cell and amniotic fluid derived; Kimera Labs, Inc.) combined with PRP in patients with less than substantial improvement with PRP injections alone. Combined with hair transplantation, injectable regenerative therapies have shown improved outcomes in the author’s experience.

Skin Rejuvenation

Several reports demonstrate improvements in traumatic scars and acne scars with PRP treatment. Increases in collagen density and dermal elastic fibers are notable benefits when using PRP in aesthetic dermatology. When PRP is used in combination with other therapies, such as laser treatments, microneedling, and hyaluronic acid fillers, further improvements in skin appearance are achieved (Figure 3). Autologous fat grafting combined with PRP to enhance long-term fat survival has preliminarily shown positive results. Furthermore, cosmetic improvements in striae distensae have been noted when combining radiofrequency, laser, and ultrasound therapies with PRP.

Acne Scars & Traumatic Scars

Multiple studies indicate significant improvement in appearance of acne scars, as well as traumatic scars, when using PRP^13,14 (Figure 4). Cutaneous injuries may result in scar tissue, presenting aesthetic and functional issues. Optical coherence tomography revealed improved acne scar depth when PRP was used with fractional laser therapy, compared to laser alone.³

A decrease in erythema and edema is observed when treating acne scars with PRP. Improved skin elasticity and increased collagen and fibroblasts are also noted when treating scars.¹⁵

Combination Therapies: Lasers & Microneedling

The use of PRP in conjunction with laser therapies and microneedling is increasingly popular in aesthetic dermatology. Fractional laser resurfacing and microneedling treatments create small holes in the skin, which act to enhance uptake and delivery of PRP.² Combining PRP with laser therapies and microneedling procedures improves wound healing and shortens recovery times, as well as reduces erythema and melanin index of treated areas.^14,16,20 Transepidermal water loss (TEWL) and inflammatory hyperpigmentation are also found to be significantly lower when combining PRP with device treatments. Patients treated with PRP after CO₂ or erbium fractional resurfacing have improved skin elasticity, increased fibroblasts, and notably thicker collagen bundles when compared to laser treated sites without added PRP.²⁰ Furthermore, there is anecdotal evidence of improved healing times with PRP combined with laser therapy, as well as earlier granulation, decreased erythema, and improved outcomes.

Dermal Augmentation

Combining PRP with hyaluronic acid-based fillers has been popular and widespread in cosmetic dermatology for several years. The “Vampire Facelift” was coined after combining PRP and dermal fillers; this technique has become well-known via social media. The numerous growth factors in PRP are thought to rejuvenate the skin, improving texture and smoothness, while also decreasing rhytids.^22,23 Hyaluronic acid fillers or other dermal augmentation agents serve as a scaffold to which PRP can bind and enhance skin rejuvenation, as well as enhance soft tissue augmentation² (Figure 5). Lasting cosmetic improvements are seen when treating nasolabial folds, horizontal neck bands, skin homogeneity and tonicity, and facial rhytids with dermal fillers combined with PRP. Studies have also indicated significant improvements in rhytids and skin tone in the infraorbital region.²⁴

Augmented Fat Injections

Combining PRP with autologous fat grafting is thought to bolster survival of the injected fat. Autologous fat injections have gained popularity for facial rejuvenation and dermal augmentation, as the fat grafts are deemed safe and free from potentially transmissible blood-borne pathogens due to the autologous origin of the fat. Pure PRP preparations with a fibrin matrix (P-PRFM) binds and traps growth factors contained within PRP, releasing them more slowly, ensuring prolonged survival of injected fat.⁷ Reports have indicated considerable potential for the use of PRP with augmented fat injections, while some investigations indicate no significant improvement was observed. Patients with HIV-associated facial fat atrophy treated with PRP fat grafting did not experience a significant difference in cosmetic appearance when compared to fat injections alone.¹⁷ However, results from other studies indicate PRP enhances volume retention of injected fat, maintains volume overtime, and reduces revision rates.^7,18,19 In the author’s opinion (JE) there is a substantial improvement in fat viability and retention with the use of PRP in a high enough ratio of PRP to fat; although that “ratio” is not defined based on the current studies in the literature and in practice at least 4-8:1 (fat to PRP) is utilized for a noticeably improved long-term outcome.

Striae Distensae

Continuous stretching of the skin often leads to atrophic dermal scars, known as striae distensae. Reports indicate beneficial cosmetic outcomes when combining intradermal radiofrequency and ultrasound devices with PRP.^21,25 Ultrasound therapies often follow radiofrequency treatments, as ultrasound assists in transepidermal penetration of PRP. Abdominal biopsies posttreatment have indicated increases in collagen density and elastic fibers, and the majority of patients report good or very good improvements in cosmetic appearance of their striae distensae.²¹

Conclusion

PRP continues to evolve as a consequential therapeutic tool in dermatology. Numerous growth factors contained within PRP promote neocollagenesis, angiogenesis, and overall proliferation of stem cells and soft tissue remodeling. PRP is easily harvested from patients’ own whole blood using numerous commercially available systems, making it a safe, in-office procedure. Top evidence-based dermatologic indications for PRP include hair restoration and skin rejuvenation, as well as improvements in acne scars. Moreover, combining PRP with other treatment modalities, such as laser therapies, microneedling, dermal fillers, and autologous fat injections has demonstrated synergistic effects, enhancing overall cosmetic outcomes. The dermatologic community stresses that more studies are needed to further standardize and define PRP protocols beyond anecdotal experience for specific indications.

Acknowledgement

The author gratefully acknowledges the editorial support from Bradford Ferrick in preparing this manuscript.

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Alan Lyell Centre for Dermatology, Glasgow, UK

Conflict of interest: None reported.

ABSTRACT
Frontal fibrosing alopecia, described just over 20 years ago, has become one of the most frequently seen causes of scarring alopecia at many specialist hair clinics. Considered a clinical variant of lichen planopilaris (LPP), it has distinctive features and associations which distinguish it from LPP. Although largely affecting postmenopausal women, a small but increasing number of men and premenopausal women are affected. The spectrum of the disease has expanded from involvement of the frontal hairline and eyebrows, to potentially affecting the entire hairline, facial and body hair. Genetic and environmental factors have been implicated but the aetiology remains uncertain. A range of treatments have been used in management of the condition, but clinical trials are required to establish effectiveness.

Key Words:
cicatricial alopecia, frontal fibrosing alopecia, hair loss, lichen planopilaris, scarring alopecia

Introduction

Frontal fibrosing alopecia (FFA) was first described in 1994 by Kossard as a new type of scarring alopecia.¹ Clinically, the follicular features appeared identical to lichen planopilaris (LPP) however, the pattern of the disease was distinct from typical LPP in several ways.² Firstly, those affected were exclusively postmenopausal women. Secondly, the condition resulted in a distinctive pattern of alopecia affecting the frontal hairline, associated with loss of eyebrows. Histologically, the findings were indistinguishable from LPP, with reduction in hair follicle numbers, perifollicular fibrosis, perifollicular lymphoid infiltrate and follicular interface dermatitis.² Since this first description, FFA has been the subject of more than 80 papers. The clinical spectrum of the disease has also expanded. As well as eyebrows, eyelashes may be lost^2,3 and involvement of facial vellus hairs can sometimes result in small flesh coloured facial papules^4-6. Limb and flexural hair are also frequently affected, usually with no associated symptoms or rash.^7,8 The condition no longer exclusively affects postmenopausal women as a small but increasing number of cases have been reported in premenopausal women and in men.⁹ There may be differing ethnic susceptibility: FFA is most frequently recorded in Caucasian women, being reported less frequently in black women^10,11 and rarely in Asians^12,13. However, it has been suggested that in black patients, FFA is under-recognized as it frequently co-presents with traction alopecia.^10,11

The clinical and histological similarities between FFA and LPP suggest that FFA is a clinical variant of LPP.² Like LPP,¹⁴ an increased association between FFA and autoimmune disease, particularly thyroid, has been noted^3,15. However, there are several areas in which FFA appears to differ from classical LPP. Firstly, FFA affects predominantly women: in two large cases series, male to female (M:F) ratio ranged from 1:289 to 1:31, whereas in LPP, M:F has been estimated at between 1:1.8 to 1:4.9.¹⁶ Lichen planus affecting other sites (cutaneous, nail, mucosal) is seen more frequently in association with LPP (28-50%)^17,18 than with FFA (1.6-9.9%)^3,9,15. Loss of facial and body hair concomitant with LPP is reported in 7-10%.^16,18 In FFA, loss of eyebrows has been reported in around 80% of cases^2,4,9,15 and may occasionally precede loss of hairline^3,15. Loss of eyelashes is uncommon^2,3,9 and has been associated with more severe disease⁹. Loss of body hair also occurs, affecting both limb and flexural hair. Loss of hair from limbs has been documented in around 20-25% of patients in large case series^3,9,15 but affected 77% of patients in a smaller case series and was confirmed histologically. Unlike typical LPP, loss of hair from eyebrows and body in FFA is clinically largely non-inflammatory.⁷ Classical diffuse LPP elsewhere on the scalp has been reported in association with FFA in <1-16%.^2,3,9,15 While scalp LPP is primarily a disorder of terminal pigmented hairs, it has been suggested that in FFA, vellus and intermediate hairs are affected preferentially,^8,19 although this has not been confirmed in another study⁷. Paradoxically, most terminal pigmented hairs on the scalp are unaffected in FFA, with only those at the hairline involved. Symptoms may also be less frequent in FFA^3,9,19 (3-55%) than in LPP (60-70%)¹⁸ but this has not been confirmed in all case series^15,20.

Currently, there are no epidemiological data on the incidence or prevalence of FFA in the general population. However, most papers published over recent years suggest that the incidence of FFA may be increasing.^3,4,9,15,21 Figures from my own hair clinic in Glasgow, UK demonstrate that the numbers of new cases of FFA have increased significantly over the last 16 years, both in terms of absolute number and as a percentage of the total number of new cases seen annually (Table 1).

It should be borne in mind that there are potential sources of bias inherent in this type of data: for instance, when a new condition is described, it is likely that the number of recorded cases will increase as awareness of the condition increases amongst medical practitioners. However, as FFA progresses slowly and may be asymptomatic, the identified cases may represent only the “tip of the iceberg”. Certainly, in a proportion of cases, hair loss is unrecognized by patients and the diagnosis is made when patients attend with another dermatological condition.^3,22 Given these observations, there is considerable interest in the aetiology(ies) of FFA and how this might explain why we are apparently seeing increasing numbers of cases.

Since the first case reports of FFA affecting siblings,^23-25 there have been an increasing number of reports of familial cases,^26,27 suggesting a possible genetic predisposition and studies are underway to try to identify genes which may be associated with FFA. However, genetic susceptibility alone would not explain the apparent increase in FFA incidence. It has been proposed that clusters of affected cases within families may indicate not only genetic susceptibility but possible environmental triggers.²⁶ Karnik et al²⁸ published experimental evidence which demonstrated a possible role for peroxisome proliferatoractivated receptor-gamma (PPAR-gamma) in pathogenesis of LPP. They established that PPAR-gamma, a transcription factor that belongs to the nuclear receptor super-gene family, is required for maintenance of follicular stem cells and demonstrated that mice with PPAR-gamma deleted from follicular stem cells developed a scarring alopecia. In scalp biopsies from patients with LPP, it was found that PPAR-gamma was down-regulated in hair follicles. The authors postulated a possible role for xenobiotic metabolism as an environmental trigger for LPP, through the aryl hydrocarbon receptor (AhR). Environmental toxins such as dioxin-like substances, activate AhR which is known to suppress PPAR-gamma.²⁸ The role of PPAR-gamma and AhR in FFA remain to be elucidated.²⁶

The possible role of environmental factors in FFA is supported by other observations. In our cohort of FFA patients, we observed a statistically significant association (p < 0.001) between FFA and affluence, as measured by the Carstairs Index, when compared with age and gender matched patients attending the hair clinic with other causes of alopecia, and with age and gender matched women in the general population. This finding was supported by the observation that the same cohort were significantly less likely to be smokers (p = 0.01), compared with the general population.³ A review of 355 Spanish patients⁹ showed 87% were non-smokers however, this was not significantly different from the general population. While it seems unlikely that affluence per se is relevant in the pathogenesis of FFA, this may be a surrogate marker for an as yet unidentified risk factor associated with affluence. Interestingly, in a cohort of US patients with FFA, affected women were significantly more likely to have attained the highest educational level (US cooperative FFA study group, Elise Olsen chairman, unpublished data).

The development of FFA/LPP following hair transplant or cosmetic surgery²⁹ further supports the role of environmental triggers in the pathogenesis of FFA/LPP. One possible explanation that has been proposed to explain this finding suggests that the immunosuppressive milieu which normally surrounds hair follicles (“immune privilege”) is disturbed by inflammatory mediators stimulated as a result of cutaneous surgery, leading to loss of follicle immune privilege and increasing hair follicle susceptibility to inflammatory attack.²⁹ Further studies examining the role of environmental agents in FFA are currently being undertaken.

As FFA was first described exclusively affecting postmenopausal women, it has been postulated that FFA may be due to hormonal changes at the time of the menopause.^9,19 However, no hormonal abnormalities have been identified in FFA patients^2,19 and hormonal changes alone would not explain the apparent increasing incidence of the condition, nor the cases of FFA arising in premenopausal women and in men. The observation of FFA affecting transplanted occipital hairs in a man with FFA concomitant with androgenetic alopecia,³⁰ suggests that hair follicle androgen susceptibility may not be required for pathogenesis of FFA. However, the possible role of hormones in the pathogenesis of FFA has been supported by the observations that 5-alpha-reductase inhibitors (5ARIs) can stabilize^9,19,21 and improve FFA9,^31,32. Hair regrowth in a scarring alopecia in which destruction of hair follicles is a cardinal histopathological feature^2,7 is a puzzling phenomenon. However, personal experience and documented cases have demonstrated improvement in eyebrow growth in some FFA patients treated with topical calcineurin inhibitors.³³ Similarly, regrowth of hair in apparently scarred areas of scalp in chronic discoid lupus erythematosus (CDLE) and other scarring alopecias is occasionally observed.^34,35 There have been several sporadic case reports of improvement in FFA with 5ARIs, which have included photographic images.^31,32 The largest published review of FFA cases suggested that of 111 patients treated with 5ARIs, 47% stabilized and 53% improved.⁹ Further clarification of these results however, indicated that clinical improvement at the hairline was minimal and response to antiandrogens was more frequent if concomitant androgenetic alopecia was present, although not exclusively so.³⁶ Where stabilization of FFA with treatment is reported, it is important to be aware that spontaneous stabilization of FFA can occur.⁴ Given the often slow progress of FFA, prolonged periods of observation would be required to confirm true stabilization. Clearly, randomized controlled trials, using objective measurements of disease, are required to assess the role of treatments for FFA.

Conclusion

In summary, the incidence of FFA, first described only 20 years ago, appears to be increasing. Clinically and histologically, it appears to be a variant of LPP. The identification of familial cases suggests a genetic susceptibility but also raises the possibility of environmental triggers. Randomized controlled trials are required to confirm the effect of treatments and epidemiological studies should be considered to confirm the incidence and prevalence of FFA within the population.

References

1. Kossard S. Postmenopausal frontal fibrosing alopecia. Scarring alopecia in a pattern distribution. Arch Dermatol. 1994 Jun;130(6):770-4.
2. Kossard S, Lee MS, Wilkinson B. Postmenopausal frontal fibrosing alopecia: a frontal variant of lichen planopilaris. J Am Acad Dermatol. 1997 Jan;36(1):59-66.
3. MacDonald A, Clark C, Holmes S. Frontal fibrosing alopecia: a review of 60 cases. J Am Acad Dermatol. 2012 Nov;67(5):955-61.
4. Tan KT, Messenger AG. Frontal fibrosing alopecia: clinical presentations and prognosis. Br J Dermatol. 2009 Jan;160(1):75-9.
5. Abbas O, Chedraoui A, Ghosn S. Frontal fibrosing alopecia presenting with components of Piccardi-Lassueur-Graham-Little syndrome. J Am Acad Dermatol. 2007 Aug;57(Suppl 2):S15-8.
6. Donati A, Molina L, Doche I, et al. Facial papules in frontal fibrosing alopecia: evidence of vellus follicle involvement. Arch Dermatol. 2011 Dec;147(12):1424-7.
7. Chew AL, Bashir SJ, Wain EM, et al. Expanding the spectrum of frontal fibrosing alopecia: a unifying concept. J Am Acad Dermatol. 2010 Oct;63(4):653-60.
8. Miteva M, Camacho I, Romanelli P, et al. Acute hair loss on the limbs in frontal fibrosing alopecia: a clinicopathological study of two cases. Br J Dermatol. 2010 Aug;163(2):426-8.
9. Vano-Galvan S, Molina-Ruiz AM, Serrano-Falcon C, et al. Frontal fibrosing alopecia: a multicenter review of 355 patients. J Am Acad Dermatol. 2014 Apr;70(4):670-8.
10. Miteva M, Whiting D, Harries M, et al. Frontal fibrosing alopecia in black patients. Br J Dermatol. 2012 Jul;167(1):208-10.
11. Dlova NC, Jordaan HF, Skenjane A, et al. Frontal fibrosing alopecia: a clinical review of 20 black patients from South Africa. Br J Dermatol. 2013 Oct;169(4):939-41.
12. Sato M, Saga K, Takahashi H. Postmenopausal frontal fibrosing alopecia in a Japanese woman with Sjogren’s syndrome. J Dermatol. 2008 Nov;35(11):729-31.
13. Inui S, Nakajima T, Shono F, et al. Dermoscopic findings in frontal fibrosing alopecia: report of four cases. Int J Dermatol. 2008 Aug;47(8):796-9.
14. Atanaskova Mesinkovska N, Brankov N, Piliang M, et al. Association of lichen planopilaris with thyroid disease: a retrospective case-control study. J Am Acad Dermatol. 2014 May;70(5):889-92.
15. Banka N, Mubki T, Bunagan MJ, et al. Frontal fibrosing alopecia: a retrospective clinical review of 62 patients with treatment outcome and long-term follow-up. Int J Dermatol. 2014 Nov;53(11):1324-30.
16. Meinhard J, Stroux A, Lunnemann L, et al. Lichen planopilaris: Epidemiology and prevalence of subtypes – a retrospective analysis in 104 patients. J Dtsch Dermatol Ges. 2014 Mar;12(3):229-35, -36.
17. Mehregan DA, Van Hale HM, Muller SA. Lichen planopilaris: clinical and pathologic study of forty-five patients. J Am Acad Dermatol. 1992 Dec;27(6 Pt 1):935-42.
18. Cevasco NC, Bergfeld WF, Remzi BK, et al. A case-series of 29 patients with lichen planopilaris: the Cleveland Clinic Foundation experience on evaluation, diagnosis, and treatment. J Am Acad Dermatol. 2007 Jul;57(1):47-53.
19. Tosti A, Piraccini BM, Iorizzo M, et al. Frontal fibrosing alopecia in postmenopausal women. J Am Acad Dermatol. 2005 Jan;52(1):55-60.
20. Samrao A, Chew AL, Price V. Frontal fibrosing alopecia: a clinical review of 36 patients. Br J Dermatol. 2010 Dec;163(6):1296-300.
21. Ladizinski B, Bazakas A, Selim MA, et al. Frontal fibrosing alopecia: a retrospective review of 19 patients seen at Duke University. J Am Acad Dermatol. 2013 May;68(5):749-55.
22. Poblet E, Jimenez F, Pascual A, et al. Frontal fibrosing alopecia versus lichen planopilaris: a clinicopathological study. Int J Dermatol. 2006 Apr;45(4):375-80.
23. Roche M, Walsh MY, Armstrong DKB. Frontal fibrosing alopecia – occurrence in male and female siblings. J Am Acad Dermatol. 2008 Feb;58(Suppl 2):AB81.
24. Junqueira Ribeiro Pereira AF, Vincenzi C, et al. Frontal fibrosing alopecia in two sisters. Br J Dermatol. 2010 May;162(5):1154-5.
25. Miteva M, Aber C, Torres F, et al. Frontal fibrosing alopecia occurring on scalp vitiligo: report of four cases. Br J Dermatol. 2011 Aug;165(2):445-7.
26. Dlova N, Goh CL, Tosti A. Familial frontal fibrosing alopecia. Br J Dermatol. 2013 Jan;168(1):220-2.
27. Tziotzios C, Fenton DA, Stefanato CM, et al. Familial frontal fibrosing alopecia. J Am Acad Dermatol. 2015 Jul;73(1):e37.
28. Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific PPARgamma deletion causes scarring alopecia. J Invest Dermatol. 2009 May;129(5):1243-57.
29. Chiang YZ, Tosti A, Chaudhry IH, et al. Lichen planopilaris following hair transplantation and face-lift surgery. Br J Dermatol. 2012 Mar;166(3):666-370.
30. Kossard S, Shiell RC. Frontal fibrosing alopecia developing after hair transplantation for androgenetic alopecia. Int J Dermatol. 2005 Apr;44(4):321-3.
31. Georgala S, Katoulis AC, Befon A, et al. Treatment of postmenopausal frontal fibrosing alopecia with oral dutasteride. J Am Acad Dermatol. 2009 Jul;61(1):157-8.
32. Donovan JC. Finasteride-mediated hair regrowth and reversal of atrophy in a patient with frontal fibrosing alopecia. JAAD Case Rep. 2015 Nov;1(6):353-5.
33. Katoulis A, Georgala S, Bozi E, et al. Frontal fibrosing alopecia: treatment with oral dutasteride and topical pimecrolimus. J Eur Acad Dermatol Venereol. 2009 May;23(5):580-2.
34. Hamilton T, Otberg N, Wu WY, et al. Successful hair re-growth with multimodal treatment of early cicatricial alopecia in discoid lupus erythematosus. Acta Derm Venereol. 2009 89(4):417-8.
35. Bianchi L, Paro Vidolin A, Piemonte P, et al. Graham Little-Piccardi-Lassueur syndrome: effective treatment with cyclosporin A. Clin Exp Dermatol. 2001 Sep;26(6):518-20.
36. Vano-Galvan S, Arias-Santiago S, Camacho F. Reply to ‘frontal fibrosing alopecia’. J Am Acad Dermatol. 2014 Sep;71(3):594-5.

¹School of Medicine, McMaster University, Hamilton, ON, Canada
²Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: None reported.

ABSTRACT
Up to a third of dermatology outpatients have a significant psychiatric issue complicating their skin complaint. Although the ideal would frequently involve psychiatric assessment, those with comorbid mental illness often refuse psychiatric referral. As a result, it is imperative that dermatologists be mindful of psychiatric comorbidity in their patients and comfortable with the fundamentals of psychodermatologic diagnosis and therapy. This update summarizes current concepts, relevance, and therapeutics in psychodermatology, including aspects pertinent to depression, anxiety, obsessive-compulsive, impulse-control, and delusional disorders as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5, published in 2013 by the American Psychiatric Association).

Key Words: anxiety, delusional disorder, depression, dermatology, DSM-5, excoriation disorder, obsessive-compulsive disorder, parasitosis,
psychiatry, psychodermatology, trichotillomania

Introduction

Mind and skin are intimately related. Up to a third of dermatology outpatients have a significant psychiatric issue complicating their skin complaint.¹ The dermatologist’s work is far from skin deep; often the most meaningful aspects of management involve success in resolving the psychosocial impact of cutaneous disease. Although the ideal management would frequently involve psychiatric assessment, those with comorbid mental illness often refuse psychiatric referral. As a result, it is imperative that dermatologists be mindful of psychiatric comorbidity in their patients and comfortable with the fundamentals of psychodermatologic diagnosis and therapy.

Categories of Psychodermatology

Psychodermatology covers a broad spectrum of diseases. The four main categories include psychophysiological disorders, primary psychiatric disorders, secondary psychiatric disorders, and cutaneous sensory disorders.²

Psychophysiologic disorders are primary skin diseases modified by psychosomatic factors. These include psoriasis, atopic dermatitis, acne, and hyperhidrosis, all skin conditions that are known to worsen with stress or emotional triggers.³

Primary psychiatric diseases include those that are psychotic, delusional, or obsessive in nature. Examples include delusions of parasitosis, neurotic excoriations, trichotillomania, and factitious disorder. No primary skin lesions will exist in most cases, as skin changes within this category will commonly be self-induced. These patients often lack insight into their condition, and as a result they require tactful clinical care. Note that factitious disorder, which in dermatology involves self-induced or alleged skin pathology without external incentive, is sometimes described as dermatitis artefacta or factitious dermatitis. These terms misleadingly suggest underlying inflammation.

Secondary psychiatric disorders, on the other hand, are psychiatric disturbances caused by skin disease. Depression, anxiety, and social phobias from acne, psoriasis, or alopecia areata are some examples. The morbidity from these diseases is predominantly a consequence of their effect on mental state. As a result, their psychiatric sequelae are often responsive to successful dermatologic therapy.

Cutaneous sensory disorders, like those in the primary psychiatric category, will involve no primary skin changes. Patients may complain of itching, burning, pain, or stinging. Cutaneous sensory disorders may involve a neuropathic etiology.

Major Diagnoses

Several high-yield diagnoses exist within the intersection of dermatology and psychiatry. These include psychotic and delusional disorders, obsessive and impulse-control disorders, depressive disorders, anxiety disorders, and cutaneous sensory disorders. Unfortunately, randomized controlled trials for the specific management of psychocutaneous diseases are sporadic and low-powered when present. Where they are relevant and robust, we will therefore emphasize Canadian guidelines, especially those from the Canadian Network for Mood and Anxiety Treatments (CANMAT) series.^4-6

As the following diagnoses can be found within any of the previously described categories, the clinical diagnosis and category remain separate judgments. Treatment should be aimed at the underlying psychopathology, regardless of whether it is primary, secondary, or merely exacerbating skin disease. Neurotic excoriations secondary to depression, psoriasis worsened by depression, and depression secondary to alopecia areata, for example, all warrant a similar therapeutic approach.

Depressive Disorders

Depression is common in our patient population. One review suggests about 30% of patients in the general dermatology practice will have some form of depression. This prevalence compares to 22% in general practice.⁷ A cross-sectional study identified 10% of 384 dermatology patients with major depression.⁸ For many skin conditions, the prevalence may be even higher. In an extensive 2014 systematic review, Dowlatshahi et al. found 19% of psoriasis patients studied met the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria for major depression.⁹ More recently, a 2015 4994-patient European cross-sectional multicenter study of dermatology outpatients reported a 12.7% rate of suicidal ideation (compared to 8.3% in the hospital employees used as controls). Psoriasis had a 17.3% association with suicidal ideation, and two-thirds of these patients responded that their ideation was a direct consequence of their skin condition.¹ Atopic dermatitis, alopecia, urticaria, pruritus, and vitiligo also correspond to lower mood.¹⁰ Degree of itch plays a role, and conversely depression may work to lessen the threshold for pruritus.¹¹ There are concerns that systemic use of corticosteroids or isotretinoin may increase the risk for depression and suicide.^12,13 Surprisingly, disease impact does not seem to correlate well with severity, and physicians tend to underestimate the psychological implications of cutaneous disorders.¹⁴

The CANMAT guidelines for unipolar depression direct firstline therapeutics for major depressive disorder towards any of the second-generation anti-depressants. These include selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) such as escitalopram, sertraline, and venlafaxine. Due to tolerability and safety, tricyclic antidepressants (TCAs) are second-line. In depression, combined treatment with both medication and psychotherapy is superior to either alone.⁴

Anxiety Disorders

Anxiety disorders are associated with typical physical symptoms and excessive worry over finances, relationships, career, and health. They frequently accompany depression, especially in psoriasis, acne, and atopic dermatitis. Although Dalgard et al. found clinical depression present in 10% of 3635 dermatology outpatients, clinical anxiety was present in 17%.¹ Both acute and chronic anxiety can contribute to skin disease,¹⁵ this link being especially well-documented in the inflammatory dermatoses.

In cases of acute anxiety, benzodiazepine anxiolytics are first-line due to their rapid onset of action. For the chronic management of generalized anxiety disorder, nonetheless, the CANMAT guidelines suggest first-line therapy by means of SSRIs/SNRIs such as sertraline, paroxetine, escitalopram, duloxetine, and venlafaxine, or by means of other agents such as agomelatine and pregabalin.⁵ Although second-line agents include other medications such as buspirone and hydroxyzine, the SSRIs and SNRIs are especially useful when anxiety coexists with depression.

Obsessive-Compulsive (OCD) and Impulse-Control
Disorders

A delineating interview question in the 2015 European Society for Dermatology and Psychiatry (ESDaP) position paper on selfinflicted lesions is the following: “How did these lesions occur?” If self-damage is not denied or kept secret by the patient, this points to an obsessive or compulsive etiology.¹⁶ In the ESDaP classification, insight is the dividing line between this group and the delusional etiologies of self-inflicted skin lesions. Indeed, patients with obsessive or impulsive disorders will often realize the irrational and inappropriate nature of their intrusive thoughts and persistent behaviors. The DSM-5, in contrast, allows for specifiers within the obsessive compulsive and related disorders – these include “good or fair insight,” “poor insight,” and “absent insight/delusional.”

Impulsive behaviors are usually isolated acts of aggression towards one’s self or others. The dermatologically-significant clinical presentations of the impulsive spectrum include cutting, burning, hitting, and scarring. Compulsive behaviors, on the other hand, are repetitive, often ritualistic, and time-consuming or problematic in work, school, or relationships. They are often associated with an obsessive ideation, as in OCD. The compulsive spectrum disorders present with a more chronic dermatologic picture. Persistent ideas, thoughts, or impulses lead to repetitive behaviors such as skin-picking, hair-pulling, or excessive washing.

New in the DSM-5 are excoriation (skin-picking) disorder and trichotillomania (hair-pulling). Both are examples of compulsive behaviors. Excoriation disorder involves recurrent skin picking resulting in skin lesions, despite repeated attempts to discontinue the behavior. Excoriation disorder is commonly secondary to acne, traditionally called acne excoriée. Trichotillomania, on the other hand, involves recurrent hair pulling resulting in hair loss, again despite repeated attempts to discontinue. A variety of rituals may accompany trichotillomania, including cutting or shaving, scalp-rubbing, hair-biting, or hair-eating.

In either, Gupta and Gupta also describe the potential for dissociative features, especially when skin picking or hair pulling occurs without preceding tension or full awareness.¹⁷ These patients will deviate from the typical OCD presentation, and present with mindless, automatic picking or pulling without full awareness of the act. Dissociative features are significant as their presence indicates that treatment must go beyond the standard habit-reversal and SSRI therapy. Rather, patients with dissociative features often have a repressive or post-traumatic stress disorder component of their illness. They require stabilization, assessment of suicide risk, and direct referral to psychiatry.

Important to note is the DSM-5 “Obsessive-Compulsive and Related Disorder Due to Another Medical Condition” and specifier “with skin-picking symptoms.” Many dermatologic conditions, especially psoriasis, atopic dermatitis, and prurigo nodularis, can lead to a skin-picking disorder. Picking, in these cases, is often secondary to itch.

Nail biting (onychophagia), nail tearing (onychotillomania), and lip chewing are examples of the DSM-5 “Body-Focused Repetitive Behavior Disorder” within the obsessive and impulse-control disorders. Self-inflicted cheilitis can also occur from repetitive lip licking.

Body dysmorphic disorder (BDD) is also categorized as an obsessive disorder in the context of the DSM-5. It involves a preoccupation with a perceived physical flaw, and by repetitive behaviors surrounding this flaw. These actions can include excessive grooming, mirror-checking, or self-other comparison. In the DSM-5, BDD is no longer coded as a delusional disorder. As in the other obsessive-compulsive and related disorders, patients can have good insight, poor insight, or absent insight accompanied by delusional beliefs. The prevalence is significant, as BDD encompasses 9-15% of dermatology patients, in comparison to only 2.4% of US adults. Patients with BDD have a high proportion of suicidal ideation, and a quarter attempt suicide in their lifetime.¹⁸

CANMAT-recommended first-line pharmacotherapy for OCD and related disorders involves the SSRIs escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Although commonly used for OCD, the TCA clomipramine is secondline due to poorer tolerability compared to the SSRIs. Cognitive behavioral therapy (CBT), especially exposure and response prevention, is also an effective cornerstone of treatment.¹⁹ For OCD and related disorders, combined treatment with both medication and psychotherapy is superior to monotherapy by medication. Combined therapy has not been shown to be superior to CBT alone. Although the CANMAT guidelines describe N-acetylcysteine as a third-line adjunctive therapy, there is promising case report evidence supporting further trials into this glutamatergic agent in the treatment of skin-picking, trichotillomania, and onychophagia.²⁰

Psychotic and Delusional Disorders

In dermatology, the psychotic and delusional disorders most commonly involve what has been historically called monosymptomatic hypochondriacal psychosis. Patients will have an “encapsulated” fixed, false belief and will usually lack any other major psychological disturbance. In contrast to obsessive or compulsive patients, these individuals will lack insight into their condition from the onset of their illness.

The most common psychotic disorder in dermatology involves delusions of parasitosis.²¹ Here, patients present with the fixed, false belief that their body is infested with a parasite despite the absence of any objective evidence to suggest infestation. They may pick, scrub, or otherwise self-injure, all in an attempt to rid themselves of this parasite. In the DSM-5, delusional parasitosis falls under the category of delusional disorder, somatic type. The DSM-5 no longer separates delusional disorder from shared delusional disorder, traditionally called folie à deux.

Other psychotic disorders in dermatology include delusions of bromosis, in which patients believe that their body emits a strong foul odor, and delusions of dysmorphosis, considered an extreme end of the BDD spectrum in the DSM-IV. Although the DSM-5 categorizes BDD as predominantly obsessive rather than delusional, in clinical reality the distinction between obsession without insight and true delusion is frequently unclear.

Standard treatment for the psychotic and delusional disorders involves antipsychotics such as pimozide, risperidone, and olanzapine.²² For delusional disorders, outcomes do not seem to vary between first and second-generation antipsychotics.²³ The challenge, nonetheless, lies in building adequate rapport for the patient to willingly embrace treatment. Often these patients will have had visited many providers, frequently having their concerns dismissed. Empathy is the key, as confrontation can be a barrier to treatment. It is equally important, nonetheless, to avoid confirming the patient’s delusion. Expanding on the above, Patel and Koo suggest verbatim how dermatologists may approach the clinical encounter with a patient suffering from delusions of parasitosis in an elegant 2015 paper.²⁴

Cutaneous Sensory Disorders

In the cutaneous sensory disorders, patients may describe itching, burning, or pain. The causes are sometimes neurologic, as in brachioradial pruritus or postherpetic neuralgia. Formication, on the other hand, describes the sensation of bugs crawling on or under the skin, and can be caused by cocaine or amphetamine abuse (called the
“cocaine bugs”). Although prolonged formication may sometimes precede delusional parasitosis, formication in itself is a cutaneous sensory rather than a delusive state.

Nonpharmacologic Therapies

Psychopharmacology is only one aspect of the ideal approach to psychodermatology. Cognitive behavioral therapy, for example, has shown excellent efficacy in specific disease states such as depression and OCD.²⁵ Combined pharmacotherapy and psychotherapy is often superior to either alone, as the CANMAT guidelines suggest in acute major depressive disorder. Even though the combination is not yet evidence-based for many other psychopathologies, most psychiatrists will offer a combination of psychotherapy and medication. Other nonpharmacologic modalities are not disease specific, but nonetheless offer global stress reduction, direct psychophysiologic effects, enhanced compliance, and as a result excellent symptom improvement. These include interpersonal therapy, bibliotherapy, relaxation training, behavioral activation, among others. Some have suggested that dermatologists align themselves with a skinemotion specialist, be it a psychiatrist, psychologist, nurse practitioner, counselor, or social worker.^26,27

Conclusion

Empathy, expectation management, and cheerleading are aspects of the clinical encounter that can foster a positive therapeutic relationship with a patient presenting with a psychodermatological complaint.² Dermatologists ought to be mindful of the potential for meaningful improvements in quality of life by addressing the psychiatric dimension of skin disease.

References

1. Dalgard FJ, Gieler U, Tomas-Aragones L, et al. The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries. J Invest Dermatol. 2015 Apr;135(4):984-91.
2. Leon A, Levin EC, Koo JY. Psychodermatology: an overview. Semin Cutan Med Surg. 2013 Jun;32(2):64-7.
3. Huynh M, Gupta R, Koo JY. Emotional stress as a trigger for inflammatory skin disorders. Semin Cutan Med Surg. 2013 Jun;32(2):68-72.
4. Lam RW, Kennedy SH, Grigoriadis S, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord. 2009 Oct;117(Suppl 1):S26-43.
5. Katzman MA, Bleau P, Blier P, et al; Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles anxieux and McGill University, Antony MM, Bouchard S, Brunet A, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1.
6. Schaffer A, McIntosh D, Goldstein BI, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. The CANMAT task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders. Ann Clin Psychiatry. 2012 Feb;24(1):6-22.
7. Filakovic P, Biljan D, Petek A. Depression in dermatology: an integrative perspective. Psychiatr Danub. 2008 Sep;20(3):419-25.
8. Cohen AD, Ofek-Shlomai A, Vardy DA, et al. Depression in dermatological patients identified by the Mini International Neuropsychiatric Interview questionnaire. J Am Acad Dermatol. 2006 Jan;54(1):94-9.
9. Dowlatshahi EA, Wakkee M, Arends LR, et al. The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Invest Dermatol. 2014 Jun;134(6):1542-51.
10. Bashir K, Dar NR, Rao SU. Depression in adult dermatology outpatients. J Coll Physicians Surg Pak. 2010 Dec;20(12):811-3.
11. Gupta MA, Gupta AK, Schork NJ, et al. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria. Psychosom Med. 1994 Jan-Feb;56(1):36-40.
12. Fardet L, Petersen I, Nazareth I. Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. Am J Psychiatry. 2012 May;169(5):491-7.
13. Sundström A, Alfredsson L, Sjölin-Forsberg G, et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ. 2010 Nov 11;341:c5812.
14. Wakkee M, Nijsten T. Comorbidities in dermatology. Dermatol Clin. 2009 Apr;27(2):137-47.
15. Huynh M, Gupta R, Koo JY. Emotional stress as a trigger for inflammatory skin disorders. Semin Cutan Med Surg. 2013 Jun;32(2):68-72.
16. Gieler U, Consoli SG, Tomás-Aragones L, et al. Self-inflicted lesions in dermatology: terminology and classification–a position paper from the European Society for Dermatology and Psychiatry (ESDaP). Acta Derm Venereol. 2013 Jan;93(1):4-12.
17. Gupta MA, Gupta AK. Current concepts in psychodermatology. Curr Psychiatry Rep. 2014 Jun;16(6):449.
18. Gupta R, Huynh M, Ginsburg IH. Body dysmorphic disorder. Semin Cutan Med Surg. 2013 Jun;32(2):78-82.
19. Kestenbaum T. Obsessive-compulsive disorder in dermatology. Semin Cutan Med Surg. 2013 Jun;32(2):83-7.
20. Odlaug BL, Grant JE. N-acetyl cysteine in the treatment of grooming disorders. J Clin Psychopharmacol. 2007 Apr;27(2):227-9.
21. Lepping P, Russell I, Freudenmann RW. Antipsychotic treatment of primary delusional parasitosis: systematic review. Br J Psychiatry. 2007 Sep;191:198-205.
22. Levin EC, Gieler U. Delusions of parasitosis. Semin Cutan Med Surg. 2013 Jun;32(2):73-7.
23. Manschreck TC, Khan NL. Recent advances in the treatment of delusional disorder. Can J Psychiatry. 2006 Feb;51(2):114-9.
24. Patel V, Koo JY. Delusions of parasitosis; suggested dialogue between dermatologist and patient. J Dermatolog Treat. 2015 Oct;26(5):456-60.
25. Lewin AB, Wu MS, McGuire JF, et al. Cognitive behavior therapy for obsessivecompulsive and related disorders. Psychiatr Clin North Am. 2014 Sep;37(3):415-45.
26. Fried RG. Nonpharmacologic treatments in psychodermatology. Dermatol Clin. 2002 Jan;20(1):177-85.
27. Fried RG. Nonpharmacologic management of psychodermatologic conditions. Semin Cutan Med Surg. 2013 Jun;32(2):119-25.

¹Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest:
None reported

ABSTRACT
Minoxidil is a Health Canada and US FDA-approved medication for hair loss in men and women. While 5% minoxidil foam has been approved for men since 2006, Health Canada and the FDA only approved 5% minoxidil foam for female pattern hair loss (FPHL) in 2014. Recent Phase III clinical trials demonstrated the efficacy of once daily 5% minoxidil foam for treatment of FPHL, where a significant change from baseline in the target area hair count was observed compared to placebo. Similar changes in hair count for 5% foam and twice daily 2% minoxidil solution established noninferiority of the 5% foam formulation. Five percent minoxidil foam provides an additional option for women with FPHL and will soon be available in Canada.

Key Words:
androgenetic alopecia, AGA, female pattern hair loss, FPHL, 5% minoxidil foam, hair loss, treatment, clinical efficacy

Introduction

Female pattern hair loss (FPHL), also known as androgenetic alopecia (AGA), is one of the most common forms of alopecia in women. Onset of hair loss can occur as early as one’s 20s and affect as many as 40% of Caucasian women over the age of 70 years.^1,2 FPHL can be a source of social distress and greatly impair quality of life.³ There are a variety of treatments for FPHL including antiandrogen medications, topical treatments, laser/light devices, and hair transplantation,⁴ with choice of treatment depending on the extent of hair loss, patient health, cost, and preference. The goal of treatment is to slow hair loss and potentially increase hair growth; however, treatment is not always successful.

Until recently, the only US FDA-approved medication for women was 2% minoxidil solution, while both the 2% and 5% solutions are available for men. Minoxidil may stimulate hair growth by increasing the anagen phase of the hair cycle, but the exact mechanisms are currently unknown.⁵ In 2006, the FDA approved 5% minoxidil foam for the treatment of androgenetic alopecia in men after clinical testing showed that it increased hair growth after 48 weeks of twice daily use.^6,7 Additionally, the incidence of pruritus in men was lower with the 5% foam than the 5% solution, likely due to propylene glycol in the solution formulation.^6,7 Because of its efficacy in treating male hair loss, 5% minoxidil became a viable option for women suffering from FPHL. Clinical trial results in women suggest that 5% minoxidil foam is an effective treatment for FPHL, leading to its Health Canada and FDA approvals for this indication in 2014.⁸

Past Clinical Evidence

In Phase III clinical trials, both the 5% and 2% minoxidil formulations have demonstrated similar efficacy in promoting hair growth in women with hair thinning over the frontoparietal scalp. Lucky et al. conducted a 48-week randomized, doubleblind, placebo controlled trial that assessed target area hair count (TAHC) following twice daily application of 5% minoxidil solution, 2% minoxidil solution, or 5% solution vehicle in women with frontoparietal hair loss that could be accompanied with, or without, frontal hairline recession.⁹ Patient and investigator assessments of hair growth and scalp coverage were performed in addition to TAHC. Both the 5% and 2% minoxidil solutions showed significantly higher TAHCs compared to placebo (P < 0.001, Table 1). The investigator assessments followed the same pattern as the TAHC results; however, patient-reported assessment of hair growth was significantly greater in the 5% minoxidil solution group than the 2% minoxidil solution or vehicle groups.⁹

The efficacy of once daily application of 5% minoxidil foam against 2% minoxidil solution in the treatment of frontoparietal hair loss in women was investigated in a randomized, singleblind Phase III trial.¹⁰ Change in non-vellus hair count and width, blind evaluator and patient review of photographs, and patient assessment of product aesthetics and benefits were assessed after 24 weeks of use. Five percent minoxidil foam applied once daily was shown to be noninferior to twice daily 2% minoxidil solution, as measured by change in non-vellus hair count (Table 2) and hair width. Women in the 5% foam group agreed more strongly that treatment did not interfere with grooming routines than did women in the 2% solution group (P = 0.002).¹⁰ In separate studies, both the twice daily use of 5% minoxidil solution and once daily use of 5% minoxidil foam were shown to be noninferior compared to twice daily use of 2% minoxidil solution.

Recent Clinical Trials

Two randomized, double-blind, parallel, international multicenter Phase III trials of 5% minoxidil foam were recently completed. Both trials assessed the efficacy of once daily use of 5% minoxidil foam in female participants aged 18 years and older.^11,12 In the first trial, participants were assigned to once a day treatment with 5% minoxidil foam or vehicle foam for 24 weeks (minoxidil: n=203, vehicle: n=201).¹¹ Efficacy was assessed at weeks 12 and 24 and safety and adverse events were monitored every 6 weeks. At weeks 12 and 24, changes in TAHC from baseline were significantly higher in the minoxidil-treated group than the vehicle-treated group (P < 0.0001, Table 2). Also at 24 weeks, patient-reported assessment of scalp coverage was determined to be significantly higher with minoxidil treatment compared to vehicle (P < 0.0001).¹¹

Participants in the second trial were assigned to once a day treatment with 5% minoxidil foam or 2% minoxidil solution twice daily for 52 weeks (n=161 in each group).¹² TAHC was assessed at weeks 12, 24, and 52 and safety and adverse events were monitored regularly. The change in TAHC from baseline in the 5% minoxidil group was shown to be similar to that of the 2% topical minoxidil solution group at weeks 12 (P < 0.4158) and 24 (P = 0.9170, Table 2), as well as at week 52 (P = 0.5980).¹²

Adverse Events

Five percent minoxidil foam was well tolerated in each of the recent clinical trials. The number of participants reporting adverse events after using 5% minoxidil foam was similar to that of participants who used 2% minoxidil solution or vehicle. The most common adverse events reported in at least 2% of participants included weight gain, headache, pruritus, and nasal and upper respiratory tract infections.^11,12 These are similar to the adverse events reported previously by Lucky et al. and Blume- Peytavi et al., who also reported dermatitis, dandruff, erythema, and burning/stinging in both 5% and 2% minoxidil treatment groups.^9,10 Additionally, 5% foam may encourage greater compliance, as Blume-Peytavi et al. reported that pruritus and dandruff occurred significantly less with application of 5% foam than with the 2% solution.¹⁰

Hypertrichosis is a well-known concern among women using hair growth products. While hypertrichosis has been reported with the use of 5% minoxidil,^9,10,13 unwanted growth in sideburn areas was significantly less with 5% foam than with the 2% solution.¹⁰ Advice to women to further limit hypertrichosis includes application of the medication 2-4 hours prior to bedtime and hand washing immediately after application;⁸ however, the presence of hirsutism or hypersensitivity may increase susceptibility to unwanted hair growth that is beyond physician and patient control.^13,14

Six participants in the 5% minoxidil group reported serious adverse events (SAEs) in the placebo controlled trial (1 incidence each of cardiac disorder, gastritis, dehydration, osteoarthritis, ovarian neoplasm, uterine leiomyoma, renal failure, and hypertensive crisis) in comparison to 4 participants in the vehicle group (1 incidence each of fatigue, ovarian cancer, memory impairment, mental status changes, and PTSD; 2 incidences each of cardiac disorder and asthenia).¹¹ In the comparative trial, 2 participants treated with 5% minoxidil reported SAEs (wrist fracture and anxiety) in comparison to 8 participants in the 2% minoxidil group (1 incidence each of angina pectoris, abdominal pain, bile duct stone, anal abscess, influenza, metastatic neoplasm, menometrorrhagia, and asthma).¹² The SAEs are not considered to be clinically relevant to the drug.

Discussion

Recent clinical trials of 5% minoxidil foam for the treatment of FPHL have demonstrated it to be safe and effective, with hair growth outcomes similar to that of the traditional 2% minoxidil solution.^11,12 Phase III clinical trials demonstrated that hair growth with once daily use of 5% minoxidil foam is noninferior to twice daily use of 2% minoxidil solution in women with frontoparietal hair loss.^10,12 Patient-reported improvement in hair volume and coverage appears to be greater with 5% minoxidil foam and once daily application does not substantially interfere with grooming routines.¹⁰ Adverse events may occur with both 5% foam and 2% solution, but these rarely lead to discontinued use. Susceptibility to hypertrichosis may be individual-specific, and should be discussed with patients as a possible side-effect of minoxidil use.

It is suggested that 5% minoxidil be applied for 3-6 months before noticeable improvement can be observed.⁸ While the results of clinical trials demonstrate a statistically significant increase in the total hair count, sometimes these results may fall short of patient expectations; therefore, patients need to be informed that individual results may vary even after 6-12 months of therapy.^4,16 Recent evidence demonstrates that a sulfotransferase enzyme test can successfully identify non-responders to minoxidil.¹⁷ To our knowledge, this test is not commercially available. In addition, some patients may experience an increase in hair shedding, or at least continued hair loss, for the first few months and should be counselled accordingly.^4,16 When women experience improvement in hair growth, continued treatment is required or else improvement will likely be lost and hair loss will revert back to its natural course.^4,18

Five percent minoxidil foam, applied only once daily, has the potential for milder side effects, improved compliance, and greater patient satisfaction with treatment. Indeed, the use of minoxidil as a treatment for FPHL has been shown to improve women’s quality of life.³ Additionally, 5% minoxidil foam provides an alternative option for women who do not wish to use, or who are unable to use, oral anti-androgen or hormonal contraceptive medications as hair loss treatments. The recent approval and availability of 5% minoxidil foam in Canada provides a safe and effective treatment for women with FPHL.

References

1. Blumeyer A, Tosti A, Messenger A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol Ges. 2011 Oct;9 Suppl 6:S1-57.
2. Norwood OT. Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg. 2001 Jan;27(1):53-4.
3. Zhuang XS, Zheng YY, Xu JJ, et al. Quality of life in women with female pattern hair loss and the impact of topical minoxidil treatment on quality of life in these patients. Exp Ther Med. 2013 Aug;6(2):542-6.
4. Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013 Oct;11(4):e9860.
5. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004 Feb;150(2):186-94.
6. Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002 Sep;47(3):377-85.
7. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebocontrolled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007 Nov;57(5):767-74.
8. Drugs@FDA: FDA Approved Drug Products. Women’s rogaine 5% minoxidil topical aerosol, approval history and label. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed September 1, 2014.
9. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004 Apr;50(4):541-53.
10. Blume-Peytavi U, Hillmann K, Dietz E, et al. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011 Dec;65(6):1126-34 e2.
11. Johnson & Johnson Consumer and Personal Products Worldwide. A phase 3 multi-center parallel design clinical trial to compare the efficacy and safety of 5% minoxidil foam vs. vehicle in females for the treatment of female pattern hair loss (androgenetic alopecia). In: ClinicalTrials.gov, Identifier: NCT01226459. Last updated June 3, 2014. Available at: http://clinicaltrials.gov/ct2/show/results/NCT01226459?term=minoxidil&sect=X4301256#othr. Accessed September 1, 2014.
12. Johnson & Johnson Consumer and Personal Products Worldwide. A phase 3 multi-center parallel design clinical trial to compare the efficacy and safety of 5% minoxidil foam vs. 2% minoxidil solution in females for the treatment of female pattern hair loss – androgenetic alopecia. In: ClinicalTrials.gov, Identified: NCT01145625. Last updated May 19, 2014. Available at: http:// clinicaltrials.gov/ct2/show/study/NCT01145625?term=minoxidil&sect=X430126. Accessed September 1, 2014.
13. Dawber RP, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol. 2003 May;17(3):271-5.
14. Peluso AM, Misciali C, Vincenzi C, et al. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol. 1997 Jan;136(1):118-20.
15. Hillmann K, Geburtsort K. Results of an investigator-initiated, two-armed, randomized, controlled clinical trial to proof efficacy of a 5% minoxidil topical foam once daily versus a 2% minoxidil solution twice daily on hair volume in women with mild to moderate androgenetic alopecia. Free University of Berlin; 2013. Available at: http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000095104. Accessed September 1, 2014.
16. Levy LL, Emer JJ. Female pattern alopecia: current perspectives. Int J Womens Health. 2013;5:541-56.
17. Goren A, Shapiro J, Roberts J, et al. Clinical utility and validity of minoxidil response testing in androgenetic alopecia. Dermatol Ther. 2014 Aug 12. [Epub ahead of print]
18. Rogers NE. Medical therapy for female pattern hair loss (FPHL). Hair Transpl Forum Int. 2014;24(3):81,86-8.

¹Department of Dermatology, Duke University School of Medicine, Durham, NC, USA
²Division of Dermatology, Department of Medicine, Duke University Medical Center, Durham VA Medical Center, Durham, NC, USA

ABSTRACT

Autoimmune blistering diseases are rare, but potentially debilitating cutaneous disorders characterized by varying degrees of mucosal and cutaneous bullae formation. Topical therapy is appropriate for mild and even some moderate disease activity, but systemic treatment can be considered for more extensive involvement. Corticosteroids remain the first-line systemic therapy for patients with moderate to severe bullous pemphigoid and pemphigus vulgaris. While the use of systemic steroids has dramatically reduced mortality from these two autoimmune blistering disorders, treatment is also associated with multiple side effects, especially when used long-term. Steroid sparing agents, therefore, are invaluable in inducing long-term remission while minimizing steroid associated side effects. Treatment must be tailored to the individual patient’s condition, and several other factors must be carefully considered in choosing appropriate therapy: 1) diagnosis, 2) severity of the condition and body site affected, 3) presence of comorbidities, and 4) ability to tolerate systemic therapy.

Key Words:
autoimmune blistering skin diseases, bullous pemphigoid, cicatricial pemphigoid, basement membrane zone, epidermolysis bullosa acquisita, pemphigus vulgaris

Introduction

Autoimmune blistering diseases (AIBD) are a heterogeneous group of chronic, acquired disorders characterized by blister formation within the epidermis, at the dermal-epidermal junction or at the basement membrane zone, and by the presence of autoantibodies directed against structural components of cellular adhesions molecules. AIBD are classified into different groups based on clinical and immunopathological criteria. Largescale, randomized studies on effective therapeutic strategies for AIBD are limited and treatment varies widely among providers. The patient population tends to be a heterogeneous mix of age, gender and comorbidities, and the mechanisms of injury to the skin are variable between blistering diseases. Management of these disorders, therefore, requires an understanding of the spectrum of available therapies. A complete discussion of the treatment of AIBD is beyond the scope of this review, however, we present some recommendations in approaching patients with pemphigus, pemphigoid, and epidermolysis bullosa acquisita (EBA). A brief description of the available medications and their roles in treating AIBD will be provided, but a thorough review of therapeutic and monitoring guidelines must be done before treatment is initiated.¹

Approach to Patients with AIBD

Several factors need to be considered in treating a patient with an AIBD (Table 1). A complete history and thorough physical examination of the skin and mucous membranes must be performed. A skin biopsy, with direct and indirect immunofluorescence analysis, is important in arriving at the correct diagnosis and planning therapy. Determining titers of autoantibodies are not always necessary to confirm the diagnosis, but may be helpful in following the patient’s progress.^2-4

First, an accurate diagnosis will help determine the likelihood of disease remission, potential for mucous membrane involvement, risk of scarring, and other long-term sequelae that may affect treatment plans. For example, bullous pemphigoid (BP) and EBA may demonstrate a similar clinical presentation, but have a different natural history. A clinician may plan to wean a BP patient off all medications in 9-12 months, whereas longer-term therapy is often needed in patients with EBA.

Second, severity and extent of disease has to be carefully evaluated. The extent of the disease can be variable in all types of AIBD. Additionally, the definition of mild, moderate and severe disease differs among experts. Some authors define limited disease as <10% body surface area, while others use the cut-off point of <10 new blisters per day to delineate between limited and severe disease.^5,6 Nevertheless, even in the absence of new blisters and regardless of affected areas, the involvement of functional critical sites (e.g., hands and feet or mucosal surfaces) may require more aggressive therapy. Ocular disease, which can result in permanent scarring or blindness, warrants systemic treatment, in addition to subspecialty referral to ophthalmology.

Third, the presence of comorbidities may dictate the type and dosage of medication that can be used and must be accompanied by careful assessment. Diseases such as diabetes mellitus, hypertension, chronic infections (e.g., hepatitis or HIV), and previous or existent malignancies need to be considered. Patients who would otherwise be treated aggressively, but whose comorbidities preclude therapy with systemic corticosteroids (i.e., elderly patients or those with uncontrolled diabetes or hypertension) or more traditional steroid sparing agents, may instead have to be treated with topical, antibiotic or antiinflammatory medications.

Finally, the choice of medications may be restricted by side effects experienced by the patient. Potential side effects, which can be significant, include alterations in mental status, sleep disturbances, and gastrointestinal (GI) discomfort. The assessment of all adverse effects throughout therapy is critical to treatment success in AIBD. The clinician must exercise judgment in weighing the risks and benefits of initial therapy in an effort to maximize efficacy while minimizing systemic toxicity.

Mild to Moderate Disease

Topical Therapy

For pemphigus vulgaris (PV) patients with mild and even moderate cutaneous and oral mucosal⁷ involvement, BP or EBA, a high potency topical steroid such as clobetasol 0.05% ointment or gel applied 2-3 times daily is appropriate.⁵ Even in the setting of extensive disease, potent topical steroids remain an option if the patient is elderly or has numerous risk factors. Clobetasol 0.05% cream 40 g/day is at least as effective as oral prednisone in treating moderate to severe BP.⁸ Some degree of systemic absorption may contribute to the efficacy of topical steroids, however, the side effect profile is still acceptable.

Antimicrobials

Antimicrobials decrease local inflammation, but have no effect on circulating autoantibodies.⁹ The combination of tetracycline 2 g PO daily plus nicotinamide 1.5 g PO is a reasonable alternative for the treatment of BP in patients who are not candidates for systemic steroid therapy. In a randomized trial of 18 patients comparing prednisone with tetracycline and nicotinamide, there was no statistically significant difference in response between the two groups. In addition, 83% of patients treated with tetracycline plus nicotinamide had some improvement and 42% experienced a complete response. At long-term follow-up, a small subset of patients in the tetracycline plus nicotinamide treatment group remained in remission with tapering of the medication.¹⁰ Several other small studies have also demonstrated variable improvement with this treatment combination.^9,11

Colchicine

Colchicine is an anti-inflammatory drug with a mild side effect profile. High doses of colchicine have been effective in patients with classical and inflammatory EBA.^12-14 The typical dosing ranges from 0.6 mg PO BID to TID. The most frequent side effects are GI complaints, particularly diarrhea, which can limit the utility of this therapy.

Moderate to Severe Disease

Systemic Corticosteroids

Much of the disease morbidity and mortality, particularly with PV and BP, has decreased with the introduction of corticosteroid therapy. Corticosteroids are the first-line systemic treatment for moderate to severe BP and PV and may have a role in treating the inflammatory subset of EBA, evidence is admittedly scant for the latter.^2,15 There is no universal consensus on dosing and tapering systemic corticosteroids for AIBD. Some guidelines use weightbased dosing, whereas others recommend a starting dose of 40-60 mg PO daily.^5,6 Patients with milder BP, PV and EBA can often be adequately managed with 0.5-0.75 mg/kg/day. However, in patients with severe disease (>10 new lesions per day), a starting dose between 0.75-1.0 mg/kg/day can be used.

Long-term use of corticosteroids is associated with multiple adverse effects including increased risk for infection, weight gain, high blood pressure, osteoporosis, fluid retention, elevated blood sugar, cognitive disturbances, cataracts, and glaucoma. Therefore, once the disease stabilizes, careful tapering of the medication is strongly recommended. We suggest re-evaluating the patient 1-2 weeks after initiating therapy. If the disease is stable, a slow tapering of prednisone may be initiated, decreasing the dose by 5-10 mg every month as tolerated. However, in patients who cannot tolerate long-term prednisone use (i.e., patients with labile blood sugar or blood pressure, significant agitation or neurologic side-effects) a more rapid tapering may be required, decreasing the dose by 5-10 mg each week. If the disease remains active, then a decision can be made to either increase the dose or initiate adjunctive therapy with steroid sparing agents. The American College of Rheumatology has established recommendations for monitoring steroid-induced osteoporosis in patients on longterm corticosteroids.^16,17

Steroid Sparing Agents

In patients who cannot be tapered off steroids without inducing disease flares, steroid sparing agents are invaluable in achieving prolonged remission. Careful review of monitoring guidelines is essential before initiating therapy.¹ Traditional immunosuppressive agents such as mycophenolate mofetil and azathioprine are more commonly used. However, with the advent of biologic therapy, treatment options such as intravenous immunoglobulin and rituximab are increasingly being employed earlier in the course of therapy.^18-20

Azathioprine
When used as adjunctive therapy, azathioprine enables a significant dosage reduction of prednisone in patients with moderate to severe BP.^5,21 Azathioprine appears to be a superior steroid-sparing agent for PV when compared to cyclophosphamide and mycophenolate mofetil,²² although there is some evidence that cyclophosphamide may induce a quicker and more sustained remission.²³ Genetics play a role in the efficacy and safety of azathioprine. The metabolism of azathioprine is dependent on xanthine oxidase and thiopurine methyltransferase (TMPT). Ten percent of the population is heterozygous with intermediate TPMT enzyme activity and 1/300 patients is homozygous or compound heterozygous with low enzyme activity.^21,24 Although the effect on heterozygotes is still unclear, homozygotes are at risk of severe neutropenia.²⁵ Other adverse effects include cytopenia, hepatitis, pancreatitis and infection. Allopurinol inhibits xanthine oxidase, potentiating the risk of myelosuppression. Azathioprine may also decrease the efficacy of warfarin, therefore, dose adjustments may be required. The recommended dose of azathioprine is 1-3 mg/kg daily.²⁶ A lower dosage is recommended in the elderly or patients who have reduced TMPT levels.¹ When TMPT levels are extremely low, azathioprine should not be used.

Mycophenolate Mofetil
Mycophenolate mofetil (MM) is effective both as combination therapy and monotherapy in PV and BP.^27-32 In a randomized controlled trial comparing MM or placebo plus prednisone in the treatment of mild to moderate PV, the MM arm exhibited an improved time to and duration of response.³³ A study comparing MM vs. azathioprine as adjuvant therapy to oral methylprednisolone demonstrated similar efficacy in both groups, but increased hepatotoxicity was observed in those who received azathioprine.³⁴ Given its similar, if not superior, efficacy to azathioprine and better side effect profile, MM is becoming the first choice therapy for adjuvant treatment in BP and PV. The most common side effects are usually mild and include nausea, diarrhea, GI discomfort and malaise. However, hepatotoxicity, infections, leukopenia and anemia can occur.²⁰ The usual dosing range is between 1-3 g/day.

Cyclophosphamide
Cyclophosphamide has a faster onset of action than azathioprine or MM, but is also associated with significant adverse effects. Therefore, its use is usually reserved for patients with refractory or rapidly progressive disease, individuals unable to tolerate first-line therapies, or those with ocular cicatricial pemphigoid. Combination therapy with cyclophosphamide and systemic corticosteroids is recommended in patients with severe mucous membrane disease, in order to decrease the potentially severe morbidities.^7,35-37 Side effects are frequent and can be severe, and include nausea, vomiting, diarrhea, alopecia, and fatigue. More severe side effects are secondary to hematopoietic suppression leading to leukopenia, anemia and thrombocytopenia. An increased risk of transitional cell carcinoma and lymphomas is also concerning. One of the metabolites of cyclophosphamide, acrolein, can cause hemorrhagic cystitis in up to 40% of patients. Standard dosing of oral therapy is 2-2.5 mg/kg daily. Intravenous (IV) pulsed therapy is more frequently recommended in order to decrease the cumulative effect dose.

Cyclosporine
Several randomized controlled trials have failed to demonstrate a beneficial effect of oral cyclosporine either alone or as adjuvant therapy.^38-41 Topical cyclosporine has been used for oral and ocular cicatricial pemphigoid.^42,43 The most common adverse reactions to cyclosporine are renal dysfunction, hypertension, tremor, hirsutism, and gingival hyperplasia.

Methotrexate
Methotrexate (MTX) can be effective in treating BP and PV by decreasing disease activity and time to remission.^44-49 The most common side effects of MTX are fatigue, nausea and vomiting. More severe adverse effects include pancytopenia and hepatotoxicity, which can be exacerbated by renal disease, chronic nonsteroidal anti-inflammatory drug (NSAID) use, hepatic disease (e.g., hepatitis, alcohol use, diabetes mellitus, and obesity), and lack of folic acid supplementation. Photosensitivity and radiation recall are also potential adverse effects, and hepatic fibrosis and cirrhosis can occur with long-term use. The issue of if and when to perform a liver biopsy is controversial, however, depending on individual risk factors, a liver ultrasound and/or biopsy should be considered after prolonged use. Some guidelines recommend liver biopsy after a cumulative dose of 4 g in the absence of risk factors for hepatic disease.^50,51 Dosing is similar to that for rheumatoid arthritis, averaging 15 mg/week and 1 mg daily of folic acid.⁴⁹

Dapsone
Dapsone inhibits the chemotaxis of polymorphonuclear leukocytes and is an extremely effective drug in treating neutrophilic dermatoses.^52-57 In many AIBD, dapsone is more successful as an adjunctive rather than single agent treatment. A 2009 meta-analysis of 170 BP patients demonstrated that 81% experienced clinical improvement with dapsone, but the best responses were observed in conjunction with steroids or other immunosuppressants.⁵⁸ A randomized, double-blind, placebocontrolled crossover trial of dapsone vs. placebo favored dapsone over placebo as a steroid sparing agent in maintaining remission among patients with PV, but the results were not statistically significant.⁵⁹

Dose-dependent hemolytic anemia and methemoglobinemia will occur to some degree in all patients. Cimetidine, 400 mg PO 3 times daily, can reduce dapsone-induced methemoglobinemia without affecting the clinical response.⁶⁰ Dapsone may also cause agranulocytosis and hepatic function abnormalities. Distal motor neuropathy is a rare and reversible side effect, and monitoring by clinical examination and nerve-conduction studies must be done. The typical dose of dapsone ranges between 100-300 mg daily, although the effective dose varies significantly between individuals.⁶¹ In low-risk patients, treatment can be initiated at a dosage of 100 mg daily.

Intravenous Immunoglobulin (IVIg)
IVIg has been shown in numerous small studies to be beneficial in refractory PV, BP and EBA.^62-81 A randomized, placebo-controlled, double-blind study demonstrated that pemphigus patients given a single cycle of high dose IVIg (400 mg/kg/day over 5 consecutive days) experienced a prolonged time to escape from the protocol compared to placebo.⁸² An earlier retrospective study found no response to IVIg in 9 of 11 patients with AIBD.⁸³ Side effects are usually mild and self-limiting and include headache, back pain, chills, flushing, fever, hypertension, myalgia, nausea and vomiting. These may improve with decreased infusion rate or premedication with NSAIDs, antihistamines, or low-dose IV corticosteroids. Mild skin reactions including erythema, pain and phlebitis can occur at the infusion site. Potential severe side effects include anaphylaxis (particularly in IgA-deficient individuals), renal failure, aseptic meningitis, and infection. The typical dosing cycle is 2 g/kg divided into 2 or 3 equal doses, given on 3 consecutive days, repeated every 4 weeks.⁶²

Rituximab
Rituximab has shown the most promise as therapy in PV, although it may also be beneficial in the treatment of BP and refractory EBA.^84-89 A majority of patients treated with various protocols of rituximab achieved either complete or partial remission. Relapses are common, but can also be successfully treated with additional courses of rituximab.⁹⁰ A group of 25 patients with mucous membrane pemphigoid (5 with mucous membrane dominant EBA) also responded well to rituximab.⁹¹ The data on rituximab use in BP is less robust due to the efficacy of steroids in this disease. In 11 patients with BP refractory to standard treatments, rituximab use resulted in either complete or partial remission.^89,92-94 The most common adverse effects are mild and self-limiting and include fever, headache, nausea, chills, hypotension, and thrombocytopenia. Many of these symptoms are infusion related. Infections can also occur and may be life threatening, particularly in immunosuppressed patients. A potentially severe consequence is progressive multifocal encephalopathy (PMLE). The estimated rate of PMLE after rituximab therapy is 4.06 per 100,000 patients. To date, no cases have been reported in patients treated for AIBD.^95,96 Nonetheless, clinicians and patients should be aware of the risk of this rare, but extremely serious, adverse event. Two dosing schedules exist for rituximab: the one traditionally used in lymphoma consists of weekly IV infusions of 375 mg/m² for 4 weeks and the other more commonly used in rheumatoid arthritis is two 1 g infusions, administered 2 weeks apart. The latter has become increasingly used as the standard protocol for AIBD.

Conclusion

The treatment of AIBD varies greatly, but usually consists of topical or systemic steroids or combination therapy with steroid sparing agents or immunomodulators.⁹⁷ For PV, BP and EBA, finding the optimal treatment can be very difficult and often requires several dose adjustments or trial of an alternative steroid-sparing agent before the disease is well-controlled. Supportive care is often necessary to reduce the risk of complications and improve quality of life. This often requires collaborative approaches to therapy with ophthalmology and/or otolaryngology, when severe mucous membrane disease is present. For PV, first-line therapy is systemic corticosteroids and first-line adjunctive therapy is usually azathioprine or MM. Rituximab has recently been gaining ground as a treatment for refractory cases. The treatment algorithm for BP is similar. However, because patients with BP tend to have more comorbidities, early transition to combination or steroid-sparing therapy may be necessary.

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66. Bewley AP, Keefe M. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J Dermatol. 1996 Jul;135(1):128-9.
67. Caldwell JB, Yancey KB, Engler RJ, et al. Epidermolysis bullosa acquisita: efficacy of high-dose intravenous immunoglobulins. J Am Acad Dermatol. 1994 Nov;31(5 Pt 1):827-8.
68. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol. 2001 Jan;44(1):83-8.
69. Godard W, Roujeau JC, Guillot B, et al. Bullous pemphigoid and intravenous gammaglobulin. Ann Intern Med. 1985 Dec;103(6 ( Pt 1)):964-5.
70. Gourgiotou K, Exadaktylou D, Aroni K, et al. Epidermolysis bullosa acquisita: treatment with intravenous immunoglobulins. J Eur Acad Dermatol Venereol. 2002 Jan;16(1):77-80.
71. Harman KE, Black MM. High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases. Br J Dermatol. 1999 May;140(5):865-74.
72. Harman KE, Whittam LR, Wakelin SH, et al. Severe, refractory epidermolysis bullosa acquisita complicated by an oesophageal stricture responding to intravenous immune globulin. Br J Dermatol. 1998 Dec;139(6):1126-7.
73. Humbert P, Derancourt C, Aubin F, et al. Effects of intravenous gammaglobulin in pemphigus. J Am Acad Dermatol. 1990 Feb;22(2 Pt 1):326.
74. Kofler H, Wambacher-Gasser B, Topar G, et al. Intravenous immunoglobulin treatment in therapy-resistant epidermolysis bullosa acquisita. J Am Acad Dermatol. 1997 Feb;36(2 Pt 2):331-5.
75. Messer G, Sizmann N, Feucht H, et al. High-dose intravenous immunoglobulins for immediate control of severe pemphigus vulgaris. Br J Dermatol. 1995 Dec;133(6):1014-6.
76. Mohr C, Sunderkotter C, Hildebrand A, et al. Successful treatment of epidermolysis bullosa acquisita using intravenous immunoglobulins. Br J Dermatol. 1995 May;132(5):824-6.
77. Mosqueira CB, Furlani Lde A, Xavier AF, et al. Intravenous immunoglobulin for treatment of severe acquired bullous epidermolysis refractory to conventional immunosuppressive therapy. An Bras Dermatol. 2010 Jul-Aug;85(4):521-4.
78. Sami N, Bhol KC, Ahmed AR. Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Long-term follow-up: influence of treatment on antibody titres to human alpha6 integrin. Clin Exp Immunol. 2002 Sep;129(3):533-40.
79. Sami N, Letko E, Androudi S, et al. Intravenous immunoglobulin therapy in patients with ocular-cicatricial pemphigoid: a long-term follow-up. Ophthalmology. 2004 Jul;111(7):1380-2.
80. Sami N, Qureshi A, Ruocco E, et al. Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol. 2002 Sep;138(9):1158-62.
81. Wever S, Zillikens D, Brocker EB. Successful treatment of refractory mucosal lesions of pemphigus vulgaris using intravenous gammaglobulin as adjuvant therapy. Br J Dermatol. 1996 Nov;135(5):862-3.
82. Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009 Apr;60(4):595-603.
83. Wetter DA, Davis MD, Yiannias JA, et al. Effectiveness of intravenous immunoglobulin therapy for skin disease other than toxic epidermal necrolysis: a retrospective review of Mayo Clinic experience. Mayo Clin Proc. 2005 Jan;80(1):41-7.
84. Schmidt E, Benoit S, Brocker EB, et al. Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab. Arch Dermatol. 2006 Feb;142(2):147-50.
85. Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol. 2002 Nov;47(5):785-8.
86. Virgolini L, Marzocchi V. Anti-CD20 monoclonal antibody (rituximab) in the treatment of autoimmune diseases. Successful result in refractory pemphigus vulgaris: report of a case. Haematologica. 2003 Jul;88(7):ELT24.
87. Crichlow SM, Mortimer NJ, Harman KE. A successful therapeutic trial of rituximab in the treatment of a patient with recalcitrant, high-titre epidermolysis bullosa acquisita. Br J Dermatol. 2007 Jan;156(1):194-6.
88. Niedermeier A, Eming R, Pfutze M, et al. Clinical response of severe mechanobullous epidermolysis bullosa acquisita to combined treatment with immunoadsorption and rituximab (anti-CD20 monoclonal antibodies). Arch Dermatol. 2007 Feb;143(2):192-8.
89. Schulze J, Bader P, Henke U, et al. Severe bullous pemphigoid in an infant–successful treatment with rituximab. Pediatr Dermatol. 2008 Jul-Aug;25(4):462-5.
90. Zakka LR, Shetty SS, Ahmed AR. Rituximab in the treatment of pemphigus vulgaris. Dermatol Ther (Heidelb). 2012 Dec;2(1):17.
91. Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, et al. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol. 2011 Jul;147(7):843-9.
92. Fuertes I, Luelmo J, Leal L, et al. Refractory childhood pemphigoid successfully treated with rituximab. Pediatr Dermatol. 2013 Sep-Oct;30(5):e96-7.
93. Lourari S, Herve C, Doffoel-Hantz V, et al. Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol. 2011 Oct;25(10):1238-40.
94. Saouli Z, Papadopoulos A, Kaiafa G, et al. A new approach on bullous pemphigoid therapy. Ann Oncol. 2008 Apr;19(4):825-6.
95. Palazzo E, Yahia SA. Progressive multifocal leukoencephalopathy in autoimmune diseases. Joint Bone Spine. 2012 Jul;79(4):351-5.
96. Tavazzi E, Ferrante P, Khalili K. Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies. Clin Microbiol Infect. 2011 Dec;17(12):1776-80.
97. Garcia-Romero MT, Werth VP. Randomized controlled trials needed for bullous pemphigoid interventions. Arch Dermatol. 2012 Feb;148(2):243-6.

¹Department of Dermatology and Skin Science, The University of British Columbia, Vancouver, BC, Canada
²Vancouver Coastal Health Research Institute, The University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology, New York University, New York, NY, USA

Introduction

Hair loss is a common dermatological problem that affects a large segment of the population both physically and psychologically. There are many causes of hair loss, such as telogen effluvium (thinning of hair as a result of hair follicles perpetually in a resting phase, as opposed to growth phase) and alopecia areata (an inherited autoimmune condition); androgenetic alopecia (AGA) also called male pattern hair loss (MPHL), is the most common. Hair loss can start anytime at or after puberty: many people have hair loss beginning in the late teens due to the effects of androgen hormones on hair follicles.¹ Its occurrence and severity increases with age, with at least 80% of Caucasian men displaying signs of MPHL by age 70.² Because of its considerable psychological impact, many patients seek treatment.³ Currently, only one topical agent is approved for treatment of hair loss in men, although other treatments are being clinically investigated.

Pathogenesis

• The pathophysiology of AGA remains to be fully determined however, as the name implies, androgens and a genetic predisposition appear to be involved.⁴
• Inherited AGA is polygenic with input from either or both parents.
• The androgenic hormones testosterone (T) and dihydrotestosterone (DHT) are the most important in regulating the growth phase duration and hair matrix volume.
  • In men, testosterone is the precursor to DHT. The conversion of T to DHT at the hair follicles is mediated by Type II 5! reductase enzyme.
• DHT, a potent metabolite of testosterone, enlarges follicles in the beard, chest and limbs and miniaturizes follicles in the bitemporal region. In genetically susceptible patients, DHT can cause miniaturisation in the vertex and frontal hairline leading to AGA-patterned thinning.

Clinical Presentation & Diagnosis

• AGA presents with fronto-temporal recession and over the vertex: the occipital scalp is preserved.
• Diagnosis is made based on the clinical history; however a scalp biopsy may be needed in situations where the cause of hair loss is uncertain.
• Telogen effluvium may present like early phase AGA.

Current Topical Treatments

Minoxidil

• Minoxidil is the current topical standard treatment of hair loss. Initially used as an oral antihypertensive medication, its association with hypertrichosis led to its development as a topical therapy for AGA.
• Minoxidil 2% solution was approved by the US FDA for the treatment of MPHL in 1988, and was subsequently approved in 5% strength in a solution format in 1997 and in a foam format in 2006. The 2% solution formulation alone was approved in the US for female pattern hair loss in 1996. Minoxidil 2% solution became available in Canada for the treatment of MPHL in 1986, and the 5% foam in November 2012.⁴
• The content discussed here relates to the branded formulation of minoxidil only and not the compounded or generic formulations.
• The precise mechanism of action of minoxidil is unknown; however it is associated with vasodilation, angiogenesis and enhanced cell proliferation, probably mediated via potassium channel opening.^5,6 Further, it has been seen to prolong duration of anagen of the hair cycle, increase miniaturized hair follicle size, and preserve and thicken preexisting hair.
• Data from a 16-week, randomized, double-blind, placebo controlled (RCT) study of the newly approved minoxidil 5% foam application showed at weeks 8, 12 and 16 the mean increase in target area hair count was significantly greater than placebo (p<0.0001).⁷ At week 16 the percentage change in target area hair count was 13.4% in men treated with minoxidil 5% foam compared with 3% for the placebo arm (21.0 hairs/cm2 vs. 4.3 hairs/cm2, respectively).^7,8 Further, 38.3% of patients in the minoxidil arm demonstrated increased hair growth at week 16, compared with 5.2% in the placebo group (p<0.0001), as rated by an expert panel.⁷
• Data from a 48-week RCT also showed an increase in target area hair count in men treated with minoxidil solution, and that the product reversed hair loss as well as slowed its progression.⁹
• The same study also showed that target area hair counts were greater with the 5% solution compared with the 2% minoxidil solution.
• Minoxidil treatment is life-long: stopping treatment will result in a shedding of all minoxidil-dependent hair growth within 4-6 months after cessation of therapy.⁴
• The recommended dosing of minoxidil 2% solution is twice daily topical application of 1 ml spread evenly over the top of the dry scalp in the hair loss area.
• With minoxidil 5% foam, half a capful is applied twice daily on the dry scalp and left in place for at least four hours. To avoid the drug coming into contact with the face and limit the risk of hypertrichosis in non-scalp body areas, patients should wash their hands with warm water after application.
• Minoxidil has a well-established safety profile. The most frequently reported adverse drug reaction following the short-term, 16-week treatment with minoxidil 5% foam was headache.⁸ The most frequently reported dermatological adverse events were erythema, rash, acne and pruritis. In long-term treatment, the most frequently reported nonserious adverse events were infection and accidental injury.⁸
• The most frequently reported adverse events in the minoxidil 2% solution clinical trials were minor respiratory events, including colds and respiratory infections, rhinitis, sinusitis and coughing. Dermatologic adverse reactions were the next most frequent and included scaling, itching and rash.⁸
• Increased hair shedding is possible in the first 2-6 weeks of treatment, which likely results from inducing anagen from the resting phase.⁸ This may be an indication that minoxidil is effective; patients should be advised not to stop treatment if they experience hair loss for two weeks or less. However, if hair loss continues for longer than two weeks, patients should be advised to stop using the product and talk to their doctor.⁸
• Careful evaluation of the risks and benefits of minoxidil treatment should be considered in patients with pre-existing cardiac, renal or hepatic disease or scalp abnormalities and those receiving potentially interacting drugs concomitantly (e.g., hypotensive agents, such as guanethidine). If minoxidil therapy is initiated in these scenarios, patients should be closely monitored.¹⁰
• Allergic reaction to minoxidil is rare. Constituents of the vehicles may cause skin irritation. Irritant dermatitis to propylene glycol (a component of minoxidil 2% solution vehicle) may occur. Patch testing for propylene glycol can be performed as a precaution. If contact dermatitis results from minoxidil use, treatment should be stopped.
• Minoxidil 5% foam is propylene glycol free. Further, it is aesthetically more pleasing to patients compared to the solution, and thus likely increases compliance.
• Data show patients using the foam product rated it significantly higher compared with the minoxidil solution, finding it easy to apply, quick to absorb and non-drip.¹⁰
• Systemic absorption of minoxidil is weak with only 0.3-4.5% reaching the circulation. It is excreted within four days.

Other Topical Agents

Prostoglandins

• The prostaglandin F2α< analogues latanoprost and bimatoprost are widely used to treat glaucoma.
• Bimatoprost topical solution 0.03% is approved for treating hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.
• Topical latanoprost is under investigation for the treatment of AGA.¹¹

Ketoconazole

• Ketoconazole is an imidazole antifungal agent known to be effective for treatment of seborrheic dermatitis and dandruff. It is available as an over-the-counter topical shampoo at a 2% strength.
• Ketaconazole’s action on scalp microflora may benefit patients with AGA-associated follicular inflammation.^12,13
• While the mechanism by which ketoconazole may improve hair growth is unclear, it is known to have anti-inflammatory effects against T-cells which are found in the balding area in patients with AGA.¹⁴
• Further, ketoconazole decreases colonization of the skin by Malassezia.
• Ketoconaole also inhibits steroid synthesis and decreases DHT levels at the hair follicle by affecting androgen receptor activity.¹⁴

Conclusion

AGA is a common issue among men and can significantly affect self-esteem and quality of life, such that they may seek treatment. While different topical agents are currently being investigated for safety and efficacy, only one topical treatment, minoxidil, is currently approved for hair regrowth. The newly approved 5% foam solution has demonstrated patient preference, which in turn may improve compliance. Given its established efficacy and safety profile, minoxidil may be useful in the topical management of AGA in male patients.

References

1. Pray J. et al. US Pharmacist. 2003; 28(8)1.
2. Gan DC, et al. J Investig Dermatol Symp Proc. 2005;10(3):184-9.
3. Budd D. Eur J Dermatol. 2000 Mar;10(2):122-7.
4. Banka N, Dermatol Clin. 2013 Jan;31(1):129-40.
5. Alsantali A, et al. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):246-53.
6. Messenger AG, et al. Br J Dermatol. 2004 Feb;150(2):186-94.
7. Olsen EA, et al. J Am Acad Dermatol. 2007 Nov; 57(5):767–74.
8. ROGAINE® Canadian Product Monograph
9. Olsen EA, et al. J Am Acad Dermatol. 2002 Sep; 47(3):377-85.10.McEvoy, GK. American Hospital Formulary Service-Drug Information 2002.
10. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements).
11. Blume-Peytavi U, et al. J Am Acad Dermatol. 2012 May;66(5):794-800.
12. Pierard-Franchimont C, et al. Dermatology. 1998;196(4):474-7.
13. Magro CM. et al. J Drugs Dermatol. 2011 Dec; 10(12):1404-11.
14. Inui S, et al. J Dermatol Sci. 2007 Jan;45(1):66-8.

¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²College of Medicine, Al Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
³Department of Dermatology, New York University, New York, NY, USA

ABSTRACT

Hair loss is a widespread complaint that carries a significant psychosocial burden for affected individuals. Androgenetic alopecia (AGA) is the predominant cause of hair loss seen in the dermatology clinic. Although a range of therapies are available, minoxidil remains the only approved topical treatment for AGA. Promising new topical agents are under current investigation.

Key Words:
androgenetic alopecia, AGA, female pattern hair loss, male pattern hair loss, topicals

Introduction

Hair loss is a common dermatological problem that affects a large segment of the population both physically and psychologically. Although there are many different causes for hair loss, such as telogen effluvium and alopecia areata, androgenetic alopecia (AGA), i.e., male pattern hair loss and female pattern hair loss, is the most prevalent form in both men and women. Onset of AGA can occur anytime at or after puberty, but incidence and severity increases with advancing age in both genders, manifesting in at least 80% of Caucasian men and 40% of women.¹ Because of its considerable psychological impact many patients actively search for new treatments.²

Androgenetic Alopecia

Clinical Presentation

Male pattern hair loss (MPHL) affects androgen-sensitive follicles and features fronto-temporal recession and hair loss over the vertex while the occipital scalp is preserved, resulting in a classic M pattern. In women, female pattern hair loss (FPHL) typically presents with diffuse central thinning or frontal accentuation forming a “Christmas tree” pattern. A third and less common presentation is a male-like pattern with fronto-temporal recession/vertex loss, which may indicate excess androgen activity.³ Diagnosis is easily determined from the clinical history, however, a scalp biopsy may be needed in situations where the cause of hair loss is uncertain. Extensive hormonal testing is usually unnecessary unless indicated by signs and symptoms of androgen excess, such as hirsutism, severe unresponsive cystic acne, virilization, or galactorrhea, which may point to the possibility of an underlying endocrine abnormality.⁴

Pathogenesis

The pathophysiology of AGA is not yet fully understood, but both genes and androgens appear to be involved. Inheritance is polygenic with input from either or both parents. Women with FPHL are less likely than men to exhibit a clear family history of the disorder.⁵

The androgens testosterone (T) and dihydrotestosterone (DHT) are the most important factors in regulating the anagen duration and hair matrix volume.

DHT, a potent metabolite of testosterone, enlarges follicles in the beard, chest and limbs, and miniaturizes follicles in the bitemporal region. In genetically susceptible individuals, DHT can cause miniaturization in the vertex and frontal hairline leading to AGA patterned thinning. The conversion of T to DHT occurs at the hair follicles elicited by a type II 5-alpha-reductase enzyme.

Topical Treatments

Minoxidil

Minoxidil is the current standard treatment for hair loss. It was initially used as an oral antihypertensive medication, but because of minoxidil’s side effect of hypertrichosis it was subsequently developed as a topical treatment in 2% strength for hair loss. US FDA approval for the treatment of MPHL was granted to the 2% formulation in 1988 and the 5% in 1997, but only the 2% strength was approved for FPHL in 1997.⁶

The precise mechanism by which minoxidil induces hair growth is unknown. However, its vasodilatory, angiogenic, and enhanced cell proliferative effects are thought to be responsible. Minoxidil is an adenosine-triphosphate-sensitive potassium channel opener reported to stimulate the production of vascular endothelial growth factor, a possible promoter of hair growth.⁷ Minoxidil prolongs duration of anagen of the hair cycle and increases miniaturized hair follicle size in addition to its significant ability to maintain and thicken preexisting hair.⁸

Minoxidil’s efficacy in pattern hair loss has been proven in doubleblind, placebo-controlled trials. In men with MPHL, minoxidil showed a rapid increase in hair count and weight peaking at 16 weeks. The average increase in target area hair count is about 8% with minoxidil 2% lotion and 10-12% with the 5% formulation. About 60% of men demonstrated improvement with the 5% formulation and 40% with the 2% formulation compared with 23% of placebo.⁶

In women with FPHL treated with minoxidil 2% solution, a 10-16% increase in regrowth compared with controls was shown, while greater effects may be derived at the higher 5% concentration.⁹ This treatment is life-long and stopping minoxidil will shed all minoxidil-dependent hair growth within 4 to 6 months.⁶

The recommended dosing of either 2% or 5% minoxidil solution is twice daily application of 1 ml (25 drops) spread evenly over the entire top of the dry scalp. For the 5% foam formulation, half a capful is applied twice daily on the dry scalp and left in place for at least 4 hours. To minimize the risk of hypertrichosis of the face, especially in women, hands should be washed with warm water after application. The minoxidil 5% foam has only just recently become available in Canada as of November 2012.

Minoxidil has a well-established safety profile.¹⁰ Adverse effects are very infrequent and include skin irritation, contact dermatitis, facial hypertrichosis, scale, dryness, tachycardia, and transient increased hair shedding, which is more prominent in the first 4 weeks and results from induction of anagen from the resting phase. This may be viewed as an indication of minoxidil’s efficacy, as such, patients should be advised to continue with treatment even if this side effect occurs.

Constituents of the vehicle (e.g., propoylene glycol and minoxidil) can cause irritant contact dermatitis, allergic contact dermatitis, or exacerbation of seborrheic dermatitis, which are more common with the 5% solution. An allergic reaction to minoxidil itself is very rare; the more common contactant inducing pruritus and scaling of the scalp is propylene glycol.¹¹ The 5% foam vehicle is propylene glycol free and, hence, reduces the potential for irritation and improves cosmetic acceptability.¹² Patch testing for propylene glycol can be performed. If positive, a less irritating butylene glycol vehicle can be substituted. If the contact dermatitis is due to minoxidil, then treatment with this agent may have to be abandoned.

The side effect of hypertrichosis is more frequently seen in female patients who already have hirsutism. It mostly affects the forehead, malar areas and sides of the face, but is totally reversible with cessation of the drug.

Systemic absorption of minoxidil is weak, with only 0.3-4.5% reaching the circulatory system, and excreted within 4 days. No changes in blood pressure or other hemodynamic effects were shown with minoxidil use,¹³ however, caution should be exercised in patients with cardiovascular disease. Minoxidil has been assigned to pregnancy category C. Although there is no evidence of teratogenicity in rats and rabbits, studies are lacking in humans and it is secreted in human milk, therefore, use in pregnant or nursing women should be avoided.

Prostaglandins

Latanoprost and bimatoprost are prostaglandin analogues widely used to treat glaucoma and recently they have been investigated for eyelash alopecia. Studies have demonstrated variable success when used as eye drops to stimulate eyelash growth in alopecia areata.¹⁴ Although their mechanism of action is not fully understood, these compounds likely work by interacting with the prostaglandin receptors in the hair follicle and inducing anagen (growth phase) in telogen (resting phase) follicles.¹⁵

The rationale for use in alopecia areata was predicated on bimatoprost’s history of drug discovery. When administered as an eye drop for glaucoma, eyelash growth was noted in 42.6% of patients treated once daily for a year.^16,17 Initially, this effect was regarded as an adverse event, but the potential aesthetic benefits of eyelash growth were quickly recognized, leading to the development of bimatoprost for hypotrichosis of the eyelashes and culminating in US FDA approval for this indication in 2008.

A 24 week double-blind, randomized pilot study of 16 men with mild AGA showed a significant increase in hair density (terminal and vellus hairs) on the treated site with latanoprost 0.1% compared to baseline and the placebo-treated area.¹⁴ Treatment was well tolerated, although erythema at the application site was observed in 5 patients.

More data is required to determine the optimal concentrations of these prostaglandin analogues. Bimatoprost may eventually be more effective at the right titrated concentration.¹⁴

Fluridil

Fluridil is a synthetic novel topical antiandrogen that is similar in structure to flutamide. Fluridil is a highly hydrophobic, systemically non-resorbable compound that demonstrates local tolerance and degrades into inactive metabolites without systemic antiandrogenic effects.^18,19 In a double-blind, placebocontrolled study of 43 men with AGA, application of fluridil for 3 months resulted in increased anagen percentage from 76% to 85% in the fluridil treated group, and at 9 months to 87%, with no change in the placebo group. Sexual function, libido, hematology and blood chemistry values were normal over the duration of the investigation.¹⁹ Fluridil is being used throughout Europe but is still awaiting approval in the US.

Ketoconazole

Ketoconazole is an imidazole antifungal agent known to be effective for the treatment of seborrheic dermatitis and dandruff.²⁰ In a 21 month study comparing topical ketoconazole to minoxidil, the effect of ketoconazole 2% shampoo was compared to that of an unmedicated shampoo used in combination with or without minoxidil 2% therapy. Hair density and size as well as proportion of anagen follicles were improved almost similarly by both ketoconazole and minoxidil regimens.²⁰ The mechanism by which ketoconzole improves hair growth is unclear, but may be attributable to anti-inflammatory effects against T cells that are found in the balding area in AGA and activity against microflora of the skin by Malassezia. It also inhibits steroid synthesis and decreases DHT levels at the hair follicle by affecting androgen receptor activity.²¹

Spironolactone

Spironolactone is an aldosterone receptor blocker that reduces enzyme activity in the biosynthesis of testosterone. In a clinical study of 60 female patients with AGA, topical spironolactone 1% was found to be effective in promoting hair growth without hypotonia or hormonal disorders reported.²² However, larger studies are necessary to determine the antiandrogenic properties of topical spironolactone and its potential utility for FPHL.

Melatonin

Melantonin has long been known to modulate hair growth. Animal testing has shown that melatonin stimulates the anagen phase of hair growth.²³ In a double-blind, randomized, placebocontrolled study 40 women with diffuse alopecia (n=28) or AGA (n=12) were treated topically for 6 months with 1 ml daily of 0.1% melatonin-alcohol solution versus vehicle. Trichograms were used to determine efficacy in the frontal and occipital scalp areas. At the end of the study, the AGA group demonstrated a statistically significant increase in anagen hairs in the occiput region compared to placebo (mean 78 to 82 hairs), but no difference was shown with placebo in the frontal area.²⁴ The group with diffuse alopecia showed a substantial increase in frontal hair. Plasma melatonin levels were elevated under treatment with melatonin, but did not exceed the physiological night peak.

Estrogens

Systemic estrogens increase production of the glycoprotein sex hormone-binding globulin (SHBG), leading to a decrease in free testosterone. A 6 month study of a topical 17α-estradiol 0.025% preparation applied by 7 women with FPHL reported stabilization of hair loss and/or increased telogen hair shedding compared to 2 female control subjects.²⁵ More studies are warranted to validate the use of topical estrogens in AGA.

Conclusion

Although the clinical diagnosis of AGA can be easily made, the array of topical treatments remains largely investigational and demonstrates variable rates of response. Hence, extensive and well designed studies are needed to confirm their efficacy and safety. Early intervention may be important to limit the associated significant psychological morbidity. Novel and more effective treatments are in persistent demand and may be developed once the pathogenesis of AGA is better understood.

References

1. Gan DC, Sinclair RD. Prevalence of male and female pattern hair loss in Maryborough. J Investig Dermatol Symp Proc. 2005 Dec;10(3):184-9.
2. Budd D, Himmelberger D, Rhodes T, et al. The effects of hair loss in European men: a survey in four countries. Eur J Dermatol. 2000 Mar;10(2):122-7.
3. Shapiro J. Clinical practice. Hair loss in women. N Engl J Med. 2007 Oct 18;357(16):1620-30.
4. Price VH. Androgenetic alopecia in women. J Investig Dermatol Symp Proc. 2003 Jun;8(1):24-7.
5. Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol. 2005 Feb;52(2):301-11.
6. Banka N, Bunagan MJ, Shapiro J. Pattern hair loss in men: diagnosis and medical treatment. Dermatol Clin. 2013 Jan;31(1):129-40.
7. Li M, Marubayashi A, Nakaya Y, et al. Minoxidil-induced hair growth is mediated by adenosine in cultured dermal papilla cells: possible involvement of sulfonylurea receptor 2B as a target of minoxidil. J Invest Dermatol. 2001 Dec;117(6):1594-600.
8. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004 Feb;150(2):186-94.
9. Atanaskova Mesinkovska N, Bergfeld WF. Hair: what is new in diagnosis and management? Female pattern hair loss update: diagnosis and treatment. Dermatol Clin. 2013 Jan;31(1):119-27.
10. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebocontrolled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007 Nov;57(5):767-74.
11. Friedman ES, Friedman PM, Cohen DE, et al. Allergic contact dermatitis to topical minoxidil solution: etiology and treatment. J Am Acad Dermatol. 2002 Feb;46(2):309-12.
12. Blume-Peytavi U, Hillmann K, Dietz E, et al. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011 Dec;65(6):1126-34 e2.
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