¹University of Central Florida/HCA Healthcare Consortium, Tallahassee, FL, USA
²Dermatology Associates of Tallahassee, Tallahassee, FL, USA
³Florida State University College of Medicine, Tallahassee, FL, USA
^* Co-first authors

Conflict of interest: None.
Funding sources: None.
Disclaimer: This research was supported in whole or in part by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Abstract:
Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin. Several factors can precipitate SD development, such as colonization of Malassezia, sebocyte activity, impaired immunity, and environmental influences. Topical antifungals, corticosteroids, and calcineurin inhibitors are the current mainstay treatment of SD. Recent clinical trials have validated the efficacy of non-steroidal roflumilast 0.3% foam for the treatment of SD. In this review, we analyze the safety and efficacy profile of roflumilast 0.3% foam.

Keywords: seborrheic dermatitis, treatment, roflumilast, PDE-4 inhibitor

Introduction

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin.¹ While clinical presentations may differ, typical findings include erythematous, pruritic plaques and patches with a yellow, greasy appearance.^1,2 This condition can significantly impact quality of life due to activity limiting symptoms and emotional distress exacerbated by cosmetic ramifications.³ SD affects approximately 5% of the global population, whereas its non-inflammatory counterpart, dandruff, likely impacts closer to 50%.⁴ Despite such high prevalence, the pathogenesis and exact mechanisms via which these yeasts cause inflammation have yet to be fully elucidated.

Malassezia is a part of the human microbiome, interacting with the innate and acquired skin immune system. Innate immunity plays a critical role in initiating the initial immune response against Malassezia.⁵ Sensitization to Malassezia can cause a type I hypersensitivity reaction leading to redness, itching, and scaling.⁶ Further studies point towards Malassezia causing an irritant, non-immunogenic stimulation of the immune system, leading to complement activation and a localized increase in NK1+ and CD16+ cells.^7,8

Currently, there are many mainstay treatments for SD. Due to the underlying mechanism of Malassezia proliferation, most commonly topical antifungals are used for long-term treatment and topical corticosteroids and calcineurin inhibitors for short-term treatment (Table 1).¹ Due to the chronicity of SD, ongoing maintenance therapy is often necessary to achieve low recurrence rates of visible signs of the condition, as well as alleviate associating symptoms, such as pruritus.

Table 1

Phosphodiesterase-4 (PDE-4) inhibitors, including roflumilast, represent a significant advancement in the treatment of SD and other inflammatory conditions. These drugs work by inhibiting the PDE-4 enzyme, which plays a role in modulating inflammatory responses by breaking down cyclic adenosine monophosphate (cAMP).^9,10 Elevated levels of cAMP result in reduced inflammation, making PDE-4 inhibitors effective in managing various ongoing inflammatory disorders such as chronic obstructive pulmonary disease (COPD) and asthma.¹⁰ In dermatology, PDE-4 inhibitors have received regulatory approval in the US and Canada for plaque psoriasis, psoriatic arthritis, atopic dermatitis and, most recently, SD. They have shown promise in off-label treatment of a myriad of other inflammatory skin conditions. Apremilast is an oral PDE-4 inhibitor FDA-approved for psoriasis and psoriatic arthritis in patients ≥6 years of age. Crisaborole is a topical PDE-4 inhibitor, currently FDA-approved for atopic dermatitis in patients ≥3 months of age. Roflumilast has also demonstrated safety and efficacy in managing chronic inflammatory skin conditions, with the regulatory approval status in the US and Canada summarized in Table 2. Compared to currently available PDE-4 inhibitors, apremilast and crisaborole, used to treat skin disease, roflumilast has demonstrated greater selectivity and potency.^9,10

Table 2

Herein, the review will focus on the treatment of SD with a particular emphasis on roflumilast 0.3% foam.

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE-4.⁹ Inhibition of PDE-4 leads to an increase in cAMP and subsequent decrease in pro-inflammatory mediators such as interleukin (IL)-17, IL-23, tumor necrosis factor alpha, and interferon gamma.¹⁰

Clinical Trials

Phase 2¹¹

The Phase 2a study design was a parallel-group, double-blind, vehicle-controlled randomized clinical trial of once-daily roflumilast 0.3% foam. A total of 226 participants aged 18 or older were enrolled in the 8-week trial conducted at 24 sites in the US and Canada with a clinical diagnosis of SD for a 3-month long duration and affecting less than 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. Roflumilast 0.3% foam demonstrated a statistically significant increase in treatment success, with 104 participants (73.8%) achieving an Investigator Global Assessment (IGA) score of 0 or 1, compared to its vehicle. At week 8, 50 individuals (35.5%) attained an IGA score indicating clearance, while 54 patients (38.3%) achieved an IGA score signifying almost clear skin. In comparison, the vehicle group exhibited lower rates of improvement, with only 10 patients (15.2%) reaching clearance and 17 patients (25.8%) achieving almost clear status. Roflumilast patients exhibited significantly higher rates of erythema success, defined as an overall erythema score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline, compared to those treated with the vehicle. At weeks 2, 4, and 8, respective absolute differences were 16.6% (95% Confidence Interval (CI): 6.4%-24.8%), 25.2% (95% CI: 13.1%-34.9%), and 23.5% (95% CI: 9.6%-35.0%). Similar results were noted for scaling success, defined as overall scaling score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline. Statistically significant differences at weeks 2, 4, and 8: absolute differences were 11.8% (95% CI: -0.3% to 21.8%), 20.4% (95% CI: 6.8%-31.8%), and 28.8% (95% CI: 14.4%-41.0%), respectively. Overall, roflumilast 0.3% foam exhibited good tolerability, with a low occurrence of adverse events.

Phase 3¹²

The Phase 3 trial design was a parallel-group, double-blinded, vehicle-controlled, multicenter (50 centers) study with participants aged ≥9 years who were clinically diagnosed with SD affecting up to 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. 457 patients were randomly assigned in a 2:1 ratio to roflumilast (n = 304) or vehicle (n = 153). The primary endpoint was an IGA score of 0 (clear) or 1 (almost clear) and a ≥2-point improvement from baseline by week 8. The secondary endpoints included IGA success by weeks 2 and 4 and a ≥4-point improvement on the Worst Itch Numeric Rating Scale score (WI-NRS).

During this 8-week trial, a statistically significant amount of roflumilast treated patients (79.5%) achieved IGA success compared with vehicle (58.0%; P < 0.001). Roflumilast also demonstrated success at weeks 2 and 4, with percentages of IGA success of 43.0% versus 25.7% (P < 0.001) and 73.1% versus 47.1% (P < 0.001). At week 8, a higher percentage of patients treated with roflumilast (62.8%) achieved WI-NRS success compared to those treated with the vehicle (40.6%: P < 0.001), with improvement observed within 48 hours after the first application, respectively (Table 3).

Table 3

Safety and Tolerability

Overall, roflumilast 0.3% foam was well tolerated, and had similar rates of adverse events (AE) as the vehicle. During all phases of the study, there were no treatment emergent adverse events (TEAEs) reported as a direct result of roflumilast 0.3% foam treatment.^11,12 The most prevalent adverse reactions, observed in ≥1% of subjects across both Phase 2 and Phase 3 study groups included nasopharyngitis (1.5%), nausea (1.3%), and headache (1.1%).^11,12 Less frequent AEs included application site pruritus, application site pain, and diarrhea.^11,12 There were no significant differences between groups noted in clinical laboratory assessments. Vital signs, body weight, and body mass index indicated no clinically meaningful variations.¹² Moreover, evaluations for depression, suicidal ideation, and behavior revealed no safety concerns.¹²

Contraindications

Contraindications include individuals with a known hypersensitivity to roflumilast or any of the components in the formulation, as this can lead to severe allergic reactions. Additionally, patients with moderate to severe liver impairment (Child-Pugh B or C) should not use roflumilast, as it may exacerbate liver dysfunction.¹³ The coadministration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 may increase roflumilast systemic exposure and result in increased adverse reactions.¹³ It should be noted that no formal drug-drug interaction studies were done with topical roflumilast and these recommendations are based on oral roflumilast, which has a much greater bioavailability.

Regulatory Approval

The roflumilast 0.3% foam formulation was approved by the US FDA in December of 2023 and Health Canada in October 2024 for the treatment of SD in individuals aged ≥9 years.¹⁴ The medication is to be applied once daily to the affected areas, with the duration determined by the healthcare provider. One pressurized can of roflumilast 0.3% foam (60 g) contains 3 mg roflumilast per 1 g.

Discussion

Current first-line therapies for SD typically include topical antifungals and topical steroids (Table 1). These treatments are often readily available and affordable, leading to their widespread use. While these are effective in many cases, some individuals require a combination of multiple topicals for control which contributes to patient non-compliance due to complex treatment regimens.⁴ Moreover, these treatments may be ineffective in some individuals and can be associated with poor tolerability due to various AEs such as local skin reactions, burning, pruritus, and blistering.⁴

Roflumilast 0.3% foam provides an additional non-steroidal anti-inflammatory treatment option in those who have failed first-line therapies or prefer a once daily treatment regimen. It marks the first regulatory approved medication for SD with a novel mechanism of action in over two decades. This foam is uniquely formulated in a water-based emollient formula without skin irritating fragrances or alcohols such as, propylene glycol, polyethylene glycol, isopropyl alcohol, or ethanol.¹⁴ It is reported to be the first-in-class drug formulated with a novel emulsifier that lacks ceramide stripping properties. The hydrating features of the vehicle itself may add to its therapeutic effect. Moreover, the non-irritating, non-steroidal formula enables use anywhere on the body, including the eyelids and genitalia. The non-greasy foam formulation lends itself to use on hairy scalps.

Roflumilast may improve adherence and tolerance due to its once daily application, potent formulation, and minimal AEs. Its greater selectivity for PDE-4 than apremilast and crisaborole, likely contributes to its low side effect profile. Few patients reported stinging, burning, application site reactions, or application site pain with roflumilast.¹² Data from key trials reported IGA success, defined as IGA of 0 (clear) or 1 (almost clear) plus ≥2-point improvement from baseline in 80% of participants, with some reaching IGA success as early as weeks 2 and 4.¹² Pruritus, measured via the WI-NRS, improved as early as 48 hours after application. These results are in-line with other first-line therapies (Table 3).

With the continual push for more effective and safer therapies, roflumilast appears to be a useful agent added to the SD armamentarium.

Conclusion

Due to its minimal AEs and favorable tolerability, the novel roflumilast 0.3% foam offers a safe treatment for the erythema, scaling, and pruritus caused by SD. Its once daily application and potent formulation provides a convenient and effective treatment for SD. This treatment highlights the importance of continued advancement in the development of innovative therapies for SD as it is essential to improve outcomes and enhance the quality of life for individuals affected by this condition.

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¹University of Central Florida/HCA Consortium, Tallahassee, FL, USA
²Dermatology Associates of Tallahassee, Tallahassee, FL, USA
³Florida State University College of Medicine, Tallahassee, FL, USA

Conflict of interest: The authors have no conflicts of interest to declare. Funding sources: None.

Abstract:
Hidradenitis suppurativa (HS) is a severe, debilitating, chronic inflammatory skin disease characterized by recurrent painful nodules, abscesses and draining sinus tracts in intertriginous areas. While this condition appears to stem from follicular unit dysfunction, its cause is multifactorial and the exact pathogenesis has yet to be fully elucidated. These factors make treatment selection challenging and contribute to variable therapeutic response among affected patients. Typical regimens consist of a combination of medical and surgical modalities, tailored to individual responses. However, HS is often refractory to traditional treatments, prompting the need for newer and more effective therapies. Herein, we review current and emerging HS therapies.

Keywords: hidradenitis suppurativa, treatment, secukinumab, bimekizumab, izokibep, upadacitinib, povorcitinib, eltrekibart

Introduction

Hidradenitis suppurativa (HS) is a severe, debilitating, chronic inflammatory skin disease characterized by recurrent painful nodules, abscesses and draining sinus tracts.¹ The condition primarily affects intertriginous areas, often leading to permanent scarring and disfigurement. There is a strong psychosocial impact of the condition, with HS patients reporting high rates of depression, anxiety, social stigmatization, and shame leading to significant reductions in quality of life. While an estimated 1% prevalence rate is often described in literature, HS is thought to be widely underdiagnosed. The onset of HS typically occurs between ages 20-40 years with a 3:1 predilection for women over men and higher rates among those of African descent.¹ HS has been linked to genetic predisposition, skin microbiota, chronic inflammatory conditions, and hormonal factors, as well as environmental factors like obesity and smoking.²

Although the pathophysiology of HS has not been fully elucidated and is multifactorial, current evidence supports an inflammatory etiology with follicular unit dysfunction.³ The current driving theory suggests disease initiation is associated with a chronic subclinical inflammatory state and/or excess keratinocyte proliferation, which results in follicular occlusion and rupture with subsequent abnormal and diffuse inflammatory response. Recurrent events lead to the eventual loss of follicular structures and replacement with dense inflammatory infiltrates and scarring. Elevated levels of many pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-10, IL-17, and IL-23 have been observed in blood and skin biopsy samples of HS patients, further implicating immune dysregulation. There is welldocumented evidence regarding positive feedback loops where IL-17 interactions with other cytokines (namely IL-1, IL-6 and TNF-α) lead to further auto-production of these cytokines as well as downstream activation of acute phase reactants, neutrophilic and complement mediated inflammatory responses.³ It should be noted that while the primary driver of HS is not infectious, bacterial colonization of lesions can complicate acute flares and worsen symptoms.

Current Management in HS

The management of HS involves a multimodal approach including lifestyle modifications, such as weight loss and smoking cessation, various medical/surgical therapies and psychological support. The efficacy of medical therapies depends largely on disease severity and, thus, clinical grading using the Hurley staging system can guide medical decision making. This system is universally accepted and classifies stage 1 (mild) as abscess formation without scarring, stage 2 (moderate) as recurrent abscesses with limited scarring and/or sinus tracts and stage 3 (severe) as diffuse involvement with extensive scarring and/or interconnected sinus tracts.¹ The mainstay of medical management in mild-to-moderate disease is oral antibiotics and topical therapies, with consideration of hormonal treatments and systemic retinoids as adjunctive therapy.⁴ Intralesional or systemic steroids are often used for acute flares. For more severe, extensive disease, however, these regimens are rarely sufficient and immunomodulatory agents should be introduced. Currently, there are two biologics approved in the US for HS treatment: adalimumab, a monoclonal antibody (MAb) that targets TNF-α, and secukinumab, an IL-17A inhibitor.

Topicals

For mild disease, topical clindamycin is considered a first-line treatment option that can reduce bacterial colonization and inflammation within HS lesions.⁴ Based on low-level evidence involving 30 patients, topical clindamycin use decreased pustules by approximately 95% after 3 months of treatment, but had no significant effect on deeper abscesses or nodules.⁵ Resorcinol is a topical keratolytic and anti-inflammatory that has shown some benefit for pain and lesion reduction in small studies, though data is limited. Of note, resorcinol is only available in the US through compounding pharmacies, further limiting its practicality. Overthe- counter cleansers containing chlorhexidine, benzoyl peroxide or zinc pyrithione, while not evidence-based, are commonly used in clinical practice as adjunct maintenance therapy across all disease stages.⁵

Systemic Antibiotics

Based on North American clinical guidelines published in 2022, oral tetracyclines or clindamycin plus rifampin are two antibiotic regimens that are generally recommended as first- or secondline options in HS management.⁴ While quality evidence is lacking across the board, previous case series have demonstrated meaningful clinical improvement with these antibiotics. A recent prospective cohort study involving 283 patients (majority with moderate or severe HS) is the first and only to compare the two antibiotic regimens head-to-head over 12 weeks.⁶ Investigators found that while a large proportion of both groups achieved 50% or greater reduction from baseline in the total abscess and inflammatory nodule count and remission, there was no significant difference between the oral tetracyclines group (40.1%) and clindamycin plus rifampin group (48.2%, P=0.26). Another recent study in 28 Hurley stage 1 HS patients reported the efficacy of combination rifampin-moxifloxacin-metronidazole therapy.⁷ They observed that 75% of patients achieved clinical remission of all lesions at 12 weeks of treatment. After the initial 12-week study period, those who achieved remission were switched to a low dose maintenance regimen of cotrimoxazole and at 1-year follow up experienced significantly less flares (average of 1/year vs. 21/ year before treatment). Substantial gastrointestinal side effects and remission rates, as well as concern for bacterial resistance, may limit long-term antibiotic use.

Adjunctive Oral Agents

While hormones are thought to play a role in HS, there have not been many studies on the efficacy of hormonal therapies in this setting. Current guidelines state that estrogen-containing contraceptives and anti-androgens therapies like spironolactone, metformin and finasteride can be considered in women, namely those with comorbid polycystic ovary syndrome and/or reported HS flares around menses.⁴ Similarly, oral retinoids can be considered if adequate control is not achieved with other therapies, as an adjunct, or in patients with concomitant nodulocystic acne. Results from small studies have been mixed and show modest improvement in milder disease.⁴ Finally, those with HS have high risk of certain vitamin and mineral deficiencies, such as vitamin D and zinc. Two case series have shown modest clinical improvements with zinc supplementation.⁸ While zinc supplementation can be considered in patients, there is insufficient evidence to recommend vitamin D supplementation based on North American guidelines.⁸

Surgery

Surgical intervention is often necessary with advanced disease refractory to medical management to address tunnels and chronic scarring. The options are beyond the scope of this review, but include laser therapies, deroofing and surgical excision. These procedures come with their own set of risks and even after radical excision, it is reported that nearly a third of patients still experienced disease recurrence.⁹

Biologics

Biologic therapies are recommended for patients with mildmoderate disease that previously failed first-line therapies or as first-line therapy in individuals with moderate-severe disease.⁴

Adalimumab (Selective TNF-α Inhibitor)

Until very recently, adalimumab was the only approved treatment of HS. In two phase 3 trials, Pioneer I and II (n=633), 316 patients were randomized to receive 40 mg adalimumab once weekly.¹⁰ Pooled data of the trials demonstrated a modest but significant clinical improvement at week 12 with 50.6% of patients in the treatment group achieving Hidradenitis Suppurativa Clinical Response score of 50 (HiSCR50, reduction of at least 50% in the total abscess and inflammatory nodule count, with no increase in abscess or draining tunnel count) compared to 26.8% receiving placebo. Additional surveillance as part of an open-label trial extension demonstrated sustained results on weekly adalimumab with HiSCR50 of 52.3% at week 168.¹¹ During this period, about 15% of patients experienced adverse events leading to discontinuation of the drug. While efficacious, this leaves about half of patients without adequate response. Other TNF-α inhibitors used in HS face the same challenges, including infliximab and etanercept.

Secukinumab (Selective IL-17A Monoclonal Antibody)

In October 2023, the FDA approved the expanded label of secukinumab to cover moderate-to-severe HS in adults. This decision was based on results from two major phase 3 randomized controlled trials (RCT)12 showing promise of subcutaneous secukinumab in patients with moderate-to-severe HS. SUNSHINE (n=541) and SUNRISE (n=543) included a placebo-controlled study period of 16 weeks, followed by long-term treatment without placebo to 52 weeks. In both trials, significantly more patients receiving secukinumab biweekly achieved HiSCR50 at 16 weeks when compared to placebo (42-45% vs. 31-34%). Response rates were sustained and even increased throughout the study period, with 56% of patients in SUNSHINE and 65% in SUNRISE achieving meaningful clinical response as well as significant pain reduction at 52 weeks. Roughly 84% of participants experienced an adverse event, though the great majority were minor with the most common being headache (10%) followed by nasopharyngitis and worsening of HS.

Emerging Biologic Therapies in HS

While the aforementioned therapies have been efficacious, there are many treatment gaps that highlight the need for better options. For one, HS is biologically complex and driven by multiple mechanisms that differ from individual to individual, as evidenced by significant variations in disease severity and lack of response to treatment in many. This warrants a shift away from a ‘one size fits all’ or random trial-and-error treatment algorithm, but rather a personalized approach that caters to the specific markers expressed in each patient. Even for those who achieve excellent results on medication, there is high probability of eventual recurrence, likely related to the fact that current treatment options do not address the underlying causes of HS.

Given the need for further therapeutic options in HS, a plethora of targets are currently being explored, including other inflammatory cytokines (IL-1, IL-17, IL-23), neutrophils, the complement pathway, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The remainder of this paper will focus on the efficacy and safety of these drugs from recent phase 2 and 3 clinical trial results. Unless otherwise stated, the primary trial endpoint was HiSCR50. Additional endpoints could also include HiSCR of 75%, 90% and/or 100%. Participants included those with moderate-to-severe HS, defined as Hurley stages 2 or 3. The main points of these clinical trials and next steps are summarized in Table 1.

IL-17 Inhibitors

Bimekizumab (Dual IL-17A and IL-17F MAb)

Bimekizumab is a MAb that selectively targets IL-17F, in addition to IL-17A. Since both subunits independently cooperate with other inflammatory mediators like IL-1 and TNF-α to drive the chronic inflammatory cascade and tissue destruction seen in HS, bimekizumab’s efficacy profile has been hypothesized to be more favorable than IL-17A inhibitors alone.

In recently released data from BE HEARD I (n=505) and BE HEARD II (n=509) phase 3 trials,¹³ those receiving bimekizumab biweekly achieved statistically significant improvements over placebo in HS severity (HiSCR50 48-52% vs. 29-32%, placebo) and self-reported quality of life at week 16, which was sustained out to 48 weeks without any unexpected safety concerns. According to a March 2023 late-breaking presentation at the annual American Academy of Dermatology (AAD) conference, in an observed case analysis of the two trials combined, over 55% of patients on continuous bimekizumab achieved the higher benchmark of HiSCR75 at week 48.¹⁴

Izokibep (Non-MAb IL-17A Inhibitor)

Izokibep is a novel fusion protein that may address several shortcomings of some other MAbs. The molecule is about oneeighth the size of a traditional MAb, which is thought to allow for high drug exposure levels and deeper tissue penetration. Additionally, izokibep is produced in an inexpensive Escherichia coli (E. coli) system versus the costly mammalian expression systems that MAbs are routinely manufactured in, which could translate into a more affordable treatment option.¹⁵

Data from a small open-label part A of phase 2b/3 trial (n=30) presented at the AAD conference in March 2023 observed 65% of participants achieved HiSCR50 at 12 weeks.¹⁶ Further, about 1 in 3 patients had complete clearance of abscesses and inflammatory nodules (HiSCR100) by week 12. The drug was generally welltolerated, with localized injection site reaction as the most common adverse event. The double-blind, placebo-controlled part B of this phase 2b/3 trial is currently ongoing with plans for an additional phase 3 trial. These results will be much more telling.

Janus Kinase Inhibitors

Expression of genes in the JAK-STAT pathway transduce proinflammatory cytokine signals like IL-6, IL-23, and interferons which have been shown to be upregulated in sites affected by HS,¹⁷ making for a potential therapeutic target. Currently, JAK inhibitors are mainly used in rheumatological conditions, but are increasingly being used and studied across a broad spectrum of dermatological disorders including atopic dermatitis, psoriasis, alopecia areata and vitiligo.¹⁸ Still, there is very limited published clinical data in the use of these drugs for HS specifically. A literature review published in April 2023 included 25 articles using JAK inhibitors in HS patients, mainly small case series and reports, and concluded encouraging findings of their efficacy and safety in this setting thus far.¹⁷ Several clinical trials are currently ongoing and upcoming to further investigate.

Upadacitinib

Results from a phase 2 RCT¹⁹ presented at AAD in March 2023 showed that 38.3% of 41 patients treated with daily oral upadacitinib achieved HiSCR50 at week 12, compared to 23.8% of the placebo group. Response rates were sustained through week 40 with no new safety concerns. They also reported similar efficacy rates in those who had previously failed anti-TNF biologics (HiSCR50 41.7%) and TNF-naïve patients (HiSCR50 37.1%). It should be noted that results were only statistically significant when compared to historic placebo levels from previous trials, but not when compared to the placebo arm within the same study.

Povorcitinib

In 2022, a phase 2 RCT²⁰ that spanned 16 weeks and enrolled 209 patients with HS of any Hurley stage met its primary endpoint of statistically significant decreases from baseline abscess and inflammatory nodule count at all three tested dose levels (povorcitinib 15 mg, 45 mg, 75 mg) compared to placebo with no new safety concerns. Early 2023, new 52-week results²¹ were presented at the European Academy of Dermatology and Venereology Congress as part of the open-label extension period in which all 174 qualifying patients received povorcitinib 75 mg daily. Nearly 30% of patients had 100% clearance of abscesses and inflammatory nodules (HiSCR100) by week 52. Additional 52-week efficacy results include HiSCR50 and HiSCR75 values of roughly 60% and 50%, respectively. Stop-HS1 and Stop-HS2 are two phase 3 RCTs currently recruiting 600 patients each with results expected in 2025 and would be the largest HS drug trial to date.

Chemokine Receptor (CXCR) Inhibitors

Eltrekibart (LY3041658) is a MAb that selectively binds to the ligands that signal CXCR1 and CXCR2. These chemokine receptors are known to play a role in neutrophil migration to areas of inflammation, which is a key aspect in the pathogenesis of HS.²² Phase 2 RCT trial (n=72) data was presented at the AAD in March 2023 where 66% of patients receiving eltrekibart biweekly achieved HiSCR50 at 16 weeks compared to 41% in the placebo arm.²³ These improvements were sustained in the treatment group to week 36. While these results are quite favorable, further quantification of safety and efficacy will need to be determined in a subsequent phase 3 trial which has not yet been announced.

Upcoming Notable Clinical Trial Results

An additional IL-17 inhibitor worth mentioning is sonelokimab, which incorporates specific desirable features of both bimekizumab and izokibep. Similar to izokibep, sonelokimab uses newer nanobody biotechnology for better drug delivery and enhanced tissue penetration while also having dual targets of IL-17A and IL-17F, like bimekizumab.²⁴ A phase 2 RCT, the MIRA trial, comprising 210 patients is currently underway testing two doses of sonelokimab compared to placebo and adalimumab.²⁴ Notably, this is the first time that a HS trial has the higher benchmark of HiSCR75 as the primary endpoint; 57% of patients achieved HiSCR75 at 24 weeks.

The same company developing secukinumab for HS, has testing underway for several other targets in HS. A phase 2 RCT is recruiting 200 individuals to determine the safety and efficacy of five different drugs for moderate-to-severe HS: Bruton’s tyrosine kinase (BTK) inhibitor, leukotriene A4 hydrolase (LTA4H) inhibitor, CD40 MAb, T-cell immunoglobulin and mucin domain 3 (TIM-3)/ IL-1β/IL-18 MAb, and anti-B-cell activating factor (BAFF) receptor MAb.²⁵ LTA4H, BTK and TIM-3 all play a role in inflammation, though have not been tested previously as targets for HS therapy.

Additional clinical drug trials with results expected in the near future are summarized in Table 2.

Conclusion

The management of HS is a challenge, in part due to its chronic and variable nature with a poorly understood pathophysiology. Further, delays in diagnosis can lead to disease progression and extensive scarring which creates another layer of complexity in treatment. In addition to its painful dermatologic implications, HS is associated with many comorbidities including inflammatory bowel disease, psoriasis, and metabolic syndromes, as well as significant mental health burden with increased depression, anxiety and suicide rates observed.²⁶ While the existing standard management with antibiotics and topicals with steroids for flares can be sufficient for mild disease, more intensive measures involving surgery and/or biologic drugs are frequently required in more severe cases.

An improved understanding of the disease mechanisms and wider range of biologic therapies aimed at these underlying inflammatory pathways and specific pathophysiology of HS is poised to create a major shift in this management conundrum. Currently, only two biologics are approved for HS. Adalimumab has demonstrated its effectiveness and sustained response in over half of individuals with moderate-severe HS across several studies. However, even in responders, complete remission is uncommon, and an even larger treatment gap exists when adalimumab fails or is contraindicated. Notwithstanding, the recent approval of secukinumab has the potential to change clinical practice by offering meaningful and durable improvement of symptoms.

Furthermore, a number of alternative biologics are being studied in HS with different targets including inhibitors of IL-17, IL-1, chemokine receptors and the JAK pathway, to name a few. The drugs discussed within this paper are furthest along in the pipeline and recent favorable phase 2/3 trial data indicate support for positive regulatory decisions in the coming future. While these therapeutics will undoubtedly bring value to patients, there remains a need for personalized medicine through enhanced insight into the etiology and progression of HS, along with identifying optimal targets. The further development of new therapies for the treatment of HS is crucial in continuing to improve outcomes and quality of life for patients with this debilitating disease.

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¹Center for Clinical Studies Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Texas A&M University College of Medicine, Temple, TX, USA
⁴University of Texas Health Science Center, Department of Dermatology, Houston, TX, USA

Conflict of interest: All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand how dermatologists can combat this issue.

Keywords: antibiotic resistance, dermatology, antibiotic, antimicrobial, infection, acne, rosacea, hidradenitis suppurativa, folliculitis decalvans, bullous pemphigoid, CARP

Introduction

There are many reasons for the development of antibiotic resistant bacteria. Aside from rampant use in agriculture settings, poor antibiotic stewardship among physicians is a major contributor. Dermatologists play an essential role in this process given the significant incidence of inflammatory dermatoses, as well as skin and soft tissue infections (SSTIs) treated with antibiotics. Furthermore, dermatologists have a higher rate of prescribing antibiotics compared to other specialists.¹ Therefore, it is crucial for dermatologists to understand strategies to combat bacterial resistance and reduce its global burden.

Combating Antibiotic Resistance in Dermatology

Molecular resistance is perpetuated through poor antibiotic stewardship. Commonly, this stems from unclear instructions on self-administration of antibiotics, use of sub-antimicrobial dosing, prescription of antibiotics for minor bacterial infections, use of antibacterial drugs for non-bacterial infections, and use of broad-spectrum antibiotics for narrow-spectrum indications.²

General methods for diminishing risk of antibiotic resistance include detailed history and physical, diagnostic laboratory and culture studies, close monitoring of clinical response, appropriate directed-therapy when the causative organism is identified, relevant empiric treatment based on local antimicrobial susceptibilities within the community, and continuing therapy for the appropriate duration.³ All of these general precautions, as well as discontinuing of antibiotics when deemed unnecessary, will aid to reduce the rate of antibiotic resistance.³

In the United States, individuals with acne vulgaris and rosacea account for 20% of the patients prescribed antimicrobials in dermatology.⁴ SSTIs account for a significant amount of the remaining portion. Specific strategies can be utilized to combat emerging resistance in the treatment of acne vulgaris, rosacea, hidradenitis suppurativa (HS), folliculitis decalvans (FD), bullous pemphigoid (BP), and confluent and reticulated papillomatosis (CARP) and SSTIs.

Acne Vulgaris

Antibiotic monotherapy is not recommended for acne vulgaris treatment. Both topical and systemic monotherapy may induce resistance among Cutibacterium acnes (C. acnes) and other organisms that comprise the commensal and transient flora.⁵ The American Academy of Dermatology (AAD) guidelines recommend coadministration of benzoyl peroxide, a topical bactericidal agent not reported to cause resistance, together with both topical and oral antibiotics.^6,7 Added to topical antibiotics, benzoyl peroxide may prevent the formation of resistance and increase treatment efficacy.⁶ Only indirect evidence supports the ability of benzoyl peroxide to limit resistance when used with oral antibiotics.^6,8 Additionally, the AAD recommends using the shortest possible courses, limiting antibiotic use to 3-4 months.⁷

Low-dose or “sub-antimicrobial” doses of doxycycline have been used in rosacea and acne vulgaris, with the intention to only derive benefits from the anti-inflammatory properties of the antibiotic.^2,9,10 However, contrary to the common belief, recent studies demonstrated that low-dose antibiotic exposure leads to the development of high-level resistance.^2,9,11

A unique method being utilized to bypass bacterial resistance in acne is the development of narrow spectrum drugs such as the new tetracycline, sarecycline. Sarecycline is a US FDA approved therapy specifically designed to treat moderate-severe acne and is the only antibiotic with a low resistance claim in its label.² It is narrow spectrum with coverage limited to clinically relevant gram-positive organisms, including C. acnes. Its structural design involves an elongated C7 moiety that extends into the 30S ribosome and directly interferes with mRNA unlike typical tetracyclines.² This newer design allows for stronger binding and increased inhibitory effects.

Rosacea

The large body of evidence supporting an inflammatory pathogenesis of rosacea not triggered by a bacterial etiology has led to rosacea management guidelines that support avoidance of antibiotics whenever possible.⁵ This includes the papulopustular subtype. Antibiotics should only be used after failure of topical and oral anti-inflammatory therapy.¹² Like acne, if antibiotics are used, the course should be as short as possible with treatment for no longer than 2 months.¹²

Hidradenitis Suppurativa (HS)

Given that topical clindamycin and oral tetracycline are firstline therapies for HS, it is not surprising that a high percentage of HS patients harbor lincosamide and tetracycline resistant bacteria.¹³ Therefore, it is recommended that antibiotics be used as adjunctive therapy with other management options, including chlorhexidine or benzoyl peroxide wash, adalimumab, smoking cessation, weight loss, and other non-antimicrobial treatments.^13,14

Folliculitis Decalvans (FD)

A small study of patients with FD who received one or more courses of antibiotic therapy demonstrated a third of patients harbored antibiotic resistant Staphylococcus aureus (S. aureus).¹⁵ The resistance rates in FD patients were significantly higher than the community reference values.¹⁵

Given FD is thought to stem from S. aureus, antibiotic therapy will likely remain the gold standard for exacerbations.¹⁵ However, treatments should be based on bacterial culture/sensitivities, with the aim to transition to nonantibiotic medical therapies (isotretinoin/dapsone/photodynamic therapy) or destructive therapies (laser hair removal/surgery) to suppress inflammation and address hair follicle structural abnormalities and biofilm formation to induce long-term remission.^15,16

Bullous Pemphigoid (BP)

Although topical and systemic steroids are considered the first-line treatment for BP, the substantial morbidity and mortality associated with these regimens presents a therapeutic challenge. Inasmuch, other treatment options are being sought. Among the plethora of agents trialed have been antibiotics, most notably tetracyclines given their anti-inflammatory properties. While some trials have concluded that systemic tetracyclines are effective in BP treatment, they are inferior in recovery rate when compared to systemic steroids.¹⁷ Moreover, those with milder BP and shorter courses of tetracyclines tend to achieve a lower proportion of remission than those with severe disease, indicating that disease severity and the potential need for prolonged treatment should to be taken into account before initiation.¹⁸ Therefore, judicious consideration is needed before placing patients on antibiotics for BP treatment. In general, tetracyclines may be appropriate in older patients with comorbidities that contraindicate systemic steroid use.¹⁸

Confluent and Reticulated Papillomatosis (CARP)

Oral tetracyclines are the most commonly cited monotherapy for CARP; minocycline is utilized most frequently, but other antibiotics used include amoxicillin and azithromycin.¹⁹ Evidence suggests dysfunctional keratinization as a cause of CARP, and this is supported by successful treatment with both topical and oral retinoids.²¹ Efficacy of this treatment is attributed to the anti-inflammatory and immunomodulating properties of retinoids and normalization of keratinization.²⁰ Advantages of retinoid therapy include higher patient compliance and decreased side effects.²⁰ Other treatment options that have demonstrated clinical effects include topical vitamin D derivatives.¹⁹

Skin and Soft Tissue Infections (SSTIs)

Resistance has emerged against many commonly used topical and oral antibiotics for SSTIs. This is likely a result of overuse and misuse.

Topical

Prophylactic use of topical antibiotics after surgical procedures is often unnecessary. A meta-analysis based on data pooled from four studies failed to demonstrate a statistically significant difference between application of topical antibiotics versus topical petrolatum/paraffin in preventing post-surgical infections after low risk office-based dermatologic procedures.^5,22 Low risk procedures include those with clean and clean-contaminated wounds, and following procedures in patients that are immunocompetent and not at high risk of infection, surgeries performed in regions above the knee, and surgeries not involving the groin, ears, or mucosal region of the nose or mouth.⁵ In cases where risk of post-operative infection is high, it is a better choice to utilize oral antibiotic prophylaxis, as topical therapy alone is not as likely to provide adequate prevention of infection.^5,23

Other prophylactic uses of topical antibiotics, such as with atopic dermatitis (AD), have not demonstrated efficacy either. When a cutaneous infection is present, antibiotic therapy is therapeutically beneficial in AD.¹⁸ However, chronic topical or oral antibiotic therapy is not advised to manage or suppress AD in the absence of a true skin infection, and it serves only to promote antibiotic resistance.¹⁸

Another factor to keep in mind is that topical antibiotic therapy is capable of inducing antibiotic resistance beyond areas of application.⁵ Topical erythromycin used on the face induced resistant C. acnes and staphylococci on the back and anterior nares where it was not applied.²⁴ Similar results have been demonstrated with other bacteria such as streptococci.⁵

Mupirocin resistance has reached up to 80% among bacterial strains such as S. aureus in certain communities with heavy usage.^13,25 Low resistance alternatives are fusidic acid and topical pleuromutilins.¹³ Moreover, regular local antiseptic treatment including octenidine or polyhexanide is broadly efficacious and confers a significantly lower risk of resistance relative to topical antibiotics.²⁶

Systemic

Prophylactic oral antibiotics are rarely appropriate for routine dermatologic surgery and are not indicated for patients who have prosthetic joints or vascular grafts.²³ It is recommended only for a small group of patients that have abnormal cardiac valves, and then only with surgery involving clearly infected skin or soft-tissue.²³

Controlled trials indicate that antimicrobial agents are unhelpful in treating cutaneous abscesses, inflamed epidermal cysts, uninfected atopic eczema, and cutaneous ulcers caused by venous insufficiency or diabetes in the absence of significant contiguous soft-tissue inflammation.²³

Between 5-10% of the North American population is classified as beta-lactam allergic.²⁷ However, only 10% of these can be confirmed by allergy diagnostics.²⁷ A false beta-lactam allergy diagnosis may lead to inappropriate use of broad spectrum antibiotics. Common reasons for a false beta-lactam allergy include misinterpretation of known predictable side effects, misinterpretation of infection-induced urticaria or viral exanthema as an immediate type drug reaction or drug exanthema; interpreting non-specific symptoms as an allergy, and considering known reactions in the family as signs of personal allergy.²⁷ To verify a true beta-lactam allergy, risk stratification of all patients should be performed. Patients with a questionable allergy may be excluded based on history alone.²⁷ Patients with an incomplete history or mild reaction may be tested on a case-by-case basis.²⁷ Patients with a medical history strongly suggesting a true allergy should undergo formal testing through a skin test (skin prick, intradermal/patch), lab test (specific immunoglobulin E, basophil activation test), and/or oral provocation test with fractionated administration of beta-lactam.²⁷

Future Directions

To confront the challenge of resistance, modification of existing antibiotics to improve potency and efficacy is underway.¹³ Additionally, development of new narrow spectrum agents with novel mechanisms of action is being pursued.¹³ Given that drug development is a slow process, it cannot keep up with the spread of resistant bacteria. Therefore, alternative methods are under investigation.

One promising avenue is modulation of the skin microbiome.¹³ Abnormalities in the skin microbiome have been observed in patients with acne.^13,28 Treatment with isotretinoin in these patients restored microbiomes to normal.²⁸ Thus, infectious and inflammatory dermatoses may respond to direct manipulation of the skin microbiome via live biotherapeutic products or transplantation of human skin microbiota.¹³ Recent trials have already demonstrated success in treating AD with skin microbiota transplantation.²⁹

Another alternative gaining traction is phage therapy, which uses bacteriophages to infect and lyse bacteria.^13,30 Recent studies have reported successful use of personalized bacteriophage therapy in patients with multidrug-resistant infections.³¹

Further strategies include implementation of electroporation, antimicrobial peptides, photodynamic therapy (PDT), photothermal therapy, nitrous oxide-releasing nanoparticles, cannabidiol, or combinations of these options.³² PDT is a therapeutic option for cutaneous infections immune to antibiotics. PDT use in acne results in reduced follicular obstruction and lower sebum excretion.³² At higher doses, it can destroy sebaceous glands.³² For cutaneous leishmaniasis and warts, PDT has demonstrated clearance rates of up to 100%.³² PDT has also been initiated as a treatment option for onychomycosis.³² Transdermal iontophoresis has been coupled with PDT to increase its effectiveness.³² It uses small electrical currents to permit controlled drug delivery and use of smaller drug concentrations.³² Its use has demonstrated broad spectrum antimicrobial efficacy against bacteria, fungi, and viruses.

Conclusion

Correct and appropriate use of antibiotics will help to preserve their utility in the face of increasing antibiotic resistance; however, greater awareness of the etiologies of resistance and how to combat each is required among prescribing providers.

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¹Center for Clinical Studies, Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand the mechanisms at play that contribute to resistance.

Key Words:
antibiotic resistance, dermatology, mechanisms of resistance, antibiotic, antimicrobial, infection

Introduction

The advent of antibiotics is arguably one of the greatest achievements in history, permitting survival among many with infections who would have previously died without intervention. Amid the fields in which the use of antibiotics is particularly widespread lies dermatology. A spectrum of inflammatory and infectious dermatologic conditions have been treated with antibiotics since their inception. The continued success of any therapeutic agent is compromised by the potential development of tolerance or resistance to that compound over time.¹ In the case of antibiotics, resistance among bacteria has become a serious issue and has been named one of the greatest threats to human health.² The number of infections caused by multidrug-resistant bacteria is increasing, and the specter of untreatable infections is now a reality.² As this number increases, new antibiotic developments cannot match the pace.²

While many factors contribute to the development of resistance, its basis stems from bacterial alterations at the molecular level. Therefore, it is important for dermatologists to understand the mechanisms at play.

Brief Review of Antibiotics in Dermatology and Mechanism of Action

Many antibiotics are utilized in dermatology. Countless isolates of bacteria may cause skin and soft tissue infections (SSTIs) resulting in a wide variety of clinical presentations. Most commonly, superficial cutaneous infections and pyodermas are caused by Staphylococcus aureus (S. aureus) resulting in impetigo, ecthyma, folliculitis, intertrigo, and paronychia. However, other bacterial organisms may also be responsible. Deeper infections like cellulitis, erysipelas, and necrotizing fasciitis are also classically caused by S. aureus or Streptococcus pyogenes, but are also commonly caused by a variety of other gram-positive and negative organisms. Antibiotics may also be used for anti-inflammatory effects, such as with the treatment of acne vulgaris, rosacea, folliculitis decalvans, and hidradenitis suppurativa.

Given the wide variety of conditions treated with antibiotics, nearly the entire gamut may be utilized by dermatologists at some point in time. Understanding the antibiotic mechanism of action is key to understanding mechanisms of resistance (Figure 1, Table 1).

Mechanisms of Resistance

Mechanisms by which bacteria evade antibiotic destruction vary in complexity. The most basic method involves mutations in the bacterial target gene, creating a mutant target protein that prevents interaction with the antibiotic, rendering it ineffective.² Given the intrinsic error prone process of DNA replication/ repair, this type of resistance is inevitable as mutations are bound to occur.³ Resistance may also occur through acquisition of genes encoding proteins that reduce antibiotic binding to molecular targets.² Bacteria can produce enzymes capable of manipulating molecular targets and blocking antibiotics from binding.² In addition to modifying the molecular target, bacteria can also reduce the concentration of antibiotics through chemical or enzymatic modification.² Finally, if an antibiotic target comprises an entity other than a single gene product, resistance to these drugs is attained via retrieval of pre-existing diversity in cell structures and altering their biosynthesis through global cell adaptations.^2,3

Modification of Antibacterial Target

Bacteria are capable of modifying any protein that an antibiotic might target.⁴ Among the most popular antibiotic protein targets is the bacterial ribosome, a complex protein producing machine.⁵ Bacterial ribosomes consist of dozens of proteins that are arranged into large (50S) and small (30S) subunits.⁶ Each subunit is associated with specialized ribosomal RNA (50S – 23S, 5S; 30S – 16S). Ribosomes produce proteins through translation – a three-step process: initiation, elongation, and termination.

By targeting ribosomal proteins, antibiotics block protein synthesis in bacteria thus halting proliferation. To survive, bacteria have evolved mechanisms to elude antibiotic protein targeting.

Target Protection

Target protection is a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition.⁵ Target protection is an important mode of bacterial resistance to many antibiotics used in dermatology, especially against tetracyclines.⁷

To disrupt tetracycline action, bacteria deploy ribosomal protection proteins (RPPs) Tet(O) and Tet(M).⁵ Both of the RPPs are hydrolases that become active in a tetracycline dependent manner. When tetracycline interacts with its ribosomal target, it induces changes in the cellular environment that results in increased affinity of the RPPs to the antibiotic-30S structure.⁵ The RPPs then hydrolyze antibiotic-30S bonds, dislodging the tetracycline, which permits normal protein synthesis to resume.⁵

Target Site Modification

By design, antibiotics are selective of target structures. When target structures are modified, chemical properties are altered which change antibiotic target affinity.² For organisms to survive with resistance, these modifications must result in a loss of target affinity while still maintaining adequate function of normal activities. Most often, this is accomplished by point mutations in genes encoding target sites, enzymatic alterations of binding sites, and replacement or bypass of target sites.²

Mutations of Target Site

Mutations of the 16S portion of the 30S ribosomal subunit target site are the most common form of resistance to aminoglycosides.⁸ Macrolides are also resisted via target site mutations. The 23S portions of the 50S ribosomal subunit targeted by macrolides can undergo multiple viable mutations.³ Quinolone resistance can occur through target mutation.⁹ Quinolone resistance determining regions (QRDR) are target gene sequences susceptible to viable mutations that decrease quinolone target affinity.¹⁰ Specifically, substitutions in the gyrA and gyrB sequences affect DNA gyrase, while substitutions in parC and parE affect topoisomerase IV.¹⁰

Enzymatic Alteration of Target Site

Many different enzymes play a role in antibiotic resistance. One method by which enzymes contribute is through modification of the target site, which results in decreased antibiotic affinity similar to target site mutations. Methylation of strategic nucleotides in the antibiotic binding site weakens antibiotic binding via steric clashes with the modified nucleotide.¹¹ Since some antibiotics share partially overlapping binding sites, methylation of a single nucleotide can result in resistance to multiple antibiotic classes.¹¹

Enzymatic methylation of the ribosome confers resistance to many antibiotics that target the 23S portion of the 50S subunit. Moreover, a specific family of genes encoding for enzymatic methylation may confer resistance against multiple antibiotics that share the same ribosomal binding region.¹² For example, the erythromycin ribosomal methylation (erm) gene confers cross resistance to macrolides, lincosamides, and streptogramin B which all bind the same ribosomal site.² This gene is commonly found in gram-positive cocci and is shared among bacteria via plasmids and transposons. The cfr gene functions similarly to erm, producing a methylation enzyme that provides resistance among gram-positive and gram-negative organisms to oxazolidinones, pleuromutilins, and streptogramin A.^2,12

Bypass or Replacement of Target Site

Bypassing of target sites occurs when the target site is changed so that the antibiotic is rendered useless. It may occur through several mechanisms.² A popular example of resistance to beta (β)-lactams is seen with the mecA gene in Staphylococcus aureus.^2,13 This gene results in replacement of normal penicillin-binding proteins (PBPs) with PBP2a that has a low affinity for β-lactams. Its induction occurs in the presence of β-lactams.^2,13

Antibiotic Alteration

One method of resistance that bacteria can employ is antibiotic alteration. This is done through enzymatic modification or degradation.^2,14 Inactivating modifications interfere with antibiotic-target site binding and include acetylation, phosphorylation, glycosylation, and hydroxylation.^2,14 Enzymatic degradation results in the destruction of antibiotics.²

Aminoglycosides are subject to modification through aminoglycoside modifying enzymes (AMEs).^2,14 AMEs consists of acetyltransferases, adenyl transferases, and phosphotransferases.² β-lactams are subject to degradation via β-lactamases.¹⁵ In gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, rendering β-lactams useless.¹⁵ β-lactamases can be encoded intrinsically (chromosomal) or disseminating on mobile genetic elements like plasmids across opportunistic pathogens.¹⁵ In the more recent past, β-lactamases have extended beyond penicillins and cephalosporins to carbapenems.¹⁵ Macrolide resistant bacteria have developed enzymes, such as erythromycin esterases, that cleave essential ester bonds and thus disrupt macrolide structure.¹⁶ The genes encoding these enzymes are found on mobile genetic elements, establishing the potential for widespread resistance.¹⁶

Membrane Permeability Variation

Antibiotic resistance can be mediated by changes to the cell membrane permeability.¹⁷ This can be done through alteration in lipid, porin, and transporter structures such as efflux pumps.²

To gain entry into the bacterial cells, antibiotics like β-lactams cross the lipid bilayer of the cell membrane via porins, whereas other lipophilic antibiotics such as macrolides traverse the bilayer via diffusion.³ Alterations to porins or lipid structure result in permeability changes that potentiate resistance. Some gram-negative bacteria intrinsically express full length lipopolysaccharide that prevent diffusion of lipophilic antibiotics.¹⁸

Porin mediated resistance is achieved through decreasing the rate of antibiotic entry.² Loss of porin function can be acquired via changes in OmpF porin protein resulting in replacement/loss of major porins and reduced permeability.¹⁹

Efflux pumps extrude toxic compounds out of bacterial cells, including antibiotics.² A variety of efflux pumps exist and are seen in both gram-positive and gram-negative organisms.¹⁷ In clinically important bacteria, such as multidrug-resistant (<MDR) Mycobacterium tuberculosis, methicillin-resistant S. aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, efflux pumps have critical roles in ensuring bacterial survival and evolution into resistant strains.¹⁷

Global Cell Adaptations

Instead of a specific change in one cellular process, some bacteria have developed resistance to antibiotics via global cell adaptations. Through years of evolution, bacteria have developed sophisticated mechanisms to cope with environmental stressors and pressures in order to survive hostile environments.² This involves very complex mechanisms to avoid the disruption of vital cellular processes such as cell wall synthesis and membrane homeostasis.² The two main examples of global cell adaptation resistance occur with lipopeptides and glycopeptides.²

Lipopeptides have a multifaceted mechanism of action that results in disruption of cell membrane homeostasis.²⁰ Activity correlates with the levels of calcium and phosphatidylglycerol in the membrane.²⁰ Resistance can be accomplished in some organisms via alteration in cell membrane charge and downregulation of phosphatidylglycerol.²⁰

Glycopeptides are susceptible to resistance via multiple adaptations observed with S. aureus including increased fructose utilization, increased fatty acid metabolism, decreased glutamate availability, and increased expression of cell wall synthesis genes.² These global adaptations result in reduced autolytic activity, a thickened cell wall, and an increased amount of free D-Ala-D-Ala, all of which reduce effective activity of glycopeptides.²

Conclusion

Awareness of the molecular mechanisms of antibiotic resistance among bacteria is necessary to understand the etiology of antibiotic resistance in dermatology at the most basic level.

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¹Center for Clinical Studies, Webster, TX, USA
²Meharry Medical College, Nashville, TX, USA
³Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
Susuana Adjei, Austinn Miller and Laurie Temiz have no conflicts of interest to disclose. Stephen Tyring was a principal investigator for the Almirall PROSES clinical trial.

Abstract:
Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile.

Key Words:
sarecycline, tetracyclines, moderate-to-severe acne, antimicrobial resistance, adverse effects

Introduction

To date, one of the first-line classes of oral antibiotic treatments for moderate-to-severe acne has been tetracycline-class antibiotics due to their anti-inflammatory effects, antimicrobial activity, bioavailability, and lipophilicity.¹ The pathogenesis of acne vulgaris is multifaceted with key factors being abnormal follicular keratinization, Cutibacterium acnes (C. acnes) proliferation/ colonization, and increased sebum production.² Inflammation also ensues with the expression and upregulation of inflammatory factors/cells such as CD3+, CD4+ T cells, interleukin-1, integrins, toll-like receptors, and macrophages.²

Various methods for grading acne severity have been debated. Consensus remains elusive, as acne assessment must account for a spectrum of factors such as the number, location, type of lesions, associated scarring, and psychosocial influences.^1,3 In fact, the established scoring tools Global Acne Grading System (GAGS) and Investigator Global Assessment (IGA), which are widely used in clinical trials, FDA efficacy endpoints, and patient care, do not account for all the associated factors in acne assessment.³

Moderate-to-severe acne classically presents with inflamed papules, pustules, and occasional nodules with lesions commonly affecting the face, chest, and back.^4,5 Oral antibiotics are a mainstay of treatment (Table 1).¹ Tetracyclines, specifically doxycycline and minocycline, are broad-spectrum antibiotics widely used for acne treatment as they limit inflammation by inhibition of protein synthesis and proliferation of C. acnes.⁶ However, because of their broad-spectrum activity, tetracyclines not only contribute to the emergence of bacterial resistance, but also disrupt the gut and skin normal microflora, resulting in dysbiosis.^7,8 Dysbiosis of the gut has been linked to inflammatory bowel disease. Doxycycline has shown to be associated with 2.25-fold increase in the risk of developing Crohn’s disease.⁹

Table 1

Discussion

Efficacy of Sarecycline

Leyden et al. compared dose ranges of sarecycline versus placebo in a 12-week phase 2 clinical trial with 285 patients. The subjects ranged from ages 12-45 years old with moderate-to-severe acne and were randomized to receive sarecycline dosed at 0.75 mg/kg, 1.5 mg/kg or 3.0 mg/kg, or placebo.¹⁰ Reductions of 52.7% and 51.8% in inflammatory lesions were reported in the 1.5mg/kg and 3.0mg/kg treatment groups, respectively, as compared to 38.3% for placebo. These results suggest no difference in efficacy for doses of 1.5 mg/kg and 3.0 mg/kg.¹⁰

In two identical 12-week phase 3 trials (SC1401 and SC1402), a total of 2002 subjects aged 9-45 years with moderate-to-severe acne were randomized 1:1 to receive sarecycline or placebo. As early as 3 weeks, there was a mean percentage reduction in inflammatory lesions of -49.9% to -51.8% in the sarecycline group versus -35.1% to -35.4% in the placebo group.^11,12 In addition, there was significant improvement in truncal and chest acne by 12 weeks, which was observed as early as 3 weeks.^11,12 In non-inflammatory facial acne, Moore et al. revealed a larger mean change from baseline in subjects using sarecycline versus placebo at week 12.¹² IGA also improved in truncal acne by 2 points (and clear or almost clear) at week 12 in subjects on sarecycline that had an IGA of more than 2 at baseline.^12,13

In a pilot study of 100 patients, sarecycline demonstrated significant efficacy in papulopustular rosacea, reducing not only lesion counts, but also erythema.¹⁴ Additionally, one case report showed the effectiveness of sarecycline in periorificial dermatitis.¹⁵

Mechanism of Action

Tetracyclines share a common four ring naphthacene core but differ by a variety of structures attached to the carbon groups.¹⁶ Sarecycline has a 7-[[methoxy(methyl)amino]methyl] group attached to the C7 position. It binds to the A site codon of tRNA, blocking protein synthesis and inhibiting bacterial growth (Figure 1).^16,17 Unlike other tetracyclines, sarecycline extends to mRNA due to its long C7 moiety and allows for direct interaction with the mRNA channel.¹⁶ This increases its stabilization, leading to better inhibitory activity by blocking tRNA accommodation and mRNA translation.^17,18

Antibacterial Resistance

Antimicrobial resistance complicates the prolonged use of antibiotics, in general. Due to its narrow-spectrum coverage, sarecycline is less likely to induce resistance.⁶ C. acnes displayed low propensity for the development of resistance to sarecycline with spontaneous mutation frequency of 10^-10 at 4-8 times the MIC.⁶ Bacteria confer resistance to tetracyclines by forming efflux pumps and acquiring Tet proteins that bind to the A site codon of the tRNA, releasing the bacteria from the antibiotics.^16,19 The acquisition of combined Tet(K) and Tet(M) genes among S. aureus strains confers resistance against tetracyclines.⁶ Compared to the other agents in its drug class, sarecycline has shown superiority in its activity against these tetracyclineresistant S. aureus strains against Tet(K) at MIC ranging from 0.12-0.5 g/mL as compared to 16-65 g/mL with the other tetracyclines.⁶ Due to its narrow-spectrum activity, sarecycline is expected to yield lower rates of antimicrobial resistance; however, it has not been found to be statistically significant when compared to other tetracyclines.⁶ Zhanel et al. noted that sarecycline’s propensity to lead to C. acnes mutations was not found to be significantly different from minocycline.⁶

Safety Profile

The broad-spectrum activity of minocycline and doxycycline elicits common adverse effects such as gastrointestinal symptoms, photosensitivity, dizziness, microbial resistance, and tinnitus.^1,19-21 Data has shown that, thus far, the most common adverse effect associated with sarecycline is nausea at an incidence of ≥1%.¹⁰ Moore et al. reported that treatment-emergent adverse events were similar in both the sarecycline and placebo groups, the most common being nausea.¹² A phase 1 randomized, double-blinded, placebo-controlled study was conducted to assess phototoxicity in 18 healthy adult males with Fitzpatrick skin types I, II, and III on 240 mg sarecycline.²² There was no significant dermal response to ultraviolet light exposure. Photosensitivity reactions were uncommon and limited to mild erythema.²² Dizziness was experienced by <1% of patients receiving sarecycline, and no vertigo or tinnitus was reported.²³ Sarecycline is less likely to penetrate the blood-brain barrier, which may explain the very low rates of vestibular adverse events observed in the clinical trials.²³

Conclusion

Sarecycline is a novel antibiotic that has shown significant promise in acne treatment due to its narrow-spectrum activity and weight-based dosing. The advantages of this new systemic therapy include improved tolerability, reduced drug resistance and potentially longer-lasting efficacy. There remain more avenues to explore including sarecycline’s utility in treating other cutaneous infections and inflammatory dermatoses.

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¹Texas A&M College of Medicine, Dallas, TX, USA
²University of Texas Medical Branch, Galveston, TX, USA
³University of Texas Health Science Center McGovern Medical School, Houston, TX, USA
⁴Center for Clinical Studies, Webster, TX, USA
⁵Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
None.

Funding resource:
None.

*Co-first authors

Abstract:
Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-in-class, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.

Key Words:
Janus kinase inhibitors, JAK inhibitors, JAK-STAT, tyrosine kinase inhibitors, TYK2 inhibitors, dermatology, ruxolitinib, abrocitinib, upadacitinib, tofacitinib, baricitinib

Introduction

Autoimmune and inflammatory diseases are common and on the rise, affecting 3% to 5% of the Western population.^1-4 These disorders are thought to evolve from a complex, incompletely understood interplay of host genetics, microbiota, and environmental factors that contribute to dysregulated T-cell and B-cell activity against the host, leading to tissue damage.¹ In the realm of dermatology, there have been considerable advances enabling examination of deep molecular processes and immunological pattern analyses that allow us to better understand the pathophysiological mechanisms of autoimmune and inflammatory skin diseases.^5-8 Furthermore, skin biopsy analysis has facilitated our ability to characterize the influencing factors such as cytokines, receptors, and signaling molecules in order to develop targeted therapeutic agents.⁵

Various therapeutics can be used to attenuate the immune response either through direct suppression of T-cell activity or by directly or indirectly blocking cytokines. Glucocorticoids have long been used to suppress an aberrant immune response; however, they have the drawback of eliciting nonspecific immunosuppressive effects. Many cells express steroid receptors and adverse effects of glucocorticoids are common, thus their use in the management of chronic autoimmune or inflammatory diseases should be cautioned given their side effect profile.¹ Cytokine activity can likewise be inhibited by biologic therapy. Most recently, inhibitors of signaling proteins have been introduced for the treatment of psoriatic arthritis and rheumatoid arthritis.¹ These inhibitors target the Janus kinases (JAKs) family of proteins by modulating the inflammatory process through activation of intracytoplasmic transcription factors called signal transducer and activator of transcription (STAT).⁵ STATs get activated, dimerize, and translocate into the nucleus where they modulate the expression of various genes.

Inflammation of the skin relies on this interaction between cytokines, as well as immune and tissue cells, to propagate the different distinct inflammatory cascades. Because of these unique mechanisms, JAK-STAT inhibitors are gaining traction in clinical development as new potential therapeutics for various inflammatory dermatological conditions.

Aims and Objectives

The aim of this literature review is to provide updates on the mechanism of JAK inhibitors and assess their efficacy in the treatment of alopecia areata, psoriasis, psoriatic arthritis, atopic dermatitis, dermatomyositis, and vitiligo. A class-wide safety review and future considerations will also be discussed.

Methods

A review of the literature regarding the mechanism of action and efficacy of JAK inhibitors in skin diseases was done by searching the PubMed, Scopus, and EBSCO databases. The following keywords were used to find articles: ‘Janus kinase-inhibitors’, ‘JAK-inhibitors’, ‘JAK-inhibitors pathway’ combined with ‘dermatology’, ‘atopic dermatitis’, ‘alopecia areata’, ‘psoriasis’, ‘dermatomyositis’, ‘vitiligo’, ‘side effects’, and ‘safety’.

JAK-STAT Signaling Pathway

The JAK-STAT pathway is activated by numerous different cytokines, which bind directly to the Janus kinase receptor and initiate transphosphorylation. This ligand-mediated receptor binding brings two JAKs in close proximity, allowing for its autophosphorylation and activation. The activated JAKs subsequently lead to the phosphorylation of the tyrosine residues on the receptor. The phosphorylation of the tyrosine residues on the receptor recruits STATs, inactive latent transcription factors in the cytoplasm. Using their SH2 domain, the STATs bind to the phosphorylated tyrosine residue on the receptor and are phosphorylated by JAKs. This causes the STATs to dissociate from the receptor, dimerize, and travel from the cytosol into the nucleus where they are able to modify gene transcription.⁹ There are four members within the JAK family of kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), and the STAT family has six proteins (STAT1, STAT2, STAT3, STAT5A/B and STAT6).¹⁰

One or more members of the JAK and STAT families may be recruited by any specific receptor influencing different aspects of immune cell development and function.¹¹ Various combinations of different types of JAK proteins can be associated with several receptors that have variable effects on specific signaling pathways of the immune system, such as the combination of JAK1 and JAK3 related to cytokine receptors fundamental for the function of lymphocytes or the TYK2/JAK2 combination that is essential for the signaling of interferon (IFN)-a, interleukin (IL)-12, and IL-23 receptors.¹¹ The varied distribution amongst different JAK/STAT proteins across distinct cell types shows how a genetic defect of JAKs or STATs might determine various clinical conditions, such as JAK3 deficiency in severe combined immunodeficiency syndrome.¹¹ Additionally, the modulation or inhibition of the activity of these intracellular pathways represents a potential target in immune mediated diseases such as psoriasis and atopic dermatitis.^11,12

The mechanism of action of JAK inhibitors targets the kinase component of JAKs. This prevents the JAK protein from phosphorylating, thus halting the intracellular signaling transduction.¹ First generation JAK inhibitors, such as baricitinib, ruxolitinib, and tofacitinib, inhibit many JAKs. For example, tofacitinib, which is FDA-approved for psoriatic arthritis, inhibits JAK1 and JAK3 mainly, with some selectivity towards the JAK2 isoform.¹³ The rationale behind the nonselective, multi-JAK inhibition is the notion that blocking multiple JAKs may enhance therapeutic efficacy.¹⁴ On the other hand, the second generation JAK inhibitors are more selective to particular JAK isoforms to limit adverse effects and possibly maintain treatment efficacy. Deucravacitinib is a second generation JAK inhibitor that specifically targets TYK2.^13-15 This drug has shown efficacy in the treatment of systemic lupus erythematosus and is currently in a phase III trial for psoriasis.¹ Research into the efficacy of JAK inhibitors continues at a rapid pace as a host of new drug candidates are under development, thus shedding light on their mechanisms in treating rheumatological and dermatological diseases.

Applications in Dermatology

JAK inhibitors have shown significant clinical efficacy in patients with psoriasis and psoriatic arthritis.¹ Currently, the FDA-approved JAK inhibitors in dermatology are oral tofacitinib and upadacitinib for the treatment of psoriatic arthritis^1,2 and topical ruxolitinib for mild to moderate atopic dermatitis. However, the use of first and second generation JAK inhibitors in other dermatological diseases such as alopecia areata, atopic dermatitis, dermatomyositis, vitiligo, and systemic lupus erythematosus is being heavily investigated in numerous clinical trials (Table 1).¹³

Alopecia Areata (AA)

AA is a chronic, autoimmune non-scarring hair loss disorder that involves the destruction of hair follicles by autoreactive CD8 T cells.³ It classically presents as smooth, circular hair loss patches with no erythema, pain, pruritus, or inflammation. JAK-STAT dependent cytokines IFN-γ and IL-15 contribute to signaling cascades through JAK1 and JAK3.³ They lead to the proliferation of autoreactive T cells that are active in AA.

Systemic and topical administration of JAK inhibitors have shown to be beneficial in patients with AA. In 2014, a case report was published featuring a patient with diagnosed alopecia universalis and psoriasis. While using tofacitinib to treat psoriasis, the patient experienced complete regrowth of body and scalp hair, as well as eyelashes and eyebrows.⁴ Since then, several other case reports and studies have been published illustrating the successful treatment of AA using JAK inhibitors (primarily tofacitinib, ruxolitinib, and baricitinib).^5-8,10 However, relapse of hair loss has been reported in the literature after drug discontinuation.⁹ In a recent phase II trial, ritlecitinib and brepocitinib were found to be well tolerated and led to clinically meaningful improvements in hair growth. Approximately 25% and 34% of patients treated with ritlecitinib and brepocitinib, respectively, saw near-complete regrowth.¹⁶ Topical JAK inhibitors for the treatment of localized AA could be proven useful, but more studies are needed for validation. In the case of topical tofacitinib, one pilot study of patients treated with 2% tofacitinib twice daily revealed a poor response with only 3 responders.17Another study describes almost complete regrowth of hair with topical 2% tofacitinib every 12 hours for 7 months.¹⁷ Topical ruxolitinib has also shown various responses in AA, with one study showcasing regrowth at 28 weeks in 5 patients in the area treated. In adolescent patients, topical ruxolitinib 0.6% applied twice daily showed complete growth of the eyebrows observed at 3 months, while there was only 10% regrowth of the scalp.¹⁷ Currently, positive results from numerous early phase clinical trials have increased interest in this area. Further investigation is needed to determine optimal dosing of JAK inhibitors in AA and whether maintenance therapy is required.

Psoriasis and Psoriatic Arthritis

Psoriasis has been the most studied dermatological disease in relation to JAK inhibitors. JAK-STAT dependent cytokines are implicated in the pathogenesis of psoriasis, with IL-12 and IL-23 being fundamental mediators.¹¹ Several phase III randomized controlled clinical trials have shown significant reduction, up to 75%, in the Psoriasis Area and Severity Index (PASI 75) when patients were treated with tofacitinib at both 5 mg and 10 mg twice daily doses, with improvement seen in a dose dependent manner.¹² Improvements from the treatment were sustained up to 52 weeks and side effects appeared to be similar in both dosing regimens. Furthermore, a phase III non-inferiority trial determined that tofacitinib at 10 mg twice daily was non-inferior to etanercept 50 mg twice weekly.¹⁴ Nevertheless, the FDA did not approve tofacitinib for psoriasis, likely attributable to the need for more safety data on the 10 mg dose.

Several other JAK inhibitors have demonstrated promising results. A phase IIb clinical trial of baricitinib showed more patients achieved PASI 75 when compared to placebo in the treatment of moderate-to-severe plaque psoriasis.18 Deucravacitinib, a novel, selective TYK2 inhibitor has demonstrated to be more advantageous in the treatment of moderate-to-severe plaque psoriasis when compared to placebo and apremilast in a phase III clinical trial.¹⁹ Patients achieved PASI 75 after 16 weeks of treatment, with the overall safety of the drug being consistent with previous results.¹⁹

As opposed to systemic therapy, medications administered topically generally have more favorable safety profiles given less systemic absorption. Topical formulations of ruxolitinib and tofacitinib have been tested in phase II clinical trials for psoriasis.²⁰ Side effects in both these trials were mild and there were no signs of systemic symptoms in any of the patients. Treatment with topical ruxolitinib twice daily showed improvement in psoriasis lesion size compared with placebo.²¹ Improvement in psoriasis was also noted in patients treated with topical tofacitinib. Discontinuation of the topical drugs led to worsening of psoriasis.²⁰

Tofacitinib was FDA-approved in December 2017 for the treatment of patients with psoriatic arthritis who have had little to no improvement in their symptoms using methotrexate or other disease-modifying antirheumatic drugs.¹³ The decision was based on the results of two phase III clinical trials that showed statistically significant improvements in American College of Rheumatology 20 (ACR 20) response at 3 months when patients were treated with tofacitinib 5 mg and 10 mg twice daily.¹³ In a recent 24-week, phase III trial, oral upadacitinib was assigned to patients with psoriatic arthritis at a dose of 30 mg or 15 mg once daily, while other patients received either placebo or subcutaneous adalimumab 40 mg every other week. Results showed that the ACR 20 response rate was significantly higher for patients receiving the two doses of upadacitinib versus placebo. Furthermore, only the 30 mg dose of upadacitinib was shown to be superior to adalimumab.²²

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common, chronic and pruritic inflammatory skin diseases. The pathogenesis of this disease is fueled by functional impairment of the epidermal barrier and abnormal immune activation. IL-4 is one of the main culprits in AD known to play a pivotal role in signaling through the JAK-STAT pathway.^1,14

Oral tofacitinib was reported to be efficacious in 6 patients with moderate-to-severe refractory AD. Tofacitinib 5 mg twice daily or daily for 14 weeks led to a decrease in the average Severity Scoring of Atopic Dermatitis (SCORAD) index by approximately 55%.²³ Moreover, the study reported significant reduction in pruritus scores as well. A recently published, randomized, double-blinded, placebo-controlled phase III clinical trial showed that the treatment of moderate-to-severe AD with oral abrocitinib resulted in greater reductions in signs and symptoms of the disease, as well as greater itch response when compared to dupilumab and placebo.²⁴ Abrocitinib’s pending FDA approval has been delayed for an unspecified amount of time as data analysis continues.²⁵ In multiple phase III clinical trials, upadacitinib has been shown to improve skin and itch symptoms in adolescent and adult patients with moderate-tosevere AD.^26,27

Topical JAK-STAT treatments such as tofacitinib, ruxolitinib and delgocitinib have also shown promise in the treatment of AD, with topical delgocitinib being approved in Japan under the trade name Corectim^® and topical ruxolitinib (Opzelura™) receiving FDA approval for mild to moderate AD.²⁸ Topical tofacitinib 2% every 12 hours in 69 patients with mild to moderate AD for 4 weeks led to an 81.7% reduction in Eczema Area and Severity Index score after 4 weeks.²⁸ Topical ruxolitinib was also found to have a therapeutic benefit for patients by week 4 with each variant of ruxolitinib regimen; the drug rapidly improved pruritus and was well tolerated.²⁸ Phase I and phase II studies of delgocitinib proved the therapeutic efficiency of the medication with respect to severity and pruritus, with pruritus improving 1 day after initiating treatment.²⁸

Evidence for clinical efficacy of JAK inhibitors in the treatment of AD has been shown in several other phase II and III clinical trials, forging a possible future when these drugs may become mainstay therapy for the disease.^29-32

Dermatomyositis

Dermatomyositis is an autoimmune myopathy that is characterized by symmetric proximal muscle weakness and rash. Pathogenesis of the disease is mediated by CD4 lymphocytes and complement activation. There have been several reported cases demonstrating the efficacy of JAK inhibitors in treatmentrefractory dermatomyositis.^33-36 A case series of three patients treated with tofacitinib reported that they had improved significantly in their Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.³⁵

Additionally, one case reported a patient with myelofibrosis and concomitant refractory dermatomyositis who improved significantly while on ruxolitinib.³³ Nonetheless, it is unknown whether the improvement of the patient’s dermatomyositis was an indirect effect of treating myelofibrosis or a direct effect of ruxolitinib-mediated JAK inhibition. Furthermore, another case report of a patient with dermatomyositis experienced significant improvement in her cutaneous disease, arthritis, and muscle strength while being treated with tofacitinib.³⁶

Vitiligo

Vitiligo is an autoimmune condition characterized by absence of pigmentation due to loss of melanocytes. While the exact etiology of the disease is unknown, evidence from literature has shown that the destruction of melanocytes is mediated by CD8 T cells.^1,37 As with AA, IFN-γ plays a vital role in the pathogenesis of vitiligo, thus making this disease susceptible to treatment with JAK inhibitors.¹ For example, a patient with generalized vitiligo showed near complete repigmentation of areas in the hands, forearms, and face over 5 months while on tofacitinib.³⁸ However, discontinuation of the drug led to depigmentation in affected areas.³⁸

An additional case report of a patient with both AA and vitiligo experienced hair regrowth and repigmentation while being treated with ruxolitinib.³⁹ As is the case with the previous patient mentioned, depigmentation occurred with discontinuation of the drug. Currently, topical ruxolitinib is in a phase 3 clinical trial to evaluate its efficacy and safety in treatment of vitiligo.⁴⁰ Clinical trials are vital for clarifying the role of JAK inhibitors in
the treatment of vitiligo.

Other Dermatologic Conditions

There is evidence from the literature suggesting that JAK inhibitors are efficacious in the treatment of refractory dermatologic cases or rare diseases with no effective therapies – chronic mucocutaneous candidiasis, cutaneous sarcoidosis, mastocytosis, polyarteritis nodosa, hypereosinophilic syndrome, and chronic actinic dermatitis. Data from case reports and case series hints at potential broader use for JAK inhibitors in the field of dermatology.^1-2,41

Adverse Effects and Safety Profile

The JAK inhibitors that are approved for autoimmune disease have an associated black box warning for the potential increased incidence of malignancy, serious infections, and thrombosis based on data from oral use in rheumatoid arthritis.¹ Tofacitinib and baricitinib have the most data on their safety and side effect profiles. However, the long-term safety of JAK inhibitors is still not completely understood. Current data suggests the safety of JAK inhibitors may be comparable to other biologics, and as investigations of this promising drug class continue, the safety profile should become more clear.¹ According to the literature, JAK inhibitors may potentially increase the risk of malignancies, as they could impair the immune system’s surveillance mechanism to vet inconspicuous cells that could eventually become cancers.¹ The rate of serious infections in patients treated with JAK inhibitors is comparable to that of other biologic agents such as TNF-a,^1,20 though there is an increased risk of herpes zoster with JAK inhibitor usage.^1,21 Baricitinib, tofacitinib, ruxolitinib and upadacitinib all include warnings for potential deep vein thrombosis, pulmonary embolism, and arterial thrombosis.^1,18 Though these risks appear to be low and dose dependent, additional studies are needed to determine the exact mechanism behind it’s pro-thrombotic effects.^1,37 Additional adverse effects include gastrointestinal perforations, hyperlipidemia, as well as impaired drug metabolism due to interaction with the CYP3A4 system.^1,42

Discussion

There is an increasing body of evidence that suggests JAK inhibitors may be an effective treatment for various inflammatory skin conditions. However, numerous cytokines and immunomodulating molecules act via the JAK-STAT pathway and blunting its activity may have unintended consequences. Long-term follow up studies are needed to establish treatment guidelines and evaluate the risk-benefit profile of JAK inhibitors. As mentioned before, tofacitinib was found to be non-inferior to etanercept for plaque psoriasis, but more studies are needed to compare the efficacy of JAK inhibitors to biologics currently approved for dermatologic use.⁴³ Lastly, future studies should assess the utility and safety of JAK inhibitors in pregnancy and for the pediatric population.

Conclusion

Many inflammatory cytokines involved in the pathogenesis of skin disorders signal via the JAK-STAT pathway. Thus, this drug class has the potential for broad therapeutic utility within dermatology. Currently, JAK inhibitors are only FDA approved for dermatologic, rheumatologic, and hematologic conditions. Recent studies show the utility of JAK inhibitors in treating atopic dermatitis, psoriasis, psoriatic arthritis, vitiligo, and alopecia areata. However, more robust studies are needed to assess long-term safety and establish treatment guidelines. JAK inhibitors are poised to become important additions to the therapeutic arsenal for a wide range of inflammatory skin conditions.

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