Melinda J. Gooderham, MSc, MD, FRCPC^1,2; H. Chih-ho Hong, MD, FRCPC^2,3; Ivan V. Litvinov, MD, PhD, FRCPC⁴

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

Conflict of interest:
M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, ASLAN Pharmaceuticals, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, and UCB. H. C. Hong has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli-Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, and UCB. I. Litvinov has received a grant or an honorarium from AbbVie, Actelion, Bausch Health, Bristol-Myers Squibb, Galderma, ICPDHM, Janssen, Johnson & Johnson, Merck, Novartis, Pfizer, and Sun Pharmaceuticals.

Funding for this manuscript was provided in the form of an educational grant from Bristol Myers Squibb Canada Co.

Abstract:
Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician’s Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Key Words:
plaque psoriasis, TYK2 inhibitor, deucravacitinib, apremilast, clinical trial, efficacy, safety, PASI, sPGA

Introduction

Psoriasis is a common, chronic, immune-mediated inflammatory disease, estimated to affect 1 million people in Canada.^1,2 The most common type is chronic plaque psoriasis, which affects 90% of this patient population.¹

Moderate chronic plaque psoriasis is typically defined as involving ≥3-10% body surface area (BSA), with severe disease involving more than 10% BSA.³ When inadequately treated, this can cause severe psychosocial impact and impair patients’ quality of life (QoL).³

Currently, various oral systemic agents, biologic agents, and phototherapy have Health Canada-approved indications for management of moderate to severe chronic plaque psoriasis. Despite numerous treatment options, unmet needs still exist. An emerging class of therapy in development are selective tyrosine kinase 2 (TYK2) inhibitors, which may meet those needs. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, recently US FDA approved and currently under review by Health Canada. Other oral selective TYK2 inhibitors for treatment of moderate to severe plaque psoriasis in various stages of development include GLPG3667 and NDI-034858.^4,5

Pathogenesis of Plaque Psoriasis

The pathogenesis of chronic plaque psoriasis starts with environmental, immunologic, and/or genetic triggers that can lead to release of cytokines from innate immune cells, activating myeloid dendritic cells.^6,7 Activated myeloid dendritic cells present antigens to T cells and release cytokines, including interleukin (IL)-23 and IL-12;^6-8 both IL-23 and IL-12 signal through TYK2-mediated pathways. IL-12 contributes to T helper (Th)1-cell differentiation and IL-23 activates keratinocytes via pro-inflammatory Th17 cells;⁶ both processes lead to tumor necrosis factor (TNF)-α and interferon (IFN)-γ production. Cytokines secreted by Th17 and Th1 cells activate keratinocytes;⁹ this is one of the first steps in the development of psoriatic lesions. A positive feedback loop recruits other immune cells, further potentiating the inflammatory process.⁶

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

TYK2 is a Janus kinase (JAK) enzyme that is coded by the TYK2 gene and constitutively expressed in immune cells.¹⁰ Mutations and polymorphisms in TYK2 impact IL-23, IFN-α/β, and IL-12 immune-mediated signalling, and are associated with an altered risk for psoriasis; for example, loss of function mutations in TYK2 have been found to be protective against autoimmunity, including psoriasis.¹⁰ Selective TYK2 inhibition blocks IL-23, IL-12, and type I IFN-driven responses, but not those driven by other JAKs (Figure 1).^11-13

Deucravacitinib: Mechanism of Action

Deucravacitinib is a specific, oral, intracellular TYK2 inhibitor that targets immune responses driven by type 1 IFN and IL-23 that contribute to psoriasis pathogenesis, including IL-17 production and Th1/Th17 polarization.^12-14 It binds with high specificity to the TYK2 regulatory domain, blocking kinase activity and conferring selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis (Figure 2).^12-14

Deucravacitinib uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range while reducing off-target effects.^11-13 In contrast, JAK 1–3 inhibitors bind to the active domain adenosine triphosphate (ATP) binding site common to all JAK molecules (including TYK2) to mediate both immune responses and broader systemic processes (e.g., myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, lipid metabolism, etc.), some of which are necessary for normal physiologic functioning, resulting in a narrower therapeutic range.¹³

Efficacy of Deucravacitinib: Key Evidence from Pivotal Phase III Clinical Trials

In a phase II trial of patients with psoriasis, deucravacitinib demonstrated superior efficacy vs. placebo based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) over 12 weeks.¹⁴ Efficacy results from two phase III pivotal trials of deucravacitinib were recently reported and confirmed results from the phase II trial.

In the 52-week, double-blinded, phase III POETYK PSO-1 trial, participants with moderate to severe chronic plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=332), placebo (n=166), or apremilast 30 mg twice daily (n=168).¹⁵ Similarly, participants in the 52-week, doubleblinded, phase III POETYK PSO-2 trial were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=511), placebo (n=255), or apremilast 30 mg twice daily (n=254).¹⁶

The coprimary endpoints of both trials were response rates for PASI 75 and static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib vs. placebo at week 16.^15,16 Key secondary endpoints included the scalp-specific Physician’s Global Assessment (ss-PGA) and patient-reported symptoms and signs of psoriasis (evaluated using the Psoriasis Symptoms and Signs Diary [PSSD]) and QoL (evaluated using the Dermatology Life Quality Index [DLQI]).¹⁵

In both PSO-1 and PSO-2 trials, PASI 75 response rates at week 16 were significantly higher with deucravacitinib (58.4% and 53.0%) vs. placebo (12.7% and 9.4%) or apremilast (35.1% and 39.8%). Response rates for sPGA 0/1 were also significantly higher with deucravacitinib (53.6% and 50.3%) vs. placebo (7.2% and 8.6%) or apremilast (32.1% and 34.3%) (Table 1).^15,16 Deucravacitinib responses improved beyond week 16 and were maintained through week 52.¹⁵ Furthermore, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1.¹⁵

Regarding key secondary endpoints, significantly greater proportions of patients in the deucravacitinib vs. placebo and apremilast arms achieved ss-PGA 0/1 and DLQI 0/1 responses, as well as greater reduction from baseline in PSSD symptom scores at week 16 and week 24 (Table 1).^15,16

Table 1. POETYK PSO-1 and PSO-2 efficacy results

Pooled PSO-1 and PSO-2 data showed that significantly greater proportions of patients receiving deucravacitinib achieved absolute PASI ≤1, ≤2, and ≤5 vs. patients receiving placebo (week 16) or apremilast (weeks 16 and 24), and proportions of patients achieving different PASI thresholds with deucravacitinib increased from week 16 to week 24.¹⁷

In an analysis of PSO-1 and PSO-2 that compared efficacy of deucravacitinib vs. placebo and apremilast in individual scoring components (erythema, induration, desquamation) and body regions of PASI (head/neck, upper extremities, trunk, lower extremities), deucravacitinib was associated with numerically greater percent reductions from baseline in each PASI body region and component scores at week 16 than placebo and apremilast.¹⁸ Higher proportions of patients in the deucravacitinib vs. placebo and apremilast groups achieved ≥75% reduction at week 16 in each PASI body region and PASI scoring; differences in efficacy when compared to apremilast were maintained at week 24.¹⁸ For patients in the deucravacitinib group, improvements occurred as early as week 1 and increased over time on treatment.¹⁸

In a long-term extension study of PSO trials, investigators analyzed the efficacy of deucravacitinib in patients who did not respond adequately to treatment with apremilast by week 24. Patients initially randomized to apremilast who failed to achieve a PASI 50 in PSO-1 (n=54) or PASI 75 in PSO-2 (n=111) were switched to deucravacitinib through week 52. After switching from apremilast to deucravacitinib, 46.3% of PASI 50 nonresponders and 42.3% of PASI 75 non-responders achieved PASI 75 by week 52.¹⁹ Improvements were also seen for sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score.¹⁹

Two-year data from a long-term extension of both PSO trials showed that deucravacitinib had durable clinical efficacy, including mean response rates of 79.8% for PASI 75 and 60.7% for sPGA 0/1 at week 60, regardless of which treatment was initiated at week 16 (when patients in the placebo group could switch to deucravacitinib) or at week 24 (when apremilast nonresponders could switch to deucravacitinib) in the parent study.²⁰

Deucravacitinib: Safety and Tolerability Profile

During weeks 0–16 and weeks 0–52 assessment periods in both PSO trials, overall adverse event (AE) rates were similar across all 3 treatment groups (deucravacitinib, placebo, and apremilast).^15,16,21 The most frequent AEs in patients treated with deucravacitinib were nasopharyngitis (9.0%) and upper respiratory tract infection (5.5%). The most frequent AEs in apremilast-treated patients were diarrhea (11.8%), headache (10.7%), nausea (10.0%), and nasopharyngitis (8.8%); placebotreated patients most frequently experienced nasopharyngitis (8.6%) and diarrhea (6.0%).16,21 Incidence rates for AEs of interest, including skin events (e.g., acne and folliculitis), herpes zoster, serious infections, malignancies, thrombotic events, cardiovascular events, creatinine kinase elevation, changes in complete blood count, and changes in lipid profile were absent or low in the deucravacitinib group.¹⁵

The frequency of serious adverse events (SAEs) reported in weeks 0–16 were low across all groups (1.8% in deucravacitinib treated patients vs. 2.9% with placebo and 1.2% with apremilast).^16,21 Discontinuation rates due to AEs were lowest in the deucravacitinib group (2.4%) vs. placebo (3.8%) and apremilast (5.2%).^16,21

A pooled analysis of PSO-1 and PSO-2 trials confirmed that deucravacitinib was well tolerated for up to 52 weeks across patient subgroups based on baseline characteristics of age, sex, race, and body weight. The frequency and type of AEs and SAEs in each subgroup were consistent with the overall patient population, with similar trends for overall AEs and AE classes in the placebo and apremilast groups across subgroups.²¹

In the long-term extension trial, safety results were consistent with those reported in PSO-1 and PSO-2 trials. SAEs remained low, including those that led to discontinuation. There were no new safety signals or clinically meaningful changes in laboratory values.²⁰ The most common AEs included nasopharyngitis (16.8% at 1 year; 17.8% at 2 years), upper respiratory tract infection (9.1% at 1 year; 9.9% at 2 years), headache (5.9% at 1 year; 6.5% at 2 years), diarrhea (5.1% at 1 year; 5.5% at 2 years), and arthralgia (4.0% at 1 year; 5.6% at 2 years).²⁰ An increase in serious infections was observed, which the authors concluded was attributable to COVID-19 infections due to the ongoing pandemic (studies were conducted during the pandemic through the cut-off date of October 1, 2021, prior to widespread availability of vaccines).

These safety results have not as of yet uncovered treatmentemergent SAEs that are more commonly associated with JAK inhibitors, such as herpes zoster, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities.^20-24

Discussion

Selective TYK2 inhibition is a promising novel target for the treatment of moderate to severe chronic plaque psoriasis. Molecules that confer selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis, without involvement of other JAKs, can lead to a broad therapeutic range while reducing off-target effects such as serious infections, malignancies, thrombosis, and MACE.

Key data from the pivotal phase III POETYK PSO-1 and PSO-2 clinical trials showed that patients with moderate to severe chronic plaque psoriasis treated with the first-in-class, oral, selective TYK2 inhibitor deucravacitinib achieved statistically significant PASI 75 and sPGA 0/1 outcomes that were superior to placebo and apremilast at week 16.^15,16 Additionally, significantly greater proportions of patients achieved absolute PASI ≤1, ≤2, and ≤5 with deucravacitinib vs. placebo or apremilast.¹⁷ Body region-specific data showed that deucravacitinib had numerically larger percentage improvements at weeks 16 and 24 from baseline vs. apremilast and placebo, across all components of scoring and with onset of action as early as week 1.¹⁸

Deucravacitinib was efficacious at week 52 in patients who had inadequate responses to apremilast at week 24 and subsequently switched to deucravacitinib, which was demonstrated in physician-assessed endpoints (PASI 75/90, percentage change from baseline in PASI, and sPGA 0/1) and in patient-reported outcomes (DLQI 0/1 and change from baseline in PSSD symptom score).¹⁹

Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast, with overall AE rates similar across all 3 treatment groups.^15,21 The most common AEs in patients treated with deucravacitinib were nasopharyngitis and upper respiratory tract infection, while incidence rates of SAEs and AEs of interest were low.^15,21

1. What are the off-target serious adverse effects associated with JAK inhibitors?
2. In the PSO-1 and PSO-2 clinical trials, what were the outcomes of apremilast non-responders who were switched to deucravacitinib at week 24?

Conclusion

Selective TYK2 inhibition is a novel target in the treatment of moderate to severe plaque psoriasis. The first-in-class oral TYK2 inhibitor deucravacitinib, already approved by the FDA in the US, has been shown to be efficacious, safe, and tolerable for up to 2 years of use. It is expected that deucravacitinib, and potentially other oral TYK2 inhibitors in development, will offer dermatologists and their patients with a convenient, effective, and safe alternative to other currently available oral systemic agents biologic agents, and phototherapy for the management of moderate to severe chronic plaque psoriasis.

Acknowledgements

The authors wish to thank Teri Morrison and Athena Kalyvas from the International Centre for Professional Development in Health and Medicine (ICPDHM) for editorial support.

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¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Division of Dermatology, St. Paul’s Hospital, Vancouver, BC, Canada

Conflicts of interest:
None Reported.

ABSTRACT
Dermatologists have within their armamentarium numerous immunosuppressant agents, both traditional and new, that are useful in the treatment of chronic cutaneous disorders such as autoimmune bullous diseases and psoriasis. It is imperative that users of these agents are aware of potential sequelae from therapy, particularly infections. In this review, we summarize the most common immunosuppressant medications currently used in dermatology, and provide recommendations for infection screening prior to initiating treatment.

Key Words:
immunosuppression, infection, TNF-α inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, clinical protocol, drug therapy, skin diseases

Introduction

Psoriasis, connective tissue diseases, and autoimmune bullous diseases such as bullous pemphigoid and pemphigus are but a few examples of the dermatological indications for which immunomodulatory/immunosuppressive therapy may be indicated. Treating patients with these inflammatory cutaneous diseases often involves one or more immunosuppressive agents, either sequentially or in combination, which increases the risk of infection-related morbidity and mortality. One of the main safety concerns for the dermatologist prior to initiating therapy is the risk of infection. Risk factors for infection include age, medical comorbidities, travel history, location of residence, occupation, as well as the type, duration and extent of immunosuppression. Although pretreatment infection-testing guidelines exist for the disciplines of gastroenterology, hepatology, rheumatology, and transplant medicine, no specific guidelines have been developed for the dermatologist wishing to begin immunosuppressive therapy. This discussion is timely and of interest within the dermatology literature, as multiple publications have emerged within the last 5 years.^1-3 The dermatologist has a therapeutic armamentarium of immunosuppressive drugs including traditional therapies such as systemic corticosteroids, methotrexate, cyclosporine, azathioprine, mycophenolate mofetil as well as novel therapeutics known as biologics. Within the last decade or so there has been an emergence of novel biologic therapeutics including inhibitors of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, CD20, p40 subunit of IL-12/23, and more recently IL-17. Herein, we discuss the current pre-treatment infection guidelines for the dermatologist prior to beginning immunosuppressive therapy.

Non-biologic immunosuppressive therapy

The non-biologic immunosuppressive therapies that will be discussed are corticosteroids, methotrexate, azathioprine, cyclosporine and mycophenolate mofetil (Table 1). Since their introduction in the 1950s, corticosteroids have revolutionized the management of inflammatory diseases.⁴ Corticosteroids are among the oldest immunosuppressants; their mechanism of action is through inhibition of gene transcription and downregulation of secreted inflammatory cytokines.^5,6 The risk of infection with corticosteroid use depends upon the patient’s underlying disease state, duration, dose and route of administration.⁷ A lower dose of corticosteroids as well as a shorter duration are associated with a reduction in infectious complications.⁸ Corticosteroid use in combination with other immunosuppressive agents, such as methotrexate or azathioprine, increases the risk of serious infections as evidenced in inflammatory bowel disease and rheumatoid arthritis.⁹ However, given the short half-life of systemic corticosteroids (e.g., prednisone plasma half-life is 60 minutes, prednisolone plasma half-life is 115-212 minutes), it is reasonable to start these medications, if needed, while awaiting infection screening results.

Azathioprine and its derivative 6-mercatopurine are structurally similar to the endogenous purines adenine and guanine. The exact mechanism of action of this immunosuppressive agent is unknown, however it is thought that the structural similarity to endogenous purines allows it to be incorporated into DNA and RNA with subsequent inhibition of purine metabolism and cell division. Azathioprine use is associated with increased bacterial, fungal and viral infections.¹⁰ Prior to initiating azathioprine, the dermatologist should ascertain whether the patient has been immunized or previously infected with varicella zoster virus and if not, immunization prior to commencing immunosuppression should be recommended.¹⁰ Furthermore, azathioprine in combination with prednisolone is associated with an increased risk of infection which can be fatal in the elderly.¹¹

Methotrexate is a potent competitive inhibitor of dihydrofolate reductase and a partially reversible inhibitor of thymidylate synthetase, which ultimately acts by inhibiting purine synthesis. However, the definitive mechanism of action of methotrexate is, to date, incompletely understood, as novel modes of action continue to be published; most recently its role as a Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway inhibitor has been described.¹² In patients receiving long-term treatment with methotrexate, hepatotoxicity is an important consideration and patients should be screened for hepatitis B and C infection prior to initiating treatment. In addition, untreated chronic tuberculosis and active tuberculosis infections are contraindications to treating with methotrexate.

Cyclosporine is postulated to act by inhibition of the intracellular enzyme calcineurin, resulting in reduced activity of the transcription factor nuclear factor of activated T-cells (NFAT-1). With decreased NFAT-1 activity, the transcription of a number of downstream cytokine genes, most notably IL-2, are suppressed. Furthermore, impaired production of IL-2 leads to a decline in the number of activated T-cells within the epidermis. Thus, cyclosporine results in decreased functional T-cell mediated immunity, leading to increased susceptibility to cytosolic microorganisms, including atypical Mycobacterium, and viruses.^13,14

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase (IMPDH). Inhibition of this critical enzyme, IMPDH, subsequently deprives T- and B-cells of purine metabolites necessary for growth and replication. The net effect is selective immunosuppression. MMF is associated with an increased risk of infection especially when doses in excess of 2 g daily are used.^15,16 Serious infections are most common in renal and cardiac (2%) and hepatic (5%) transplant patients at doses of 2-3 g daily. Viral (herpes zoster, herpes simplex), bacterial, atypical mycobacterial and fungal infections have been reported in the literature.^17-20

Biologic Immunosuppressive Therapy

The biologics account for a relatively novel class of medications refered to as specialty drugs or specialty pharmaceuticals.²¹ Biologics are derived from living cells and are administered by injection, infusion or oral route, and are used to treat a variety of rare conditions. Biologic immunosuppressive therapies include TNF-α inhibitors (infliximab, adalimumab, etanercept), IL-12/23 inhibitors (ustekinumab), CD20 inhibitors (rituximab) and most recently the IL-17 pathway inhibitors (secukinumab, ixekizumab, brodalumab) (Table 2). Given the relative success of TNF-α inhibitors and ustekinumab in the treatment of psoriasis, there has been an emergence of biologics targeting various other cytokines. Inhibitors of IL-17 are the latest wave of therapeutics developed for the treatment of psoriasis and psoriatic arthritis, which deplete the Th17 population of T-cells. Other types of IL-17 inhibitors are currently in various phases of clinical trials for psoriasis and psoriatic arthritis.²² The clinical trials for these agents are currently ongoing and data pertaining to incidence and type of infections have not yet been published.

Rituximab, a biologic that targets the B-cell surface antigen CD20, can be used in several dermatologic conditions including pemphigus vulgaris. Rituximab became the first monoclonal antibody approved by the US FDA for the treatment of cancer. Since rituximab depletes CD20+ B-cells, it should not be administered to patients with active infections. Live vaccines should not be given to patients taking rituximab, and recombinant or killed vaccines should be given at least 4 weeks prior to initiating treatment. Patients should undergo screening for active and latent infections. Rituximab has been associated in particular with reactivation of hepatitis B virus (HBV).²³ The time from last rituximab dose to reactivation of HBV was 3 months, although 29% occurred >6 months after last rituximab. Patients with previous exposure to HBV should be screened prior to initiating rituximab. Carriers should be closely monitored for clinical and laboratory signs of infection as reactivation may lead to liver failure and death in the months following therapy. There is an argument for the consideration of prophylactic treatment in selected patients.²⁴ Reactivation of the JC virus (a type of human polyomavirus), leading to progressive multifocal leukoencephalopathy (PML) has also been associated with rituximab treatment.²⁵ Among human immunodeficiency virus (HIV)-negative patients, the median time to diagnosis of PML was 5.5 months following the last dose of rituximab and a 90% fatality was reported. These data warrant vigilant monitoring for new onset neurologic findings during and after the course of treatment.

Pretreatment Infection Workup

Recent publications within the dermatology literature have provided recommendations for an infection workup for the dermatologist prior to initiating immunosuppressive agents.^2,3 In general, the suggested steps apply to all immunosuppressants, whether non-biologic or biologic. Table 3 provides a summary of these and our recommendations.

Although the morbidity and mortality from infectious complications can be significant, careful patient selection and monitoring can mitigate risk and reduce potential harm. General recommendations include conducting a thorough history and physical exam, with particular focus on country of birth and residence, travel history, sexual and social risk factors and exposure to sick contacts. Vaccination records should be reviewed and, if feasible, age-appropriate vaccinations should be updated prior to initiating immunosuppressive therapy. Patients should be educated on the importance of general hygiene (i.e., handwashing), signs and symptoms of early infection and when they should seek urgent medical care. Likewise, the dermatologist should be vigilant for early signs and symptoms of infection, and have a low threshold to treat bacterial, fungal and viral illness. Physicians should assess patients at each visit for impetiginization and treat appropriately.

All patients should undergo HIV, HBV, and hepatitis C virus (HCV) testing. Furthermore, testing and diagnosis of tuberculosis should be undertaken as per Centers for Disease Control and Prevention (CDC) and Health Canada recommendations and CDC: http://www.cdc.gov/tb/topic/testing/).
Testing for parasitic infections, particularly Strongyloides stercoralis (S. stercoralis) should be considered and done on an individualized basis. Infection with S. stercoralis is usually chronic and asymptomatic in immunocompetent patients and may persist undetected for many years. In immunosuppressed patients, strongyloidiasis can cause hyperinfection and dessimination and carries a high mortality rate. It is reasonable to screen those who have resided in an endemic area for a prolonged period even if it was in the distant past (i.e., southeastern United States and subtropical areas, Europe) and those who possess other risk factors (i.e., occupation, activities). Unexplained hypereosinophilia should also trigger the physician to screen for Strongyloides. Conversely, the physician should be mindful that prolonged corticosteroid use can suppress hypereosinophilia. Stool microscopy for ova and parasites is currently the gold standard for diagnosis, however, up to seven collections may be required in order to reach a sensitivity of 100%.²⁶ A single stool sample collection has a low sensitivity of 30-75%.^27,28 Sensitivity for the enzyme-linked immunosorbent assay (ELISA) for S. stercoralis serology is 83-93% with 95-97% specificity.²⁹

Conclusion

We have provided an overview of some of the major immunosuppressant drugs used in dermatology and have presented a summary of recommendations prior to initiating these medications (Table 3). Regardless of the immunosuppressive agent used, the type of infections that the dermatologist needs to screen for and prevent are similar. Overall, the risk of infection is likely to be directly proportional to the dose and duration of immunosuppressant therapy.

References

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19. Rowin J, Amato AA, Deisher N, et al. Mycophenolate mofetil in dermatomyositis: is it safe? Neurology. 2006 Apr 25;66(8):1245-7.
20. Saha M, Black MM, Groves RW. Risk of herpes zoster infection in patients with pemphigus on mycophenolate mofetil. Br J Dermatol. 2008 Nov;159(5):1212-3.
21. Gleason PP, Alexander GC, Starner CI, et al. Health plan utilization and costs of specialty drugs within 4 chronic conditions. J Manag Care Pharm. 2013 Sep;19(7):542-8.
22. Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol. 2015 Mar;27(2):127-33.
23. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011 May;22(5):1170-80.
24. Leung C, Tsoi E, Burns G, et al. An argument for the universal prophylaxis of hepatitis B infection in patients receiving rituximab: a 7-year institutional experience of hepatitis screening. Oncologist. 2011;16(5):579-84.
25. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009 May 14;113(20):4834-40.
26. Sarubbi FA. Hyperinfection with Strongyloides during treatment of pemphigus vulgaris. Arch Dermatol. 1987 Jul;123(7):864-5.
27. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001 Oct 1;33(7):1040-7.
28. Cartwright CP. Utility of multiple-stool-specimen ova and parasite examinations in a high-prevalence setting. J Clin Microbiol. 1999 Aug;37(8):2408-11.
29. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000 Oct;49(RR-10):1-125, CE1-7.

Head Lice

An estimated 1 in 10 children in Canada will be affected by a lice infestation this year and it is more common worldwide than the common cold. Head lice infestations, i.e., Pediculosis humanus capitis, is common, occurs worldwide and affects people of all ages and socioeconomic groups. Lice are wingless, bloodsucking insects. They are difficult to see because they are about the size of a sesame seed and they adapt to take on the color of their surroundings.

• The most common type of lice infestation.
• Occurs most commonly in school-aged children, especially girls between 3 and 11 years of age.
• Is often epidemic.
• Personal hygiene and socioeconomic status are not related to the likelihood of developing lice infestation.
• Not known to transmit bloodborne diseases.
• Spread though close head-to-head contact or through fomites (inanimate objects) which come into contact with the infested scalp and then are shared (e.g., combs, brushes, and hats).
• Most common places for outbreaks include schools, daycares, and play groups.

Clinical Manifestations & Diagnosis

Head lice are typically confined to the scalp and while itching is the main symptom of lice infestation, the lice themselves are not itchy and the bites are generally painless. Itching is caused by the body’s immune reaction to the saliva injected into the skin at the time of the blood meal. Redness and scaling may also be seen in the scalp as can small, itchy bumps on the posterior neck. Enlargement of lymph glands in the neck can occasionally be seen.

Diagnosis can be made ONLY by identification of a living louse. Nits or eggs are often empty shells and not an indication of an active infestation. Nits are also often mistaken for dandruff, sand or dirt, or dried hair gel.

Myths and Facts

Myths about head lice are abundant. Belief in these myths is often why treatments are not used properly and why people believe their lice treatment has failed. The myths include:

• • All children with lice scratch or itch.
    Fact: Initial infestation may produce no signs or symptoms for 4 – 6 weeks; only 1 in 3 children will complain of itching.

• • Lice jump or fly from head to head.
    Fact: Lice do not jump or fly, but can be dislodged from hair by air movements giving the appearance of flying.

• • Lice live in carpets, beds, clothes, and sofas.
    Fact: lice can only live for 24 hours away from a human host.

• • Lice die immediately after treatment.
    Fact: lice may take several hours to die following treatment.

• • One treatment is enough.
    Fact: due to loss of residual activity of pediculicides, two treatments, seven days apart, are recommended to kill newly hatched nymphs.

• • Permethrin based products are 100% ovicidal.
    Fact: permethrin kills 70% of eggs with one treatment.

• • Everyone in the family should be treated.
    Fact: only those with a proven infestation should be treated, although everyone should be checked daily to weekly.

• Head lice prefer long or dirty hair.
  Fact: lice do not care about hair length or cleanliness.

Treatment Options

There are many proposed “natural” and alternative cures for treating head lice, including various oils, petroleum jelly, peanut butter and mayonnaise; the effectiveness of most are dubious. However, there are no clinical studies to demonstrate effectiveness of these agents and many are messy and difficult to use.

Most patients will need to be treated with a commercial product designed to kill lice. Most of these are available over-thecounter and work by attacking the central nervous system of the louse. No pediculicide is 100% ovicidal. In order to achieve maximum effectiveness of the pediculicide, it needs to be applied to dry or nearly dry hair. It should be saturated to allow sufficient pediculicide to penetrate lice and nits and left on for the entire recommended time.

Permethrin 1% cream rinse (Nix®/Kwellada-P^®)

• Wash hair with conditioner-free shampoo and towel dry until hair is almost dry; then apply at least 25ml, and up to 50ml for thick or long hair, to hair and scalp especially behind the ears and the nape of the neck.
• Leave product on for 10 minutes, then rinse with cool water over a sink (not in a shower or bath)
• Comb wet hair with nit comb to remove any dying lice and nits
• A second treatment in 7 days should be carried out for maximum efficacy
• Minimal systemic absorption and low risk for toxicity
• Contraindicated in patients with chrysanthemum allergy

Synergized pyrethrins (R & C^® shampoo)

• Apply to dry hair and scalp, especially behind the ears and the nape of the neck. Hair must be completely dry.
• Leave on 10 minutes, then add water to form lather. Rinse with cool water over a sink. Do not use conditioner.
• A second treatment in 7 days should be carried out for maximum efficacy
• Low risk of toxicity
• Do not use if known allergy/sensitivity to chrysanthemum or ragweed

Lindane shampoo 1%

• Inexpensive
• Apply to dry hair, leave on for 5 minutes and rinse with cool water over a sink (not in a shower or bath)
• Comb wet hair with nit comb to remove any dying lice and nits
• Concern re: neurotoxicity with high dose or repeated exposure
• Contraindicated in neonates, young children (less than 2 years of age), pregnant women, and nursing mothers or those with a history of seizures.
• Resistance has been seen for more than 2 decades.

Regardless of the type of treatment recommended, patients should be encouraged to use a nit comb (fine toothed metal comb) such as the LiceMeister® comb, on wet hair to manually remove the nits, which can become cemented to the hair shafts. Treated patients should also be monitored for reinfestation.

Fomite Control

Following treatment, all clothing should be machine laundered and dried in the dryer (hot cycle). In addition, bed linens, towels, stuffed animals, and any headgear should be cleaned. Clothing that cannot be washed can be dry cleaned or sealed in a bag for 2 weeks. Combs and brushes can be covered in the pediculicide and then washed in hot water for 20 minutes; alternatively they can be soaked in a disinfectant solution (e.g., 2% Lysol for 1 hour). All interior areas should also be cleaned and vacuumed to remove any shed hairs.

Reasons for Failure of Treatment

• Wrong diagnosis
• Poor adherence / improper use of chemical lice treatment (e.g., applied to wet hair, insufficient product applied)
• Inadequate time to evaluate treatment (lice do not die on contact with product)
• Poor manual removal of nits
• New exposure to lice (re-infestation)
• Not repeating treatment 1 week later

Conclusion

Head lice are a common and embarrassing problem with many good treatments. Patients should be appropriately counseled to minimize spread of infestation and then advised on appropriate topical treatments. For further information about lice and lice eradication as well as counseling tips and patient material go to www.SkinPharmacies.ca/ce.html

Head Lice

An estimated 1 in 10 children in Canada will be affected by a lice infestation this year and it is more common worldwide than the common cold. Head lice infestations, i.e., Pediculosis humanus capitis, is common, occurs worldwide and affects people of all ages and socioeconomic groups. Lice are wingless, bloodsucking insects. They are difficult to see because they are about the size of a sesame seed and they adapt to take on the color of their surroundings.

• The most common type of lice infestation.
• Occurs most commonly in school-aged children, especially girls between 3 and 11 years of age.
• Is often epidemic.
• Personal hygiene and socioeconomic status are not related to the likelihood of developing lice infestation.
• Not known to transmit bloodborne diseases.
• Spread though close head-to-head contact or through fomites (inanimate objects) which come into contact with the
• infested scalp and then are shared (e.g., combs, brushes, and hats).
• Most common places for outbreaks include schools, daycares, and play groups.

Clinical Manifestations & Diagnosis

Head lice are typically confined to the scalp and while itching is the main symptom of lice infestation, the lice themselves are not itchy and the bites are generally painless. Itching is caused by the body’s immune reaction to the saliva injected into the skin at the time of the blood meal. Redness and scaling may also be seen in the scalp as can small, itchy bumps on the posterior neck. Enlargement of lymph glands in the neck can occasionally be seen.

Diagnosis can be made ONLY by identification of a living louse. Nits or eggs are often empty shells and not an indication of an active infestation. Nits are also often mistaken for dandruff, sand or dirt, or dried hair gel.

Myths and Facts

Myths about head lice are abundant. Belief in these myths is often why treatments are not used properly and why people believe their lice treatment has failed. The myths include:

• • All children with lice scratch or itch.
    Fact: Initial infestation may produce no signs or symptoms for 4 – 6 weeks; only 1 in 3 children will complain of itching.

• • Lice jump or fly from head to head.
    Fact:Lice do not jump or fly, but can be dislodged from hair by air movements giving the appearance of flying.

• • Lice live in carpets, beds, clothes, and sofas.
    Fact: lice can only live for 24 hours away from a human host.

• • Lice die immediately after treatment.
    Fact: lice may take several hours to die following treatment.

• • One treatment is enough.
    Fact: due to loss of residual activity of pediculicides, two treatments, seven days apart, are recommended to kill newly hatched nymphs.

• • Permethrin based products are 100% ovicidal.
    Fact: permethrin kills 70% of eggs with one treatment.

• • Everyone in the family should be treated.
    Fact: only those with a proven infestation should be treated, although everyone should be checked daily to weekly.

• Head lice prefer long or dirty hair.
  Fact: lice do not care about hair length or cleanliness.

Treatment Options

There are many proposed “natural” and alternative cures for treating head lice, including various oils, petroleum jelly, peanut butter and mayonnaise; the effectiveness of most are dubious. However, there are no clinical studies to demonstrate effectiveness of these agents and many are messy and difficult to use.

Most patients will need to be treated with a commercial product designed to kill lice. Most of these are available over-thecounter and work by attacking the central nervous system of the louse. No pediculicide is 100% ovicidal. In order to achieve maximum effectiveness of the pediculicide, it needs to be applied to dry or nearly dry hair. It should be saturated to allow sufficient pediculicide to penetrate lice and nits and left on for the entire recommended time.

Permethrin 1% cream rinse (Nix®/Kwellada-P^®)

• Wash hair with conditioner-free shampoo and towel dry until hair is almost dry; then apply at least 25ml, and up to 50ml for thick or long hair, to hair and scalp especially behind the ears and the nape of the neck.
• Leave product on for 10 minutes, then rinse with cool water over a sink (not in a shower or bath)
• Comb wet hair with nit comb to remove any dying lice and nits
• A second treatment in 7 days should be carried out for maximum efficacy
• Minimal systemic absorption and low risk for toxicity
• Contraindicated in patients with chrysanthemum allergy

Synergized pyrethrins (R & C^® shampoo)

• Apply to dry hair and scalp, especially behind the ears and the nape of the neck. Hair must be completely dry.
• Leave on 10 minutes, then add water to form lather. Rinse with cool water over a sink. Do not use conditioner.
• A second treatment in 7 days should be carried out for maximum efficacy
• Low risk of toxicity
• Do not use if known allergy/sensitivity to chrysanthemum or ragweed

Lindane shampoo 1%

• Inexpensive
• Apply to dry hair, leave on for 5 minutes and rinse with cool water over a sink (not in a shower or bath)
• Comb wet hair with nit comb to remove any dying lice and nits
• Concern re: neurotoxicity with high dose or repeated exposure
• Contraindicated in neonates, young children (less than 2 years of age), pregnant women, and nursing mothers or those with a history of seizures.
• Resistance has been seen for more than 2 decades.

Regardless of the type of treatment recommended, patients should be encouraged to use a nit comb (fine toothed metal comb) such as the LiceMeister® comb, on wet hair to manually remove the nits, which can become cemented to the hair shafts. Treated patients should also be monitored for reinfestation.

Fomite Control

Following treatment, all clothing should be machine laundered and dried in the dryer (hot cycle). In addition, bed linens, towels, stuffed animals, and any headgear should be cleaned. Clothing that cannot be washed can be dry cleaned or sealed in a bag for 2 weeks. Combs and brushes can be covered in the pediculicide and then washed in hot water for 20 minutes;
alternatively they can be soaked in a disinfectant solution (e.g., 2% Lysol for 1 hour). All interior areas should also be cleaned and vacuumed to remove any shed hairs.

Reasons for Failure of Treatment

• Wrong diagnosis
• Poor adherence / improper use of chemical lice treatment (e.g., applied to wet hair, insufficient product applied)
• Inadequate time to evaluate treatment (lice do not die on contact with product)
• Poor manual removal of nits
• New exposure to lice (re-infestation)
• Not repeating treatment 1 week later

Conclusion

Head lice are a common and embarrassing problem with many good treatments. Patients should be appropriately counseled to minimize spread of infestation and then advised on appropriate topical treatments. For further information about lice and lice eradication as well as counseling tips and patient material go to www.SkinPharmacies.ca/ce.html