








key: cord-356040-qdpkidn8
authors: Ghazawi, Feras M.; Lim, Megan; Dutz, Jan P.; Kirchhof, Mark G.
title: Infection risk of dermatologic therapeutics during the COVID‐19 pandemic: an evidence‐based recalibration
date: 2020-07-03
journal: Int J Dermatol
DOI: 10.1111/ijd.15028
sha: 
doc_id: 356040
cord_uid: qdpkidn8

Recommendations were made recently to limit or stop the use of oral and systemic immunotherapies for skin diseases due to potential risks to the patients during the current severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) COVID‐19 pandemic. Herein, we attempt to identify potentially safe immunotherapies that may be used in the treatment of cutaneous diseases during the current COVID‐19 pandemic. We performed a literature review to approximate the risk of SARS‐CoV‐2 infection, including available data on the roles of relevant cytokines, cell subsets, and their mediators in eliciting an optimal immune response against respiratory viruses in murine gene deletion models and humans with congenital deficiencies were reviewed for viral infections risk and if possible coronaviruses specifically. Furthermore, reported risk of infections of biologic and non‐biologic therapeutics for skin diseases from clinical trials and drug data registries were evaluated. Many of the immunotherapies used in dermatology have data to support their safe use during the COVID‐19 pandemic including the biologics that target IgE, IL‐4/13, TNF‐α, IL‐17, IL‐12, and IL‐23. Furthermore, we provide evidence to show that oral immunosuppressive medications such as methotrexate and cyclosporine do not significantly increase the risk to patients. Most biologic and conventional immunotherapies, based on doses and indications in dermatology, do not appear to increase risk of viral susceptibility and are most likely safe for use during the COVID‐19 pandemic. The limitation of this study is availability of data on COVID‐19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also named 2019 novel coronavirus disease COVID-19, is the causative agent of the ongoing pandemic. 1 and MIP-1a. 5, 6 This is consistent with the reported elevation of proinflammatory cytokines in SARS 7 and MERS infections. 8 The massive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokine responses result in acute lung injury and ARDS. 4, 9, 10 Part 2: Infectious risks associated with biologics: evaluating cytokine knockout data and reviewing data from randomized controlled trials (RCTs) and biologic treatment registries

Infecting TNF-a À/À , TNF receptor 1 (R1) À/À , and TNFR2 À/À mice with mouse hepatitis virus-3 (MHV-3, belongs to the coronavirus family) revealed that a deficiency of either TNF-a or TNFR1 decreased morbidity and mortality (Table 1) . 11 TNF receptors 1/2 knock-out mice infected with SARS-CoV were protected from infection-related morbidity. 12 Collectively, TNF-a promotes the deleterious effects of coronavirus infection presumably through excessive inflammation. From clinical trials ( 

The B-lymphocyte antigen CD20 is highly expressed on B cells starting at the pre-B-cell stage and on mature B cells, and it is downregulated during terminal differentiation into plasma cells.

While the precise function of CD20 is not fully elucidated, IgM expression in immature and mature B cells from CD20-deficient mice was markedly reduced compared to wildtype. 16 Furthermore, reduced humoral immunity to adeno-associated viral antigens was demonstrated in CD20-deficient mice. 17 A patient who lacked CD20 expression due to homozygous mutations reported intermittent respiratory infections, associated with persistent hypogammaglobulinemia and strong reductions in circulating memory B cells. 18 No significant differences in URTI, nasopharyngitis, bronchitis, cough, and sinusitis between rituximab (anti-CD20) 19 and placebo were demonstrated in a double-blind RCT for rheumatoid arthritis (RA). 20 However, in a prospective, open-label RCT, it was noted that lung infections/ pneumonia were higher in the rituximab treatment arm by more than twofold (11% vs. 5% in control, no confidence intervals were presented). 21 The role of CD20 + cells in presenting antigen to T cells and in generation of antibodies to protect from new infections remains unclear.

The IL-12/IL-23 common pathway plays a key role in the induction of inflammation in adaptive immune responses, where IL-12 induces a Th1 immune response with a downstream induction of cytokines such as TNF, interferon (IFN)-c, and IL-23 promotes a Th17 immune response through the induction of inflammatory cytokines such as IL-17 and IL-22. 22 Mice defective in both IL-12/23 (p40 À/À ) and IL-12 alone (p35 À/À ) were infected with a murine coronavirus (MHV). 23 IL-12 and IL-12/23 knockout mice had similar survival to wild-type animals. 23 Therefore, IL-12 does not seem to contribute to antiviral function or survival. Mice deficient in IL-23 alone (p19 À/À ) were infected with murine coronavirus, and viral control was similar to wild-type mice, demonstrating that IL-23 does not significantly confer protection from infection. 24 This was also demonstrated thorough neutralization of mice using anti-IL-23p19specific and anti-IL-12/23p40 antibodies, followed by infection of mice with MHV. 25 In the absence of IL-12/23 signaling, specific antiviral T-cell response was intact. 25 Clinical trials using IL-12/23 or IL-23 inhibitors demonstrated no significant increase in respiratory adverse events (Table 2) . Furthermore, the PSOLAR study reported that ustekinumab had no increased risk of serious infections. 13 Of note, a recent case study reported COVID-19 in a patient during IL-23 inhibitor (guselkumab) treatment for psoriasis, and the patient had a good outcome. 26 

IL-17 is a proinflammatory cytokine with important roles in Tcell activation and neutrophil mobilization and activation. 27 IL-17 expression is induced during influenza infection as part of the Th1 immune response that contributes to viral clearance. 28 However, a growing body of evidence suggests that IL-17 is also associated with promotion of viral infections and tissue pathology. This is thought to occur through direct suppression including TNF-a, IL-1b, and IL-6. 32 In humans, chronic mucocutaneous candidiasis has been attributed to the disruption of Th1 and Th17 pathways. This was illustrated in patients with identified mutations in IL-17RA and STAT1 genes. 33 These patients have no increased risk of viral infections. 34 Clinical trials using IL-17 inhibitors demonstrated no significant increase in respiratory adverse events (Table 2) . A recent case report reported a patient receiving therapy with an IL-17 inhibitor (ixekizumab)

who was completely asymptomatic but tested positive for COVID-19. 35 ity. 38 The use of anakinra in clinical trials was associated with a slightly higher frequency of serious infectious episodes, primarily pneumonia (2.1% vs. 0.4%, comparative risk 5.25), than the placebo group. 39 It appears that normal IL-1 expression/ function is required to mount an optimal antiviral immune response.

IL-4 is a key regulator in humoral and Th2 adaptive immunity.

Mouse models demonstrated that the constitutive overexpression of IL-4 prior to RSV infection delayed viral clearance, increased the density of the lymphocytic infiltrate in the lungs, and diminished induction of primary cytotoxic T lymphocyte responses. 40 Conversely, IL-4 À/À mice cleared RSV readily after primary infection, with minimal pathology. 40 

Cyclosporine is a calcineurin inhibitor that blocks IL-2 signaling

and T-cell proliferation. 52, 53 The most common infectious side effects from cyclosporine were flu-like symptoms seen in 15% of patients enrolled in an RCT for chronic idiopathic urticaria. 54 Psoriasis registries examining cyclosporine reported infection Trials that combined MMF with corticosteroids had significantly higher rates of infections, up to 59%. 62 MMF is reported to increase patients' susceptibility to viral infections, 63 and an increase in nasopharyngitis and URTIs was noted comparing prednisone plus MMF to prednisone monotherapy in pemphigus vulgaris. 62 Of note, MMF was used to treat eight patients with MERS with a 100% survival rate; however, when analyzing the severity of illness and treatment, MMF was given to less severely ill patients. 64 Azathioprine Azathioprine inhibits purine synthesis and downregulates B-cell and T-cell function. 65, 66 Documented types of infection with use of azathioprine include lower respiratory tract infections (LRTI) and URTI, which had rates of 5% and 5-20%, respectively. 67, 68 Thirty-six percent of patients in one study had infections of moderate intensity. 69 There were no registries evaluating the prevalence of infections during azathioprine therapy for dermatologic uses. One systematic review evaluating the off-label use of azathioprine found mild infections reported in 0.36% of patients and severe infections in only 0.30% of patients 70 (Table 3 ).

The use of methotrexate (MTX), 71 a folic acid antagonist that inhibits nucleotide synthesis, 72 infection were similar to the placebo group. 76 A review of infectious risks in rheumatoid arthritis (RA) patients indicated that although MTX has previously been implicated not only with increased risk of infection but also increased severity, the evidence was not clear. 77 The review concluded that MTX appears to be associated with minimal, if any, increased infection risk in the RA population. 77

Hydroxychloroquine is an antimalarial medication that inhibits lysosomal functions and interferes with a myriad of immune pathways. 78 Its exact mechanism in many dermatologic processes has never been fully elucidated. Hydroxychloroquine has been shown to have a favorable side effect profile in terms of infection risk in many clinical trials. 79, 80 It is currently under investigation in numerous phase 2 clinical trials as treatment for COVID-19 as it may inhibit viral fusion to the host cell and inhibit viral assembly and release. 81

Apremilast is a phosphodiesterase 4 (PDE4) inhibitor, 82 with side effects including nasopharyngitis and URTI. 83 The incidence of URTI in the apremilast-treated groups is comparable to placebo ranging from 4.8 to 26.0% and 4.4 to 14.0%, with higher rates being accounted for from one study examining apremilast in palmoplantar psoriasis (Table 3 ). Overall, rates of infection were not increased in patients treated with apremilast. [84] [85] [86] [87] [88] [89] A recent case was reported of a patient with erythrodermic psoriasis, with contraindication to most treatments due to a recurrent brain oligodendroglioma who had psoriasis Thalidomide Thalidomide, 91 an immunomodulatory drug with a range of activity that is not fully characterized, 92 is effective for various refractory dermatoses, but its side effect profile is unfavorable, and risks of teratogenicity and neuropathy often preclude its use. 91 Table 3 highlights four RCTs where there was no increased risk of infection in thalidomide compared to placebo.

Prolonged use of oral corticosteroids is generally avoided due to side effects. 93 None of the following studies reported infection as an adverse reaction. 94 

Immunosuppression is not a comorbidity that is commonly reported in COVID-19 patients despite it commonly being referred to as a risk factor. 104 The limited data do not suggest increased risk of severe complications compared to the general population. Lei et al. 105 reported two heart transplant patients in China who survived COVID-19 infections. Two reported renal transplant patients who contracted COVID-19 and succumbed to the illness had similar clinical courses compared to non-transplant patients. 106 Transplant recipients may practice more stringent physical distancing practices compared to the general population, resulting in falsely low numbers.

The literature surrounding SARS and transplant recipients is sparse. Risk factors for severe SARS included hypertension, diabetes, coronary heart disease, hepatitis, and pregnancy with a mortality rate with ≥1 risk factor compared to none of 54.5% vs. 7.5%; P < 0.01. 107 There is no evidence that suggests transplant recipients had poorer outcome in the SARS epidemic.

A retrospective cohort study of a MERS outbreak in Korea revealed that the number of affected immunosuppressed patients was low and did not identify any transplant patients. 108 Immunosuppression was not identified as a poor prognostic factor in MERS infection. 109

Immunomodulatory regimens have revolutionized the treatment of dermatological diseases. With the current COVID-19 pandemic, it is imperative to examine the evidence and conduct a risk-benefit analysis for each patient. There may be patients who require more or less treatment, for instance some patients with existing comorbidities may require a more conservative Figure 1 A pictorial representation of COVID-19 risk assessment of dermatologic treatments where green represents "safe" and red represents "higher risk"

approach. 110 The greatest risk of infections in biologics appear to occur with CD20 inhibition (Fig. 1) . For non-biologic immunotherapies, the greatest risk of infection appears to occur with the use of high doses of oral corticosteroids. A slight increased infection risk is seen with cyclosporine, although cyclosporine has been shown to inhibit coronavirus replication and did not increase susceptibility in transplant patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges

COVID-19 and psoriasis: is it time to limit treatment with immunosuppressants? A call for action

Should biologics for psoriasis be interrupted in the era of COVID-19?

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Dysregulation of immune response in patients with COVID-19 in Wuhan, China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province

COVID-19 infection: the perspectives on immune responses

Tumor necrosis factor alpha (TNFalpha) receptor-I is required for TNF-alpha-mediated fulminant virus hepatitis caused by murine hepatitis virus strain-3 infection

The effect of inhibition of PP1 and TNFalpha signaling on pathogenesis of SARS coronavirus

Risk of serious infection with biologic and systemic treatment of psoriasis: results from the psoriasis longitudinal assessment and registry (PSOLAR)

Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology

A randomized, open-label, controlled trial for the efficacy and safety of Adalimumab Injection in the treatment of patients with severe novel coronavirus pneumonia (COVID-19)

Mouse CD20 expression and function

Reduced T-dependent humoral immunity in CD20-deficient mice

CD20 deficiency in humans results in impaired T cell-independent antibody responses

Rituximab: uses in dermatology

Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial

IL-12 and IL-23 cytokines: from discovery to targeted therapies for immunemediated inflammatory diseases

Mice lacking IL-12 develop polarized Th1 cells during viral infection

Interleukin-12 (IL-12), but not IL-23, deficiency ameliorates viral encephalitis without affecting viral control

Generation of a protective T-cell response following coronavirus infection of the central nervous system is not dependent on IL-12/23 signaling

SARS-CoV-2 infection in a psoriatic patient treated with IL-23 inhibitor

Immunity to infection in IL-17-deficient mice and humans

The protective and pathogenic roles of IL-17 in viral infections: friend or foe?

IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease

Th17 cells contribute to viral replication in coxsackievirus B3-induced acute viral myocarditis

Deficiency of autophagy protein Map1-LC3b mediates IL-17-dependent lung International Journal of Dermatology 2020 ª 2020 the International Society of Dermatology pathology during respiratory viral infection via ER stressassociated IL-1

Critical role of IL-17RA in immunopathology of influenza infection

Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity

STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis

SARS-CoV-2 infection in a psoriatic patient treated with IL-17 inhibitor

MyD88 is required for protection from lethal infection with a mouseadapted SARS-CoV

The NLRP3 inflammasome and IL-1beta accelerate immunologically mediated pathology in experimental viral fulminant hepatitis

An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist

Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial

Overexpression of interleukin-4 delays virus clearance in mice infected with respiratory syncytial virus

Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2)

Safety of dupilumab in severe atopic dermatitis and infection of Covid-19: two case reports

No evidence of increased risk for COVID-19 infection in patients treated with Dupilumab for atopic dermatitis in a high-epidemic area

Belloni Fortina A. SARS-CoV-2 asymptomatic infection in a patient under treatment with dupilumab

COVID-19 infection in a patient with severe chronic rhinosinusitis with nasal polyps during therapy with dupilumab

Omalizumab for treating chronic spontaneous urticaria: an expert review on efficacy and safety

Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria

Similar efficacy with omalizumab in chronic idiopathic/spontaneous urticaria despite different background therapy

Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial

A randomized doubleblind trial of intravenous immunoglobulin for bullous pemphigoid

A randomized doubleblind trial of intravenous immunoglobulin for pemphigus

Inhibition of neutrophil responses by cyclosporin A. An insight into molecular mechanisms

Product monograph

Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria

Long term safety of nine systemic medications for psoriasis: a cohort study using the Biobadaderm Registry

Drug safety of systemic treatments for psoriasis: results from the German Psoriasis Registry PsoBest

Infections in moderate to severe psoriasis patients treated with biological drugs compared to classic systemic drugs: findings from the BIOBADADERM registry

Suppression of coronavirus replication by cyclophilin inhibitors

Cyclosporin A inhibits the replication of diverse coronaviruses

Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation

Mycophenolate mofetil

Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial

Risk of herpes zoster infection in patients with pemphigus on mycophenolate mofetil

Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes

Product monograph

Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial

Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial

A randomized trial of methotrexate versus azathioprine for severe atopic eczema

Off-label use of azathioprine in dermatology: a systematic review

Product monograph

Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebocontrolled, phase 3 trial

A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis

A randomized placebo-controlled trial of methotrexate in psoriatic arthritis

Low-dose methotrexate for the prevention of atherosclerotic events

rheumatoid arthritis and infection risk: what is the evidence?

Hydroxychloroquine in systemic lupus erythematosus (SLE)

Effects of hydroxychloroquine in patients with cutaneous lupus erythematosus: a multicenter, double-blind, randomized, Parallel-Group Trial

Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study)

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Apremilast in psoriasis and beyond: big hopes on a small molecule

Otezla â (apremilast)

Efficacy and safety of apremilast in systemic-and biologic-naive patients with moderate plaque psoriasis: 52-week results of UNVEIL

Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment: findings from the LIBERATE study

Apremilast for the treatment of moderate-to-severe palmoplantar psoriasis: results from a double-blind, placebo-controlled, randomized study

Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1)

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2)

Apremilast for moderate hidradenitis suppurativa: results of a randomized controlled trial

COVID-19 pulmonary infection in erythrodermic psoriatic patient with oligodendroglioma: safety and compatibility of apremilast with critical intensive care management

Thalidomid â (Thalidomide)

Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production

Product monograph

The role of systemic steroids and phototherapy in the treatment of stable vitiligo: a randomized controlled trial

Placebo-controlled oral pulse prednisolone therapy in alopecia areata

A comparison of the efficacy, relapse rate and side effects among three modalities of systemic corticosteroid therapy for alopecia areata

A randomized comparative study of oral corticosteroid minipulse and lowdose oral methotrexate in the treatment of unstable vitiligo

Adverse events of low-to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis

the International Society of Dermatology

Risk of infectious complications in patients taking glucocorticosteroids

but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an International Registry

RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials

The natural history of influenza infection in the severely immunocompromised vs nonimmunocompromised hosts

Coronaviruses and immunosuppressed patients. The facts during the third epidemic

Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis

First cases of COVID-19 from China

COVID-19 in kidney transplant recipients

Prognostic factors for severe acute respiratory syndrome: a clinical analysis of 165 cases

Host susceptibility to MERS-CoV infection, a retrospective cohort study of the 2015 Korean MERS outbreak

Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission

Available at

Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection

Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial

Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks from 2 phase 3, multicenter, randomized, doubleblinded

Secukinumab in plaque psoriasis-results of two phase 3 trials

A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction

Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial

Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)

Phase 3 studies comparing brodalumab with ustekinumab in psoriasis

Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials

Safety of guselkumab in patients with moderate-to-severe psoriasis treated through 100 weeks: a pooled analysis from the randomized VOYAGE 1 and VOYAGE 2 studies

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placeboand active comparator-controlled VOYAGE 2 trial

Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials

Safety of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials

A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate

Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebocontrolled trial

Adalimumab or cyclosporine as monotherapy and in combination in severe psoriatic arthritis: results from a prospective 12-month nonrandomized unblinded clinical trial

Cyclosporine for moderate-tosevere alopecia areata: a double-blind, randomized, placebocontrolled clinical trial of efficacy and safety

A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid

Efficacy and safety of mycophenolate mofetil vs. methotrexate for the treatment of chronic plaque psoriasis

Evaluation of mycophenolate mofetil as a steroid-sparing agent in pemphigus: a randomized, prospective study

Mycophenolate mofetil (CellCept) for psoriasis: a two-center, prospective, open-label clinical trial

A randomized, investigator-masked, double-blind, placebo-controlled trial on thalidomide in severe cutaneous sarcoidosis

Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study

Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial

Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, double-blind, placebo-controlled trial

Cyclosporin in the treatment of patients with atopic eczema -a systematic review and meta-analysis

Long-term efficacy and safety of azathioprine in ulcerative colitis

Effectiveness of methotrexate in moderate to severe psoriasis patients: realworld registry data from the Swiss Dermatology Network for Targeted Therapies (SDNTT)

Real-world data on the efficacy and safety of apremilast in patients with moderate-to-severe plaque psoriasis

Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti-tumor necrosis factor agents versus classic therapies: prospective meta-analysis of Psonet registries

the International Society of Dermatology

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. JPD is a Senior Scientist at BC Children's Hospital Research Institute.

