¹John P. and Kathrine G. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic, inflammatory disease with heterogeneous clinical features. The pathogenesis of PsA involves a complex interplay of genetic, immunologic, and environmental factors, leading to the activation of the immune system and subsequent inflammation. Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23/T helper 17 pathway in the disease process. Guselkumab, a novel IL-23 inhibitor, has emerged as a promising therapeutic option for PsA, offering an alternative to conventional therapies and other biologics. This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Keywords: psoriatic arthritis, guselkumab, treatment, efficacy, psoriasis, arthritis

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease that will develop in about 30% of individuals with psoriasis. The condition is characterized by a wide range of clinical features, making it complex and diverse in its presentation. The pathogenesis of PsA involves a multifaceted interaction between genetic, immunologic, and environmental factors, which leads to immune system activation and subsequent inflammation.¹

Currently, there are no specific diagnostic criteria or tests for PsA. Diagnosis is typically based on the presence of inflammatory musculoskeletal symptoms in joints, entheses, or the spine, alongside skin and/or nail psoriasis, and the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The progression from psoriasis to PsA may occur in stages, although the underlying mechanisms remain unclear. Interestingly, the severity of musculoskeletal inflammation does not always correlate with the severity of skin or nail psoriasis, a phenomenon likely influenced by genetic variability, particularly in the human leukocyte antigen (HLA) region.¹

Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23 (IL-23)/T helper 17 (Th17) pathway in the disease process. Guselkumab is a human monoclonal antibody that selectively binds to the p19 subunit of IL-23, thereby inhibiting its interaction with the IL-23 receptor. By blocking IL-23 signaling, guselkumab prevents the activation and proliferation of Th17 cells, which are pivotal in the pathogenesis of PsA. Th17 cells produce several pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22, which contribute to the inflammation and joint damage observed in PsA. By targeting IL-23, guselkumab effectively reduces the levels of these downstream cytokines, thereby attenuating the inflammatory response and improving clinical outcomes in patients with PsA.²

Guselkumab has been approved by the United States Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) for the treatment of adult patients with active psoriatic arthritis and moderate-to-severe psoriasis (PSO) who are candidates for systemic therapy. Additionally, the EMA has approved guselkumab for the treatment of active psoriatic arthritis in adults who have had an inadequate response to, or are intolerant of, previous disease-modifying antirheumatic drug (DMARD) therapy.²

This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Methods

Our search focused on English-language literature concerning clinical trials of guselkumab in adults with psoriatic arthritis. We conducted a search in the Medline database via PubMed up until September 1, 2024, using the MeSH terms “guselkumab” AND “psoriatic arthritis.” This search yielded 177 results. We excluded books, meta-analyses, reviews, and systematic reviews, narrowing our focus to clinical trials and randomized controlled trials, resulting in 30 trials. Out of these, we included 9 trials and excluded 10 due to integrated analysis of multiple trials, 7 due to duplication, and 4 due to a focus on topics other than PsA.

Results

The included studies primarily consisted of double-blind, randomized, placebo-controlled Phase 3 trials that evaluated the efficacy of guselkumab in patients with PsA (Table 1). Across these trials, guselkumab demonstrated significant efficacy in achieving American College of Rheumatology (ACR) response criteria at various time points:

Table 1

ACR20 Response

Guselkumab consistently showed superior results compared to placebo. For instance, Deodhar et al. reported that 59% of patients treated with guselkumab every 4 weeks and 52% treated every 8 weeks achieved ACR20, compared to 22% in the placebo group.³ Similar trends were observed in other studies, with response rates ranging from 44% to 76% for guselkumab, significantly higher than the placebo groups, which ranged from 20% to 33%.^4-7

ACR50 and ACR70 Responses

Some trials also assessed higher response thresholds. McInnes et al. observed ACR50 and ACR70 responses in 48-56% and 30-36% of patients, respectively, in the guselkumab-treated groups.⁸ Ritchlin et al. noted that 33% and 31% of patients achieved ACR50 at week 24 in the every-4-weeks and every-8-weeks groups, respectively, compared to 14% in the placebo group. ACR70 responses were achieved by 13-19% of guselkumab-treated patients, compared to 4% in the placebo group.⁹

Additional Outcomes

Beyond ACR responses, trials such as Curtis et al. and Orbai et al. assessed work productivity and patient-reported outcomes, showing significant improvements in these domains among patients treated with guselkumab. Improvements in presenteeism, work productivity, non-work activity, and Patient-Reported Outcomes Measurement Information System® (PROMIS)-29 scores were all more substantial in guselkumab groups compared to placebo, with improvements continuing through week 52 after placebo patients were switched to guselkumab.^10,11

These results highlight the efficacy of guselkumab in improving clinical outcomes in PsA patients, particularly in achieving ACR response criteria and enhancing patient-reported outcomes.

Discussion

In the management of PsA, the primary objective of pharmacological treatment is to enhance patients’ health-related quality of life. This is achieved by alleviating symptoms, preventing structural joint damage, and restoring normal function and daily activities. A significant reduction in inflammation is crucial to reaching these goals. Within this therapeutic landscape, guselkumab offers several distinct advantages over other biologics, particularly tumor necrosis factor (TNF) inhibitors and IL-17 inhibitors.

TNF inhibitors are commonly used in PsA treatment, but their efficacy in managing skin symptoms can be variable, and they are associated with a higher risk of certain adverse events (AEs), such as infections and demyelinating diseases. IL-17 inhibitors, including secukinumab and ixekizumab, are effective for both skin and joint manifestations but may increase the risk of inflammatory bowel disease. In contrast, guselkumab specifically targets the IL-23 pathway, offering a more focused modulation of the immune response in PsA. This targeted inhibition may lead to fewer offtarget effects and a more favorable safety profile, particularly concerning infections and autoimmune-related AEs. Additionally, guselkumab has shown efficacy in patients who have not responded adequately to TNF inhibitors, making it an invaluable option for this challenging subset of patients.¹²

The safety profile of guselkumab has been thoroughly evaluated in both clinical trials and post-marketing surveillance. Across these studies, the incidence of AEs was comparable between guselkumab and placebo groups, with the most common being nasopharyngitis, upper respiratory tract infections, and headaches. Serious adverse events were infrequent and occurred at similar rates across treatment groups. Importantly, guselkumab did not increase the risk of serious infections, malignancies, or major cardiovascular events, which supports its suitability for long-term use.

Overall, guselkumab emerges as a promising therapeutic option for PsA, particularly for patients who require an alternative to TNF inhibitors or those concerned with the safety profiles of currently available biologics. Its focused mechanism of action, combined with a robust safety profile, positions guselkumab as an effective and well-tolerated treatment in the ongoing effort to improve patient outcomes in PsA.

Conclusion

Guselkumab represents a significant advancement in the treatment of PsA, providing a novel mechanism of action with robust clinical efficacy and a favorable safety profile. The evidence from RCTs and real-world studies supports its use in a broad range of patients, including those who are biologic-naïve and those with previous biologic exposure. As the understanding of the IL-23/Th17 pathway continues to evolve, guselkumab and other IL-23 inhibitors are likely to play an increasingly important role in the management of PsA, offering patients new hope for improved disease control and quality of life. Future research should focus on long-term outcomes, comparative effectiveness with other biologics, and the identification of biomarkers to personalize treatment strategies for patients with PsA.

References

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¹Department of Medicine, University of Toronto, ON, Canada
²Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
³Department of Dermatology, Women’s College Hospital, Toronto, ON, Canada
⁴Probity Medical Research, Peterborough, ON, Canada
⁵SKiN Center for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: Karla Machlab has no conflicts of interest. Jensen Yeung has served as an investigator, speaker, and/or advisory board member for, and/or received grants/honoraria from: AbbVie, Amgen, Anacor, Astellas, Arcutis, Bausch Health, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, Incyte, Janssen, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, and Xenon. Melinda Gooderham serves as the Vice President of the Dermatology Association of Ontario and has served as an investigator, speaker, advisor and/or consultant for, and/or received grants/honoraria from: AbbVie, Akros, Amgen, Arcutis, Aslan, Aristea, AnaptysBio, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Meiji, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, and UCB. Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease associated with psoriasis. Its major clinical domains include peripheral and axial arthritis, enthesitis, dactylitis and skin and nail involvement. Approximately 30% of patients with psoriasis develop psoriatic arthritis. The pathophysiology of PsA is complex and involves a dysregulated immune response. In particular, interleukin (IL)-23 is a major regulatory cytokine that has been implicated in PsA, including bone remodeling, enthesitis, synovitis and psoriatic lesions. Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that targets the p19 subunit of IL-23. It has been approved for the treatment of moderate-to-severe plaque psoriasis and, more recently, PsA. The efficacy and safety of risankizumab for the treatment of PsA has been demonstrated in phase 2 and phase 3 clinical trials. Risankizumab showed efficacy in decreasing the number of swollen and tender joints, clearing psoriatic plaque and improving quality of life. Treatment with risankizumab was well-tolerated, with the most common adverse event being upper respiratory tract infection. Overall, the current literature demonstrates that risankizumab is both a safe and effective therapeutic option for the treatment of PsA. Herein, week 24 and 52 results are reviewed.

Keywords: risankizumab, Skyrizi®, IL-23, psoriatic arthritis

Introduction

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease characterized by a range of clinical features including arthritic inflammation, dactylitis, enthesitis, and skin and nail changes. PsA may also be associated with multiple comorbidities including type 2 diabetes, hypertension, metabolic syndrome and cardiovascular disease.^1,2 Accordingly, PsA can greatly impair one’s quality of life (QoL) and therefore prompt intervention is crucial.^3,4

PsA affects males and females equally with an estimated prevalence of 1-2 in 1000.⁵ Approximately 30% of patients with psoriasis will develop PsA.^6-8sup> Given the high prevalence of PsA, it is important to continue to find effective and safe therapeutic options. This review focuses on the current literature regarding the efficacy and safety of risankizumab for the treatment of PsA up to 52 weeks of treatment.

Pathophysiology

The pathophysiology of PsA is complex and multifactorial. Although the exact mechanism is not completely understood, genetic and environmental factors interact to trigger immune pathways. PsA is associated with class II major histocompatibility complex (MHC) alleles, including HA-B*27, B*0801, B*3801 and B*3901.⁹ Risk factors include severe psoriasis, scalp, inverse or nail psoriasis, obesity and trauma (Koebner phenomenon).¹⁰ T-cells are major effectors in PsA and the role of CD8+ T-cells is supported by a strong association with HLA-1 alleles.¹¹ Type 17 T-cells, which include CD4+ type 17 helper T (Th17) cells, and type 3 innate lymphocytes, which produce interleukin (IL)-17 and IL-22, are increased in synovial fluid in patients with PsA.¹²

IL-23/IL-17 and tumor necrosis factor (TNF) pathways also play a central role and contribute to most domains of PsA, including synovitis, enthesitis, axial inflammation and psoriatic plaques. Dendritic cells produce IL-23, which triggers the differentiation and proliferation of Th17 cells, and activates other cytokine pathways including IL-17, IL-22 and TNF-α.¹³ These subsequently activate downstream effector cells, including keratinocytes, fibroblasts, osteoclast precursors, B-cells and macrophages. An inflammatory immune response is initiated resulting in keratinocyte proliferation, bone erosion and pathologic bone formation. Murine models have shown that administration of IL-23 leads to entheseal inflammation, inflammatory arthritis, bone erosion, periosteal bone formation, and increased production of IL-17.^14,15

Overview of Therapy

Treatment of PsA is initially guided by severity of disease and, importantly, the degree of activity in each of the domains. Mild PsA can be managed with non-steroidal anti-inflammatory drugs (NSAIDs) or intra-articular steroids. However, in moderateto- severe PsA, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, leflunomide or sulfasalazine are typically used first line. Newer novel agents, such as phosphodiesterase-4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, and biologic DMARDs (bDMARDs) are also approved efficacious agents. Biologics include TNF, IL-17, and IL-12/23 or IL-23 inhibitors.

TNF inhibitors were previously considered gold standard and are effective at improving clinical signs and symptoms of PsA and reducing radiographic progression of disease.¹⁶ Currently, five TNF inhibitors (etanercept, adalimumab, golimumab, certolizumab and infliximab) are approved for the treatment of PsA. The efficacy and safety of these agents are comparable;^17,18 ultimately, the choice of agent depends on factors such as patient preference for route and frequency of administration, physician experience, availability, and cost. Patients must be screened for latent tuberculosis and hepatitis B virus (HBV) infections and treated prophylactically if there is evidence of current or prior infection.¹⁹ Moreover, TNF inhibitors are contraindicated in patients with significant heart failure, recent malignancy or a family history of multiple sclerosis.^20,21 Newer classes of biologics have also been approved for the treatment of PsA and these include cytokine inhibitors anti-IL-17 (secukinumab and ixekizumab), anti-IL-12/23 (ustekinumab), and anti-IL-23 (guselkumab and risankizumab). These cytokine inhibitors have proven to be effective in treating PsA and are especially useful in patients who have contraindications to TNF inhibitors, but caution should be exercised with IL-17 inhibitors in patients with a history of inflammatory bowel disease.

Risankizumab for the Treatment of Psoriasis

Risankizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets the p19 subunit of IL-23. In 2019, it was approved for the treatment of moderate-to-severe plaque psoriasis. Administration follows a dosing schedule of 150 mg at week 0, week 4, and then every 12 weeks thereafter. Several clinical trials have established its ability to treat psoriasis with high efficacy and safety compared to biologics from each of the other classes. Two randomized, double-blinded phase 3 trials, UltIMMA-1 (n = 506) and UltIMMa-2 (n = 491), showed that risankizumab has significantly greater efficacy than ustekinumab and placebo.²² Skin clearance was seen as early as 4 weeks of treatment. Treatmentrelated adverse events (TEAEs) were comparable across all groups. Risankizumab was also proven superior to adalimumab in the phase 3 trial IMMvent (n = 605) where subjects were randomly assigned to a standard dosing regimen of risankizumab or adalimumab.²³ Efficacy was measured by the Psoriasis Area and Severity Index (PASI) and after 16 weeks of treatment 70% of patients on risankizumab achieved a 90% decrease in their PASI score from baseline (PASI90), compared to 44% those on adalimumab. In the phase 3b trial IMMerge, risankizumab was found to be superior to secukinumab at week 52 with PASI90 rates of 86.6% for risankizumab versus 57.1% for secukinumab.²⁴ These head-to-head studies have demonstrated risankizumab’s superior efficacy for plaque psoriasis when compared to adalimumab, ustekinumab and secukinumab.

Risankizumab for the Treatment of PsA

Given the critical role that IL-23 plays in the pathogenesis, risankizumab is an important therapeutic option for PsA. In a phase 2 trial, 185 subjects with active PsA were randomized into five groups: risankizumab 150 mg at week 0, 4, 8, 12 and 16 (arm 1); risankizumab 150 mg at week 0, 4 and 16 (arm 2); risankizumab at week 0 and 12 (arm 3); risankizumab 75 mg at week 0 (arm 4), or placebo.²⁵ The primary endpoint at week 16 was American College of Rheumatology 20 (ACR20) response. ACR20 is a composite measure defined as a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement in three or more of five variables: patient-assessed global activity, evaluator-assessed global activity, patient pain activity, functional disability, and acute phase response (ESR or CRP). Secondary endpoints included ACR50/70, dactylitis count, Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index, and health assessment questionnaire and disability index (HAQDI), a questionnaire designed to evaluate functional status and QoL in patients with arthritis. After 16 weeks of treatment, ACR20 was significantly higher across all treatment arms (57.1- 65.0%) compared to placebo (35.7%). ACR50 was higher across all treatment arms, and significant in arm 3 (39%) compared to placebo (12%). ACR70 was also higher across all treatment arms, and significant in arms 1, 1+2, 3 and 4 (14.3-25.6%) compared to placebo (0.0%). PASI75/90/100 responses were also significantly greater in all treatment groups (PASI75: 67-75%, PASI90: 52- 67%; PASI100: 33-56%) compared to placebo (10%; 10%; 7%, respectively). Dactylitis counts were similar across all groups, and improvements in enthesitis and HAQ-DI were greater in treatment groups compared to placebo but not statistically significant. Of the 185 subjects enrolled in the study, 145 continued in a 52-week single arm open-label extension (OLE). Subjects received 150 mg of risankizumab every 12 weeks for 36 weeks and continued to respond positively over all efficacy measures during this period. TEAEs were comparable in all arms and were similar in the 24- week study and OLE. Approximately 60% of subjects experienced a TEAE, with the most common being viral upper respiratory tract infection (11%). There was one serious adverse event (SAE) reported, but no malignancies, deaths or active cases of tuberculosis. Overall, risankizumab was well-tolerated and only 3.4% of patients discontinued due to side effects.

Notably, risankizumab was not found to be effective in the treatment of ankylosing spondylitis (AS)26 in a double-blinded phase 2 study. In this trial, 159 subjects were randomized to four treatment groups (risankizumab 18 mg one dose at week 0; risankizumab 90 or 180 mg at week 0, 8, 16 and 24; and placebo) over a 24-week period. The primary endpoint was Ankylosing Spondylitis Disease Activity Score (ASDAS) 40, a composite measure defined as a 40% improvement from baseline in three or more out of four variables: back pain, peripheral pain and swelling, duration of morning stiffness and patient global assessment. After 12 weeks of treatment, risankizumab failed to meet the primary endpoint as ASDAS40 responses were comparable and non-significant in treatment groups (15.0-25.0%) and placebo (17.5%). Similarly, in three multicentered, randomized, placebo-controlled studies, patients with AS were treated with ustekinumab.²² However, ustekinumab also did not demonstrate clinical efficacy in treating AS, as it failed to meet both primary and secondary endpoints including Assessment in Ankylosing Spondylitis (ASAS)20/40. These studies support the hypothesis that axial disease is driven by different mechanisms that are less reliant on IL-23.^27,28

Development Program for PsA

Pivotal phase 3 studies of risankizumab in PsA are currently ongoing. Two randomized, double-blinded studies compare risankizumab to placebo in subjects with active PsA who have failed to respond to at least one csDMARD (KEEPsAKE-1, NCT03675308) or bDMARD (KEEPsAKE-2, NCT03671148).^29,30 Subjects were randomized 1:1 to the treatment group (risankizumab at week 0, 4, 16 or 24) or placebo for a 24-week period. The study design for these trials is shown in Figure 1.

Similarly in KEEPsAKE-2, ACR20/50/70 response rates at week 24 were significantly higher with risankizumab (risankizumab: 51/26/12%; placebo:27/9/6%) (Figure 3). Subjects in the treatment group achieved greater resolution of enthesitis at week 24 (risankizumab: 43%, placebo: 30%) and dactylitis (risankizumab: 73%, placebo: 42%) and a greater change from baseline in HAQ-DI (risankizumab: -0.22; placebo: -0.05). In addition, PASI90 and MDA response rates were significantly higher with treatment (PASI90: 55%; MDA: 26%) compared to placebo (10%; 11%). Overall, in both trials, risankizumab produced more favorable outcomes in reducing disease activity, the number of affected joints, as well as improving psoriasis clearance and QoL.

After week 24, patients continued in an open label extension (OLE, Period 2) and received risankizumab 150 mg every 12 weeks until week 208. ACR 20/50/70 rates continued to improve to week 52 in KEEPsAKE-1 (risankizumab: 70/43/26% and placebo to risankizumab: 63/37/20%) and KEEPsAKE-2 (risankizumab: 59/32/17% and placebo to risankizumab: 56/32/21%) (Table 1b). Pooled data from both studies showed resolution of enthesitis in 55% of patients receiving risankizumab from baseline and in 57% of patients who transitioned from placebo to risankizumab in Period 2. Similarly, pooled data for resolution of dactylitis was reported in 76% of risankizumab patients and 73% of placebo to risankizumab patients in Period 2. The mean change in HAQ-DI at week 52 was -0.41 and -0.32 in risankizumab and placebo to risankizumab, respectively, in KEEPSaKE-1 and -0.26 and -0.34 in risankizumab and placebo to risankizumab, respectively, in KEEPSaKE-2. PASI90 responses were stable (risankizumab: 68% and placebo to risankizumab: 60%) in KEEPSaKE-1 and (risankizumab: 64% and placebo to risankizumab: 60%) in KEEPSaKE-2. The proportion of patients achieving MDA improved through week 52 (risankizumab: 38% and placebo to risankizumab: 27%) in KEEPSaKE-1 and (risankizumab: 27% and placebo to risankizumab: 34%) in KEEPSaKE-2 (Table 1b).

Adverse events were similar across all groups as of the data cut-off for week 52 analysis. By week 24, serious infection was reported in 2.7-2.9 events per 100 patient years (E/100PYs) of patients on risankizumab and did not increase in the long-term 52-week analysis (2.8 and 2.0E/100PY in KEEPsAKE-1 and -2, respectively). Serious TEAEs also did not increase from week 24 with 7.4E/100PY in KEEPsAKE-1 and 9.4E/100PY in KEEPSaKE-2 in the long-term. There were no reports of active tuberculosis or anaphylaxis in either study, but there was one case of oropharyngeal candidiasis in each study. There were no deaths in KEEPsAKE-2 but there were two deaths in KEEPsAKE-1; an 81-year-old male with dementia who was hospitalized with pneumonia and died of urosepsis and a 41-year-old male experienced sudden death on day 502. There were no reports of major cardiovascular events in KEEPsAKE-1 and three events in KEEPsAKE-2 which were reported as a non-fatal stroke in a patient with a history of hypertension and two non-fatal myocardial infarctions in patients with risk factors. Once again, risankizumab proved to be well-tolerated and discontinuation due to adverse events was low and occurred in 2.3E/100PY in KEEPSaKE-1 and 1.6E/100PY in KEEPSaKE-2.

Future Outlook

PsA is a multi-faceted, complex disease affecting multiple domains including skin, entheses, peripheral and axial joints. Although there are currently many options for treatment, there remains an unmet need for more efficacious and safer options. The addition of IL-23 inhibitors to the therapeutic landscape is welcomed given their tolerability, safety, and convenience of use. Conventional treatments for PsA including methotrexate, sulfasalazine, and leflunomide are burdened with tolerability issues, adverse effects, and end-organ toxicity. Newer oral agents also present challenges. Apremilast provides modest benefit but has issues with gastrointestinal intolerance and headaches. The JAK inhibitors are efficacious but have a boxed warning for serious infection and venous thromboembolism; more recent warnings for tofacitinib of cardiovascular events and malignancy, based on results from the ORAL Surveillance study,31 may make their use unsuitable in high-risk patients. The strength of IL-23 inhibition is the proven safety of this class in the psoriatic population. There is no signal for tuberculosis or other serious infections and can safely be used in patients with other comorbidities such as cardiac, renal, or hepatic disease. The convenient dosing schedule of injections as frequent as every 8 weeks to as infrequent as every 12 weeks will contribute favorably to QoL for patients by reducing the treatment burden and improving adherence. The current agents approved for use in PsA to target IL-23 are guselkumab, risankizumab and ustekinumab.

Risankizumab provides efficacy similar to that of other biologic agents for PsA, however the effect may take longer as we have not observed the early responses seen with other agents such as JAK inhibitors or IL-17 blocking agents. Guselkumab has shown in a network meta-analysis to have efficacy similar to IL-17 and TNF-α inhibiting biologic therapies supporting the important role of blocking IL-23 in the management of PsA.³² For patients with a prominent skin domain, targeting IL-23 may be preferred as it is very effective at clearing the skin in the majority of patients. Limiting its use will be the lack of efficacy in AS and further research will be required to understand the impact of risankizumab on axial PsA.

Conclusion

When choosing a treatment for PsA, ACR scores only tell part of the story, and we need to consider other disease measures such as enthesitis, dactylitis and QoL scores such as HAQ-DI, which were all shown to be significantly improved with risankizumab compared to baseline. Risankizumab has the potential to offer a treatment with a combination of efficacy, safety, convenience and overall improvement in QoL. However, more data is required and the complete long-term 208-week results from clinical studies for the management of PsA are eagerly anticipated.

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

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

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

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

Background

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

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

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

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

Clinical Applications in Dermatology

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

Psoriasis and Psoriatic Arthritis

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

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

Atopic Dermatitis

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

Alopecia Areata

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

Vitiligo

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

Systemic Lupus Erythematosus

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

Lichen Planopilaris

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

Other Dermatologic Diseases

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

Adverse Effects and Safety Considerations

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

Infection

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

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

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

Malignancy

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

Thromboembolism

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

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

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

Lab Abnormalities

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

Discussion

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

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

Conclusion

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

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Introduction

Phosphodiesterase 4 (PDE4) is a key enzyme in the regulation of immune responses of inflammatory diseases through degradation of the second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP). Apremilast (APR), a selective PDE4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines by increasing intracellular levels of cAMP and promoting the production of anti-inflammatory cytokines. The efficacy and safety of APR in the treatment of psoriasis and psoriatic arthritis has been demonstrated in phase 2/3 studies and is reviewed here. Across all studies, treatment was generally well-tolerated with some mild gastrointestinal complaints that occurred early and resolved over time. Meaningful improvement of psoriasis and psoriatic arthritis including dactylitis and enthesitis were observed. Routine monitoring is not required given the absence of drug associated physiologic, biochemical, and haematological changes. APR proves to be a new promising systemic therapy for treating psoriatic disease.

Background

• Psoriasis is an immune mediated disease involving skin, joints, and possibly the bowel.^1-4
• Recent clinical studies have shown precise blockade of phosphodiesterase 4 (PDE4) to be effective in the treatment of psoriasis⁵ and PsA.^6,7
• PDE4 belongs to the phosphodiesterase family of enzymes involved in the breakdown of cyclic adenosine 3′,5′-monophosphate (cAMP).^8,9
• Increase in cAMP leads to a cascade of cellular events resulting in a reduction of inflammatory mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-23, and IL-17, as well as increase in anti-inflammatory cytokines such as IL-10.^8,9,10
• Inhibition of PDE4 leads to an increase in the intracellular cAMP concentration, thereby reducing the production of inflammatory mediators and increasing anti-inflammatory mediators.^8,11

PDE4 Inhibitor in the Treatment of Psoriasis

• Apremilast (APR, CC-10004, Otezla™), a PDE4 inhibitor, has been shown to block the production of pro-inflammatory cytokines that play a major role in the pathogenesis of psoriasis.
• APR demonstrated a range of anti-inflammatory effects on a variety of cell lines in vitro,¹¹ and biologic activity in a pilot study in humans.¹²
• APR has been evaluated in a number of phase 2^5,13,14 and phase 3 clinical trials (Efficacy and Safety Trial Evaluating the Effects of APR in Psoriasis [ESTEEM] 1 and 2 and LIBERATE), demonstrating efficacy in psoriasis^15-17 and psoriatic arthritis (PsA).^6,7,19-21

Apremilast Use in Psoriasis

Results from Phase 3 Studies in Plaque Psoriasis

• Efficacy and safety of APR 30 mg BID was evaluated in two phase 3 randomized, placebo-controlled studies ESTEEM 1¹⁵ and ESTEEM 2¹⁶ and compared with etanercept and placebo (PBO) in a phase 3b study (LIBERATE)¹⁷, the results of which are not described here.
• In ESTEEM1, 844 patients with plaque psoriasis (Psoriasis Area Severity Index (PASI) ≥12, Body Surface Area [BSA] ≥10%, static Physician’s Global Assessment [sPGA] ≥3) were randomized 2:1 to APR 30 mg BID (n=562) or PBO (n=282) for the first 16 weeks. See Figure 1 for study design after week 16.¹⁵
• In ESTEEM 2, 413 similar patients with psoriasis were randomized to PBO (n=138) or APR 30 mg BID (n=275) through Week 16. See Figure 1 for study design after Week 16.¹⁶

Figure 1.ESTEEM 1 and 2 study design^15,16

^aDoses of APR were titrated during the first week of administration.

^bA responder was defined as a patient achieving ≥PASI-75 (ESTEEM 1) or ≥PASI-50 (ESTEEM 2) at Week 32.

^cIn ESTEEM 1, patients were switched to APR at the time of loss of PASI-75, but no later than Week 52

In ESTEEM 2, patients were switched to APR at time of loss of effect, defined as time of loss of 50% of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52.

^dAt Week 32, patients will have the option of adding topical and/or UVB therapy. The decision may be made at Week 32 only, but does not need to be initiated at this visit. T = topicals; P = UVB phototherapy.

• Significant improvements with APR 30 mg BID were observed at Week 16 for PASI-75 (a reduction of ≥75% in PASI scores) and sPGA scores.
• In ESTEEM 1, significantly more patients in the APR group achieved PASI-75 (33.1%), PASI-50 (58.7%) and sPGA 0-1 (21.7%) vs. PBO (*P<0.0001, all),¹⁵ (Figure 2A)
• In ESTEEM 2, patients treated with APR achieved PASI-75 (28.8%), PASI-50 (55.5%) and sPGA 0-1 (20.4%) vs. PBO (*P<0.0001, all).¹⁶ (Figure 2B)

Figure 2A and 2B.PASI-75 (primary endpoint), PASI-50, and sPGA response at Week 16^15,16

Patients achieving PASI-75, PASI-50, and sPGA response with APR 30 mg BID vs. PBO. A. Response at Week 16 in ESTEEM 1. B. Response at Week 16 in ESTEEM 2. sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline. *P

• For the subgroup of patients who received APR 30 mg BID from Day 0 and continued on therapy, with PASI-75 responders at Week 32, there was a mean percent change from baseline in PASI score of -80% at Week 52.¹⁵
• Improvements with APR 30 mg BID were also seen in nail, scalp and palmoplantar psoriasis as well as quality of life and pruritus.^15,16,18
• Patients treated with APR 30 mg BID achieved a 50% improvement in the Nail Psoriasis Severity Index (NAPSI-50) response at Week 16 vs. PBO. In ESTEEM 1, 33.3% of APR patients achieved NAPSI-50 response vs. 14.9% PBO (P<0.0001),¹⁵ and in ESTEEM 2, 44.6% of APR patients achieved NAPSI-50 vs. 18.7% PBO (P<0.0001).¹⁶
• Patients in the APR 30 mg BID group achieved significant scalp improvement, with ScPGA 0-1 (Clear-Minimal) at Week 16 vs. those in the PBO group. In ESTEEM 1, 46.5% APR vs. 17.5% PBO (P<0.0001),¹⁵ and in ESTEEM 2, 40.9% APR vs. 17.2% PBO (P<0.0001)¹⁶.
• Palmoplantar psoriasis also improved. In ESTEEM 2, 65.4% of patients treated with APR 30 mg BID achieved PPPGA 0-1 (Clear-Minimal) vs. 31.3% of patients treated with PBO.¹⁶
• APR 30 mg BID was associated with an improvement in quality of life with significantly higher proportion of patients who achieved clinically important differences in the Dermatology Life Quality Index (DLQI) and pruritus VAS from baseline at Week 16.
• In ESTEEM 1, 70.2% of patients in the APR group achieved a clinically significant improvement in DLQI response vs. 33.5% with PBO (P<0.0001),^15,22 and in ESTEEM 2, 70.8% of patients treated with APR achieved a significant DLQI response vs. 42.9% with PBO (P<0.0001).²³
• For pruritus VAS, 70.6% of patients in ESTEEM 1 treated with APR achieved significant improvement vs. 33.7% with PBO (P<0.0001) in ESTEEM 1.²²

Safety and Tolerability Profile

• APR demonstrated an acceptable safety profile and was generally well-tolerated for up to 52 weeks as most adverse events (AEs) were mild or moderate in severity.
• Discontinuation rates for diarrhea and nausea were each <2% in the APR 30 mg BID group through Week 52.^15,16
• The most frequently reported AEs during the PBO-controlled period and APR-exposure period were diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis, tension headache, and headache.^15,16
• Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes were not significantly affected.
• AEs in ≥5% reported during Weeks 0-16 and Weeks 0-52 in ESTEEM 1 are shown in Table 1.¹⁵ AEs reported during Weeks 0-16 in ESTEEM 2 are shown in Table 2.¹⁶

The apremilast-exposure period (Weeks 0-52) included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated.
Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times the number (n) of patients reporting the event divided by patientyears
within the phase (up to the first event start date for patients reporting the event).¹⁷

APR Use in Psoriatic Arthritis

Results from Phase 3 Studies in Psoriatic Arthritis

• Efficacy and safety of APR were evaluated in four phase 3 trials in the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical program in patients with PsA.^6,7,9,19-21
• Key inclusion criteria in PALACE 1,2 were adults with a documented diagnosis of PsA at baseline (duration ≥6 months; met the Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), ≥3 swollen and ≥3 tender joints despite past or current disease-modifying antirheumatic drugs (DMARDs) and/or biologics.^6,7,19 In PALACE 3, patients also had at least one psoriatic lesion ≥2 cm, and in PALACE 4, DMARD and/or biologics naïve patients were included.^20,21 Study design for the PALACE clinical trial program is shown in Figure 3.²⁰
• The results of a 24-week PBO-controlled phase of PALACE 1 have been published, as well as the 52-week period results.^6,7
• In PALACE 1, patients with active PsA (n=504) were randomized (1:1:1) to PBO, APR 20 mg BID or APR 30 mg BID. See Figure 3 for details.

Figure 3.PALACE Study Design^6,7,19-21

p class=”p-sm”>Note: Plasma samples for the biomarker assay were obtained at baseline and Weeks 4, 16, 24, and 40.
*All doses were titrated over the first week of treatment.
§Patients whose swollen and tender joint counts had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized
(1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo. Apremilast-treated patients continued on their initial apremilast dose.
‡At Week 24, all remaining placebo patients were re-randomized to apremilast 20 mg BID or 30 mg BID.

• At Week 16, significantly more patients receiving APR 20 mg BID (30.4%; P=0.0166) and 30 mg BID (38.1%; P=0.0001) achieved an ACR20 response vs. PBO (19.0%).⁶
• At Week 24, an ACR20 response of 45.3% was observed in patients treated with APR 30 mg BID independent of their response at Week 16.⁶
• At Week 52, ACR20 response was observed among patients receiving APR continuously for 52 weeks (n=254) in 63.0% (20 mg BID) and 54.6% (30 mg BID) of patients.⁷ ACR50 and ACR70 responses were observed in 24.8% and 15.4% of patients receiving APR 20 mg BID and 24.6% and 13.8% of patients receiving APR 30 mg BID, respectively.⁷
• Patients treated with APR had a statistically significant improvement in physical function, as measured by changes from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score (P=0.0004 vs. PBO) and the 36-Item ShortForm Health Survey v2 Physical Functioning domain score (P=0.0001 vs. PBO).
• Significant improvements were also seen in most ACR component scores, particularly swollen and tender joint counts and patient assessment of pain (P6
• In patients with enthesitis, the mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was significantly higher for APR 30 mg BID vs. PBO (P=0.0334), and significantly greater proportions of patients receiving APR 20 mg BID (32.0%; P=0.0037) and 30 mg BID (33.6%; P=0.0013) achieved a MASES score of 0 at Week 24 vs. PBO (14.4%).⁶
• In patients with dactylitis, mean change from baseline in dactylitis severity score was higher with APR vs. PBO. Greater proportions of patients with dactylitis achieved scores of 0 at Week 24 with APR 20 mg BID (50.9%), APR 30 mg BID (47.7%) vs. PBO (40.9%); these differences did not reach statistical significance at Week 24.⁶
• At Week 52, in patients who received APR continuously from baseline, the median change in MASES was 100% with APR 20 mg BID and 66.7% with APR 30 mg BID, and a MASES score of 0 was observed in 50.7% (35/69) of patients receiving APR 20 mg BID and 38.2% (34/89) receiving APR 30 mg BID.⁷
• AEs in the PALACE 1 trial were similar to the psoriasis studies with gastrointestinal, mild or moderate in severity, occurred early, self-limited, did not recur, and infrequently led to discontinuation (<2.5%) through Week 24.⁷
• No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.
• For an overview of AEs occurring in ≥5% of PALACE 1 see Table 3.

Warning and Precautions: Data from Studies in Psoriasis and PsA

Weight Decrease

• During the controlled period of the trials, weight decrease between 5%-10% of baseline body weight was reported in 12% of psoriasis and 10% of PsA patients treated with APR 30 mg BID vs. 3-5% treated with PBO. Weight decrease of ≥10% of body weight occurred in 2% of patients treated with APR 30 mg BID vs. 1% in the PBO group.
• It is recommended that patients treated with APR should have their weight monitored regularly.²⁴

Depression

• While treatment with APR was associated with a risk of depression, data from the clinical trials do not suggest an increase in depression nor suicidal ideation in subjects treated with APR vs. PBO.²⁴

Drug Interactions

• Co-administration with cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) resulted in a reduction of systemic exposure of APR, which may result in a loss of its efficacy and is not recommended.²⁴

Approval and Indications

Apremilast was approved by Health Canada in November, 2014. It is indicated for the treatment of plaque psoriasis in adult patients with moderate to severe disease who are candidates for phototherapy or systemic therapy. It is also indicated for psoriatic arthritis either alone or in combination with methotrexate, for the treatment of active arthritis in adult patients who have had an inadequate response, intolerance, or contraindication to a prior disease-modifying anti-rheumatic drug (DMARD).²⁴ The recommended daily dosing is 30 mg PO BID. However, an initial titrated dose from 10 mg to 30 mg over the first week is recommended and is available in a convenient dosing pack.

Conclusion

Treatment with APR demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis^15-17 and improving signs, symptoms and physical function in PsA.^6,7,19-21 APR demonstrated an acceptable safety profile and was well-tolerated with generally mild GI complaints occurring early in the course of the treatment and resolving with time, and there was no requirement for laboratory monitoring.^5-7,15-21 Based on these results, APR should be considered as a therapeutic option in the treatment of plaque psoriasis and PsA.

Acknowledgement

The authors gratefully acknowledge the medical editorial support from Flora Krasnoshtein in preparing the original manuscript.

References

1. Najarian DJ, Gottlieb AB. J Am Acad Dermatol. 2003 Jun;48(6):805-21; quiz 22-4.
2. Nestle FO, et al. N Engl J Med. 2009 Jul 30; 361(5):496-509.
3. Ritchlin CT. Curr Opin Rheumatol. 2005 Jul;17(4):406-12.
4. Salari-Sharif P, et al. Curr Pharm Des. 2010 16(33):3661-7.
5. Papp K, et al. Lancet. 2012 Aug 25;380(9843):738-46.
6. Kavanaugh A, et al. Ann Rheum Dis. 2014 Jun;73(6):1020-6.
7. Kavanaugh A, et al. J Rheumatol. 2015 Mar;42(3):479-88.
8. Schafer P. Biochem Pharmacol. 2012 Jun 15;83(12):1583-90.
9. Schafer PH, et al. Cell Signal. 2014 Sep;26(9):2016-29.
10. Baumer W, et al. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
11. Serezani CH, et al. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
12. Gottlieb AB, et al. Curr Med Res Opin. 2008 May;24(5): 1529-38.
13. Papp KA, et al. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e376-83.
14. Strand V, et al. J Am Acad Dermatol 2011:64(2): AB154. [Poster abstract P3337]. Presented at the American Academy of Dermatology 2011 69th Annual meeting; February 4-8, 2011; New Orleans, LA.
15. Papp K, Reich C, Leonardi C, et al. J Am Acad Dermatol 2015;73:37-49.
16. Paul C, Cather J, Gooderham M, et al. Br J Dermatol. 2015. doi:10.1111/bjd.14164.
17. Reich K, Soung J, Gooderham M, et al.: Presented at the 73rd Annual Meeting of the American Academy of Dermatology; San Francisco; March 20-24, 2015.
18. Rich P, Gooderham M, Bachelez H, et al. J Am Acad Dermatol http://dx.doi.org/ 10.1016/j.jaad.2015.09.001
19. Cutolo M, et al. [Presentation number 815]. Presented at ACR 2013. American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
20. Edwards CJ, et al. [Poster 311]. Presented at ACR 2013 American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
21. Armstrong AW, et al. [Poster P1691]. Presented at: the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
22. Gooderham M, et al. [Poster P1688]. Presented at the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
23. Otezla® (APR) [Full Prescribing information]. Summit, NJ: Celgene Corporation; revised June 2015.

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²K. Papp Clinical Research, Waterloo, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada

ABSTRACT
Phosphodiesterase 4 (PDE4) is a key enzyme in the regulation of immune responses of inflammatory diseases through degradation of the second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP). Apremilast, a selective PDE4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines by increasing intracellular levels of cAMP and promoting the production of anti-inflammatory cytokines. The efficacy and safety of apremilast in the treatment of psoriasis and psoriatic arthritis has been
demonstrated in phase 2 and 3 studies and will be reviewed here. Across all studies, treatment was generally well-tolerated with some mild gastrointestinal complaints that occurred early and resolved over time, resulting in few drop-outs. Meaningful changes in dactylitis and enthesitis were also observed. Routine monitoring is not required given the absence of drug associated physiologic,
biochemical, and haematological changes. Apremilast proves to be a new promising systemic therapy for treating psoriatic disease.

Key Words:
psoriasis, chronic plaque psoriasis, apremilast, PDE4 inhibitors, psoriatic arthritis, immunology, inflammation

Introduction

Psoriasis is a disease complex involving skin, joints, and possibly the bowel.¹ Each manifestation of the psoriasis disease complex is expressed through an inflammatory, immune-mediated process. This has been described in the skin,² joints³ and bowel⁴. Therefore, interference in the immunological pathways common to psoriasis and psoriatic arthritis (PsA) could demonstrate clinical improvement of both. Recent clinical studies have shown precise blockade of phosphodiesterase 4 (PDE4) to be effective in the treatment of psoriasis⁵ and PsA^6,7.

PDE4 belongs to the phosphodiesterase family of
enzymes involved in the breakdown of cyclic adenosine
3′,5′-monophosphate (cAMP).^8,9 cAMP is a secondary messenger central for immune response regulation, and the inhibition of its breakdown leads to a cascade of cellular events resulting in a reduction of inflammatory mediators such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-23, as well as production of anti- inflammatory cytokines such as IL-10.^8,9

PDE4, found in cells of the immune system and keratinocytes, is the key enzyme responsible for cAMP breakdown. Through their cAMP-blocking actions, PDE4 inhibitors can prolong or enhance the effects of cAMP resulting in the reduction of both T-helper 1 (Th1) and Th2 immune responses.¹⁰ PDE4 is
expressed selectively in immune cells and plays a central role in the activation of these cells, which are upregulated in chronic plaque psoriasis and other inflammatory conditions such as PsA.⁹ Inhibition of PDE4 leads to an increase in the intracellular cAMP concentration, thereby reducing the production of inflammatory mediators and increasing anti-inflammatory mediators.^8,11 PDE4
inhibitors and their immune-modulating effects are currently under investigation in a variety of inflammatory conditions such as asthma, chronic obstructive pulmonary disease (COPD), atopic
dermatitis, psoriasis and PsA.^8-10

PDE4 Inhibitor in the Treatment of Psoriasis

The PDE4 inhibitor, apremilast (CC-10004, Otezla™), has been shown to block the production of interferon (IFN)-gamma, TNFalpha, IL-12 and IL-23 – the pro-inflammatory cytokines that play a major role in the pathogenesis of psoriasis. Apremilast, through its action to increase intracellular cAMP concentration,
demonstrated a range of anti-inflammatory effects on a variety of cell lines in vitro, ¹² reduction in the psoriasiform response in a preclinical model of psoriasis in vivo, as well as biologic activity
in a pilot study in humans¹³.

To date, apremilast has been evaluated in a number of phase 2^14-16 and phase 3 clinical trials (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1 and 2), demonstrating efficacy in psoriasis^17,18 and PsA^6,7,19-21. Another phase 3b study evaluating the efficacy and safety of apremilast, compared with etanercept and placebo in patients with moderate to severe plaque psoriasis, is ongoing (ClinicalTrials.gov Identifier: NCT01690299).

Apremilast Use in Psoriasis

Results from Phase 2 Studies in Plaque Psoriasis

Apremilast demonstrated efficacy in phase 2 clinical trials.^14-16 In a 12-week, phase 2, randomized, placebo-controlled trial in 259 patients, apremilast 20 mg twice daily (BID) achieved a Psoriasis
Area and Severity Index (PASI)-75 in 24.4% of patients vs. 10.3% in the placebo group. A dose-response was observed with a mean percent reduction in PASI from baseline of 17.4%, 30.3% and 52.1% for placebo, apremilast 20 mg once daily (OD) and apremilast 20 mg BID, respectively.¹⁴

Efficacy of apremilast was also shown in the phase 2b doubleblind, randomized, placebo-controlled crossover trial in 352 patients, which compared apremilast 10 mg, 20 mg, 30 mg or placebo BID for 16 weeks, at which point patients receiving placebo were then randomized to 20 mg or 30 mg BID up to 24 weeks. Primary endpoint of PASI-75 at 16 weeks was 11% for 10 mg, 29% for 20 mg, and 41% for 30 mg BID vs. 6% of patients on placebo.¹⁵

Treatment with apremilast also resulted in significant
improvement on patient-reported quality of life outcomes, with particular benefit noted at the 30 mg BID dose.¹⁶ Adverse effects were mild to moderate, and included headache, nausea, urinary tract infection (UTI) and diarrhea. No significant changes in laboratory values were observed in any of the trials.

Results from Phase 3 Studies in Plaque Psoriasis

The efficacy and safety of apremilast 30 mg BID was evaluated in two phase 3 randomized, placebo-controlled studies ESTEEM 1¹⁷ and ESTEEM 2¹⁸. The efficacy and safety of apremilast compared with etanercept and placebo in patients with moderate to severe plaque psoriasis is being evaluated in a phase 3b study (NCT01690299).

In ESTEEM1, 844 patients with moderate to severe plaque
psoriasis (PASI ≥12, Body Surface Area [BSA] ≥10%, static Physician’s Global Assessment [sPGA] ≥3) were randomized 2:1 to apremilast 30 mg BID (n=562) or placebo (n=282). At Week 16, all patients in the placebo group were switched to apremilast 30 mg BID through Week 32. At Week 32, all patients in the apremilast 30 mg BID group who achieved PASI-75 were
randomized (1:1, blinded) to continue apremilast 30 mg BID or receive placebo. Upon loss of PASI-75, patients who were rerandomized to placebo resumed apremilast 30 mg BID.¹⁷

In ESTEEM 2, 413 patients with moderate to severe psoriasis (PASI ≥12, BSA ≥10%, and sPGA ≥3) were randomized to placebo (n=138) or apremilast 30 mg BID (n=275) through Week 16. As in ESTEEM 1, at Week 16, all patients receiving placebo were switched to apremilast 30 mg BID through Week 32, followed by a randomized withdrawal phase through Week 52. At Week 32, all patients in the apremilast 30 mg BID group who achieved PASI-50 were randomized (1:1, blinded) to
continue apremilast 30 mg BID or receive placebo. Upon loss of PASI-50, patients who were re-randomized to placebo resumed apremilast 30 mg BID.¹⁸

Patients re-started apremilast at the time of loss of effect, defined as time of loss of 75% (ESTEEM 1) and 50% (ESTEEM 2) of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52. Patients initially on placebo or randomized to apremilast 30 mg BID who did not attain a PASI-75 or PASI-50, in ESTEEM 1 and ESTEEM 2, respectively, were
able to add topicals and/or ultraviolet B (UVB) phototherapy at Week 32 at the discretion of the investigator.^17,18 Study design of ESTEEM clinical trial program is shown in Figure 1.

Figure 1. ESTEEM 1 and 2 study design^{17, 18}

^aDoses of apremilast were titrated during the first week of administration.
^bA responder was defined as a patient achieving ≥PASI-75 (ESTEEM 1) or ≥PASI-50 (ESTEEM 2) at Week 32.
^cIn ESTEEM 1, patients were switched to apremilast at the time of loss of PASI-75, but no later than Week 52. In ESTEEM 2, patients were switched to apremilast at
time of loss of effect, defined as time of loss of 50% of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52.
^dAt Week 32, patients will have the option of adding topical and/or UVB therapy. The decision may be made at Week 32 only, but does not need to be initiated at
this visit. T = topicals; P = UVB phototherapy.

Figure 2A and 2B. PASI-75 (primary endpoint), PASI-50, and sPGA response at Week 16^17,18

Patients achieving PASI-75, PASI-50, and sPGA response with apremilast 30 mg BID vs. placebo. A. Response at Week 16 in ESTEEM 1. B. Response at Week 16 in
ESTEEM 2. sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline. *P

Significant improvements with apremilast 30 mg BID were
observed at Week 16 for PASI-75 (a reduction of ≥75% in PASI scores) and sPGA scores. In ESTEEM 1, significantly more patients in the apremilast group achieved PASI-75 (33.1%), PASI-50 (58.7%) and sPGA 0-1 (21.7%) vs. placebo (*P<0.0001, all),17 and in ESTEEM 2, patients treated with apremilast achieved PASI-75 (28.8%), PASI-50 (55.5%) and sPGA 0-1 (20.4%) vs. placebo (*P<0.0001, all)18. (Figure 2)

Improvements with apremilast 30 mg BID were also seen in the Nail Psoriasis Severity Index (NAPSI-50), scalp PGA (ScPGA 0-1), Palmoplantar Psoriasis Physician’s Global Assessment (PPPGA), Dermatology Life Quality Index (DLQI), and pruritus scores on the Visual Analogue Scale (VAS).^17,18

More patients treated with apremilast 30 mg BID achieved NAPSI-50 response at Week 16 vs. placebo. In ESTEEM 1, 33.3% of patients in the apremilast group achieved NAPSI-50 response vs. 14.9% with placebo (P<0.0001),¹⁷ and in ESTEEM 2, 44.6% of patients in the apremilast 30 mg BID group achieved NAPSI-50
vs. 18.7% with placebo (P<0.0001)¹⁸.

As well, a higher proportion of patients in the apremilast 30 mg BID group achieved ScPGA 0-1 (Clear-Minimal) at Week 16 vs. those in the placebo group. In ESTEEM 1, 46.5% in the apremilast group vs. 17.5% with placebo (P<0.0001),¹⁷ and in ESTEEM 2, 40.9% of patients in the apremilast group achieved ScPGA 0-1 vs. 17.2% with placebo (P<0.0001)¹⁸. In ESTEEM 2, 65.4% of patients treated with apremilast 30 mg BID achieved PPPGA 0-1 (Clear-Minimal) vs. 31.3% of patients treated with placebo.¹⁸ PPPGA 0-1 was not reported in ESTEEM 1.¹⁷

Apremilast 30 mg BID was associated with a significantly higher proportion of patients who achieved minimum clinically important difference (MCID) in DLQI and pruritus VAS from baseline at Week 16. Over 90% of patients receiving apremilast 30 mg BID, who were PASI-75 responders at Week 16, achieved MCID in DLQI and pruritus VAS. In ESTEEM 1, 70.2% of patients in the apremilast group achieved a MCID DLQI response vs. 33.5% with placebo (P<0.0001),^17,22 and in ESTEEM 2, 70.8% of patients treated with apremilast achieved a MCID DLQI response vs. 42.9% with placebo (P<0.0001)²³. For pruritus VAS, 70.6% of patients in ESTEEM 1 treated with apremilast achieved MCID vs. 33.7% with placebo (P<0.0001) in ESTEEM 1.²²

Time to loss of PASI improvement and PASI-75 response
were also evaluated at 52 weeks in ESTEEM 1. Of the patients re-randomized to placebo, 70.3% regained PASI-75 response after re-initiation of treatment with apremilast 30 mg BID. The duration of re-treatment ranged from 3.4-22.1 weeks.¹⁷ The median time to loss of PASI-75 response was 5.2 and 15.7 weeks for patients re-randomized to placebo and apremilast 30 mg BID, respectively. For the subgroup of patients who received apremilast 30 mg BID from Day 0 and continued on therapy, with PASI-75 responders at Week 32, there was a mean percent change from baseline in PASI score of -80% at Week 52.¹⁷

Safety and Tolerability Profile

Apremilast demonstrated an acceptable safety profile and was generally well-tolerated for up to 52 weeks in the treatment of plaque psoriasis. Most adverse events (AEs) were mild or moderate in severity. Discontinuation rates for diarrhea and nausea were each <2% in the apremilast 30 mg BID group through Week 52. The most frequently reported AEs during the
placebo-controlled period and apremilast-exposure period were diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis, tension headache, and headache.²⁴

In ESTEEM 1, apremilast 30 mg BID was generally welltolerated for up to 52 weeks with no increase in the incidence of AEs over time. Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes were not significantly affected, which is consistent with prior apremilast trials. AEs in ≥5% reported during Weeks 0-16 and over the entire apremilastexposure period (Weeks 0-52) of either placebo or apremilasta 30 mg BID group are shown in Table 1.¹⁷

In ESTEEM 2, the majority of AEs were mild or moderate in severity and discontinuation rates due to AEs during Weeks 0-16 were low (placebo: 5.1%; apremilast: 5.5%). In patients receiving apremilast, diarrhea and nausea were mostly mild in severity, with the highest incidence during the first week of dosing, generally resolving within 1 month, with few patients reporting use of concomitant medications. Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes again were consistent with prior apremilast studies; laboratory values were not significantly changed and serious AEs were low across treatment groups. AEs
reported during Weeks 0-16 in ≥5% are presented in Table 2.¹⁸

Apremilast Use in Psoriatic Arthritis

Results from Phase 3 Studies in Psoriatic Arthritis

The efficacy and safety of apremilast were evaluated in the phase 3 Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial program studies in patients with PsA.^6,7,9,19-21

The key inclusion criteria in PALACE 1 and 2 were adults with a documented diagnosis of PsA at baseline (duration ≥6 months; met the Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), ≥3 swollen and ≥3 tender joints despite past or current disease-modifying antirheumatic drugs (DMARDs) and/or biologics.^6,7,9,19 In PALACE 3, in addition to the above inclusion criteria for PALACE 1 and 2, patients also had to have at least one psoriatic lesion ≥2 cm, and PALACE 4 was in DMARD and/or biologics naïve patients.^20,21 Study design for the PALACE clinical trial program is shown in Figure 3.²⁰

Figure 3. PALACE Study Design^6,7,19-21

Note: Plasma samples for the biomarker assay were obtained at baseline and Weeks 4, 16, 24, and 40.
*All doses were titrated over the first week of treatment.
§Patients whose swollen and tender joint counts had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized
(1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo. Apremilast-treated patients continued on their initial apremilast dose.
‡At Week 24, all remaining placebo patients were re-randomized to apremilast 20 mg BID or 30 mg BID.

The results of a 24-week placebo-controlled phase of PALACE 1 have been published, as well as the 52-week period results, and will be presented here.^6,7 Patients with active PsA (n=504) were randomized (1:1:1) to placebo, apremilast 20 mg BID or apremilast 30 mg BID. At Week 16, patients without ≥20% reduction in swollen and tender joint counts were required to
be re-randomized equally to either apremilast dose if initially randomized to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses. Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology 20% improvement criteria (ACR20) at Week 16. ^6,7

At Week 16, significantly more patients receiving apremilast 20 mg BID (30.4%; P=0.0166) and 30 mg BID (38.1%; P=0.0001) achieved an ACR20 response vs. placebo (19.0%).⁷ At Week 24, a significantly greater proportion of patients receiving apremilast 20 mg BID and 30 mg BID achieved ACR20, ACR50 and ACR70 vs. placebo, and these response rates were maintained in the active treatment groups (P≤0.0001 vs. placebo, all). An ACR20 response of 45.3% was observed at Week 24 in patients treated with apremilast 30 mg BID independent of their response at Week 16.⁷ At Week 52, ACR20 response was observed among patients receiving apremilast continuously for 52 weeks (n=254) in 63.0% (20 mg BID) and 54.6% (30 mg BID) of patients.⁷

Patients who continued receiving apremilast through Week 52 demonstrated sustained rates of ACR20 response over 52 weeks. At Week 52, 63.0% of patients who received apremilast 20 mg BID from baseline and 54.6% who received 30 mg BID achieved an ACR20. ACR50 and ACR70 responses were observed in 24.8% and 15.4% of patients receiving apremilast 20 mg BID and 24.6% and
13.8% of patients receiving apremilast 30 mg BID, respectively.⁷

Patients treated with apremilast had a statistically significant improvement in physical function, as measured by changes from baseline in Health Assessment Questionnaire–Disability Index
(HAQ-DI) score (P=0.0004 vs. placebo) and the 36-Item ShortForm Health Survey v2 Physical Functioning domain score (P=0.0001 vs. placebo). Significant improvements were also seen in most ACR component scores, particularly swollen and tender joint counts and patient assessment of pain (P placebo).⁶

Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses compared to placebo (P6 Among patients receiving apremilast continuously for 52 weeks, response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function.⁶

In patients with baseline enthesitis, the mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was significantly higher for apremilast 30 mg BID vs. placebo (P=0.0334), and significantly greater proportions of patients receiving apremilast 20 mg BID (32.0%; P=0.0037) and
30 mg BID (33.6%; P=0.0013) achieved a MASES score of 0 at Week 24 vs. placebo (14.4%). In patients with baseline dactylitis, mean change from baseline in dactylitis severity score was higher with apremilast vs. placebo. Greater proportions of patients with dactylitis achieved scores of 0 at Week 24 with apremilast 20 mg BID (50.9%), apremilast 30 mg BID (47.7%) vs. placebo (40.9%); these differences did not reach statistical significance at Week 24.⁶ At Week 52, in patients with enthesitis and dactylitis at baseline who received apremilast continuously through Week 52, the median change from baseline in MASES at Week 52 was 100% with apremilast 20 mg BID and 66.7% with apremilast 30 mg BID, and a MASES score of 0 was observed in 50.7% (35/69) of patients receiving apremilast 20 mg BID and 38.2% (34/89) receiving apremilast 30 mg BID.⁷

At Week 16, treatment with apremilast was associated with significantly greater reductions (improvements) in HAQ-DI vs. placebo (key secondary endpoint, SE). The mean SE changes from baseline were -0.09 (0.04) (placebo), -0.20 (0.04) (apremilast 20 mg BID; P=0.0252 vs. placebo), and -0.25 (0.04) (apremilast 30 mg BID; P=0.0015 vs. placebo).⁶

As well, HAQ-DI scores were maintained in both apremilast groups over 52 weeks with continued treatment. At Week 52, mean reductions in HAQ-DI score were –0.37 (0.48) with apremilast 20 mg BID and –0.32 (0.55) with apremilast 30 mg BID, with improvements of ≥0.13 observed in 60.0% and 59.8%, respectively, and improvements of ≥0.30 observed in 45.8% and 44.7%, respectively.⁷

The most common AEs in the PALACE 1 trial were gastrointestinal (GI), mild or moderate in severity, occurred early, self-limited, did not recur, and infrequently led to discontinuation (<2.5%) in the apremilast 20 mg BID and 30 mg BID groups through
Week 24. No imbalance in major adverse cardiac events,
serious or opportunistic infections, malignancies or laboratory abnormalities was observed. For an overview of AEs occurring in ≥5% in any treatment group during the placebo-controlled phase (Weeks 0-24) and apremilast exposure period (Weeks 0-52) of PALACE 1 see Table 3. There were no new emergent AEs over the
52-week period.⁷

Warnings and Precautions: Data from Studies in
Psoriasis and PsA

Weight Decrease

Psoriasis: During the controlled period of the trials, weight decrease between 5%-10% of body weight was reported in 12% of psoriasis patients treated with apremilast 30 mg BID vs. 5% treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% of patients treated with apremilast 30 mg BID vs.
1% in the placebo group. It is recommended that patients treated with apremilast should have their weight monitored.

PsA: During the controlled period of the trials, weight decrease between 5%-10% of body weight was reported in 10% of patients with PsA treated with apremilast 30 mg BID vs. 3.3% of placebo. It is recommended that patients treated with apremilast should have their weight monitored regularly.²⁵

Depression

Psoriasis and PsA: While treatment with apremilast was associated with a risk of depression, data from the clinical trials do not suggest an increase in depression nor suicidal ideation in subjects treated with apremilast vs. placebo.²⁵

Drug Interactions

Psoriasis and PsA: The use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with apremilast is not recommended. It has been shown that the coadministration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of its efficacy.²⁵

Conclusion

Treatment with apremilast demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis^17,18 and improving signs, symptoms and physical function in PsA.^6,7,19-21 Apremilast demonstrated an acceptable safety profile and was well-tolerated with generally mild GI complaints occurring early in the course of the treatment and resolving with time, and there was no requirement for laboratory monitoring.^6,7,19-21,24 Based on these results, apremilast should be considered as a therapeutic option in the treatment of plaque psoriasis and PsA.

Acknowledgement

The authors gratefully acknowledge the medical editorial support from Flora Krasnoshtein in preparing this manuscript.

References

1. Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol. 2003 Jun;48(6):805-21; quiz 22-4.
2. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009 Jul 30; 361(5):496-509.
3. Ritchlin CT. Pathogenesis of psoriatic arthritis. Curr Opin Rheumatol. 2005 Jul;17(4):406-12.
4. Salari-Sharif P, Abdollahi M. Phosphodiesterase 4 inhibitors in inflammatory bowel disease: a comprehensive review. Curr Pharm Des. 2010 16(33):3661-7.
5. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012 Aug 25;380(9843):738-46.
6. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014 Jun;73(6):1020-6.
7. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015 Mar;42(3):479-88.
8. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012 Jun 15;83(12):1583-90.
9. Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014 Sep;26(9):2016-29.
10. Baumer W, Hoppmann J, Rundfeldt C, et al. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
11. Serezani CH, Ballinger MN, Aronoff DM, et al. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
12. Serezani CH, Ballinger MN, Aronoff DM, et al. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008 Aug;39(2):127-32.
13. Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin. 2008 May;24(5): 1529-38.
14. Papp KA, Kaufmann R, ThaÁi D, et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind,placebo-controlled, parallel-group, dose-comparison study. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e376-83.
15. Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet. 2012 Aug 25;380(9843):738-46.
16. Strand V, Hu A, Day R, Sloan V. P3337: Improved quality of life with apremilast (APR) in the treatment of psoriasis: results from a phase IIb randomized controlled study J Am Acad Dermatol 2011:64(2): AB154. [Poster abstract P3337]. Presented at the American Academy of Dermatology 2011 69th Annual meeting; February 4-8, 2011; New Orleans, LA.
17. Papp K, Reich K, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from the randomized treatment withdrawal phase of a phase 3, randomized, controlled trial (ESTEEM 1). [Poster 8359]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
18. Paul C, Cather J, Gooderham M, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). [Poster 8412]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
19. Cutolo M, Myerson GE, Fleischmann RM, et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2). [Presentation number 815]. Presented at ACR 2013. American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
20. Edwards CJ, Blanco FJ, Crowley J, et al. Long-term (52-Week) Results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement (PALACE 3). [Poster 311]. Presented at ACR 2013 American College of Rheumatology 2013 Annual Meeting; October 25-31,2013; San Diego, CO.
21. Edwards CJ, Wells AF, Adebajo AO, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, is associated with long-term (52-Week) improvements in enthesitis or dactylitis in patients with psoriatic arthritis: results from the PALACE 4 phase 3, randomized, controlled trial. Presented at European League Against Rheumatism Congress; June 1-14, 2014; Paris, France.
22. Armstrong AW, Griffiths CEM, Tencer T, et al. Effect of apremilast on patientreported outcomes in patients with moderate to severe plaque psoriasis in the ESTEEM 1 trial. [Poster P1691]. Presented at: the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
23. Gooderham M, Cather J, Crowley J, et al. Effects of apremilast on healthrelated quality of life in patients with moderate to severe plaque psoriasis: 16-week results from the ESTEEM 2 trial. [Poster P1688]. Presented at the 23rd Congress of the European Academy of Dermatology and Venereology; October 8-12, 2014; Amsterdam, the Netherlands.
24. Reich K, Papp K, Leonardi C, et al. Long-term safety and tolerability of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from a phase III, randomized, controlled trial (ESTEEM 1). [Poster 8296]. Presented at the 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2014; Denver, CO.
25. Otezla^® (apremilast) [Full Prescribing information]. Summit, NJ: Celgene Corporation; revised December 2014. Available at: http://www.otezla.com/ otezla-prescribing-information.pdf. Accessed August 2, 2015.

¹Center for Clinical Studies, Houston, TX, USA
²University of Texas Medical Branch at Galveston School of Medicine, Galveston, TX, USA
³Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

ABSTRACT
Biologic compounds are being used more frequently to treat a multitude of systemic inflammatory conditions. These novel compounds are composed of antibodies or other peptides that act through one of three mechanisms: inhibiting inflammatory cytokine signaling (typically tumor necrosis factor or TNF), inhibiting T-cell activation, or depleting B-cells. The increase in use and ever expanding list of new immune modulating therapies make knowledge of the infectious complications associated with immune modulation even more important. Of particular concern is the risk for developing atypical and opportunistic infections including tuberculosis, herpes zoster, Legionella pneumophila, and Listeria monocytogenes.

Key Words:
adverse effects, anti-tumor necrosis factor-alpha, infections, monoclonal antibodies, psoriasis, risk factors, TNF-α inhibitors

Background

The availability of immune modulating drugs has revolutionized treatment for psoriasis and psoriatic arthritis, as well as a variety of other inflammatory diseases. After approximately one decade of post-marketing surveillance and experience with biologics, they are generally regarded as safe and efficacious therapy for an increasing number of diseases. However, the risk of infection is a concern with long-term immunosuppressive treatment. We review current literature regarding the risk of infection associated with the biologic therapies most commonly used by dermatologists today: tumor necrosis factor-alpha (TNF-α) inhibitors and ustekinumab.

Infliximab (a chimeric monoclonal anti-TNF antibody) (Remicade®), adalimumab (a fully human anti-TNF monoclonal antibody) (Humira®), and etanercept (a recombinant soluble decoy TNF-receptor) (Enbrel®) exert therapeutic effects via the suppression of TNF-α, a cytokine released by macrophages that is central to cell-mediated immunity.

Ustekinumab (Stelara®), an interleukin 12 and interleukin 23 antibody, targets the p40 subunit shared by the two cytokines to prevent receptor interaction, thereby inhibiting signaling and further cytokine production. Pooled data from phase 2 and 3 clinical trials suggest that there is no clear pattern of heightened infection risk compared with controls (placebo, etanercept) for up to 3 years.¹ However, ustekinumab has only been US FDA approved since 2009, so knowledge of long-term risk is limited. Some associations have been reported and are outlined below.

Herpes Zoster

Available evidence regarding the risk of herpes zoster (HZ) with TNF-α therapy is conflicting. One retrospective analysis of psoriasis patients treated with anti-TNF therapy, acitretin, cyclosporine, methotrexate, corticosteroids, UVB phototherapy, or PUVA showed an elevated incidence of HZ infection in patients receiving any treatment except alefacept, efalizumab, or adalimumab when compared with controls (patients without any treatment for 1 month or without treatment for 3 months if most recent treatment was infliximab). None of the biologic drugs studied were associated with a clinically significant increased risk of HZ, however, treatment with infliximab approached clinical significance (hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 0.92-3.43).²

Strangfeld et al. demonstrated a significantly higher risk of HZ in rheumatoid arthritis (RA) patients treated with etanercept, infliximab, or adalimumab compared with conventional disease-modifying antirheumatic drugs (DMARDs). The crude incidence rate per 1000 person-years of HZ was 11.1 (95% CI: 7.9-15.1) for infliximab or adalimumab, 8.9 (95% CI: 5.6-13.3) for etanercept, and 5.6 (95% CI: 3.6-8.3) for conventional RA treatments. Adjustments for age, rheumatoid arthritis severity, and glucocorticoid use demonstrated a significantly higher risk with treatment using monoclonal antibodies (HR: -1.82 [95% CI: -1.05-3.15]), but not for etanercept or the anti-TNF-α antagonists as a class.³

While ustekinumab was not included in the aforementioned studies, there is a report of two patients developing severe, mulitdermatomal herpes zoster 1 and 9 months after initiating therapy with usetkinumab. Vaccination against HZ is strongly encouraged before initiating therapy with ustekinumab.⁴ Currently, there are no clear recommendations regarding HZ vaccine (Zostavax®) administration during treatment with TNF-α inhibitors. Interestingly, results of a recent study suggest that treatment with TNF-α inhibitors may be associated with a lower incidence of postherpetic neuralgia,⁵ this finding is also supported by Strangfeld’s data³ as noted by Whitley in his editorial discussing the prevalence of herpes zoster during immunosuppressive therapy.⁶

Tuberculosis

The risk of latent tuberculosis (TB) reactivation in patients treated with biologics is well-established. A Cochrane review evaluating the adverse reactions of all biologic therapies (all TNF-α inhibitors, anakinra, tocilizumab, abatacept, and rituximab) for any indication found an increased risk of TB reactivation (odds ratio [OR]: 4.68, 95% CI: 1.18-18.60) in comparison with the control treatment group, and a number needed to treat to harm (NNTH) of 681.⁷ Several of the drugs included in this review are not commonly used by dermatologists. A recent analysis of the risks associated with TNF-α inhibitors in psoriasis patients found that the lifetime risk of TB was 0-17.1% in comparison to 0.3% without the use of TNF-α inhibitors. The authors point out that while there is an increased risk, the risk of tuberculosis is still far lower than the lifetime risk of America’s more common afflictions: cancer (40.4%), heart disease (36.2%), and stroke (18.4%).⁸

Variation in the risk of TB reactivation in patients treated with TNF-α inhibitors may be expected based on the endemic rates of TB. A recent Spanish study of psoriasis patients receiving any anti-TNF therapy found a 29% incidence of latent TB infection (LTBI), which was comparable to the incidence found in the general population.⁹ Conversely, a Swedish study found an increased risk of TB infection for RA patients compared with the general population. Treatment with either infliximab or etanercept was associated with a higher risk of TB in RA patients compared with RA patients not treated with TNF-α inhibitors.¹⁰

Among all TNF-α inhibitors, infliximab is the agent most heavily associated with greater risk of TB. A study of the FDA Adverse Event Reporting System (AERS) between 1998-2002 concluded an increased risk of developing TB for infliximab and etanercept users (144 per 100,000 infliximab-treated patients compared with 35 per 100,000 etanercept-treated patients, p<0.001) with a rate ratio of 4.17.¹¹ In France, a case-control analysis of newly diagnosed TB associated with anti-TNF agents found that exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB, OR: 13.3 (95% CI: 2.6-69.0) and OR: 17.1 (95% CI: 3.6-80.6), respectively.¹²

Listeria monocytogenes

Infection with the intracellular bacterium Listeria monocytogenes (L. monocytogenes) in patients receiving biologic therapy is well-documented. An assessment of the incidence of Listeria infections in patients using TNF inhibitors was performed by comparing data from the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases (BIOBADASER) with the Spanish Rheumatoid Arthritis Registry Cohort Study (EMECAR). RA patients treated with TNF-α antagonists had an increased rate of Listeria infection in comparison to RA patients treated with conventional therapy, as well as the general population.¹³

A recent review described the first case of L. monocytogenes endocarditis associated with infliximab, and identified 92 cases of L. monocytogenes infections related to infliximab treatment in the FDA AERS database. Meningitis was the most common type of infection reported (69 cases, 75%), followed by sepsis (20 cases, 21.7%) and listeriosis (3 cases, 3.3%). Further information was lacking on most of the cases in the AERS database, however, additional immunosuppressive therapy was being used in 22 out of 24 cases detailed in the review.¹⁴ Infectious complications with Listeria are seen more frequently in patient treated with infliximab versus etanercept,¹⁵ perhaps because of the more versatile binding of infliximab to both soluble and cell surface TNF-α instead of predominantly soluble TNF-α. However, there have been several cases of L. monocytogenes septic arthritis in patients treated with etanercept.^15-17 Adalimumab is reported less frequently in association with L. monocytogenes infections, but a case of L. monocytogenes meningitis with this therapy has been documented.¹⁸

Legionella pneumophila

Legionella pneumophila (L. pneumophila) infections account for up to 15% of cases of community-acquired pneumonia requiring hospitalization.¹⁹ Antigenic components of L. pneumophila are potent stimuli of TNF-α production, which along with interferongamma, interleukin-6, and interleukin-1 drive induction of the innate immune response. Inhibiting this response with TNF-α antagonists should predispose to legionellosis.

In France, a registry of 486 multidisciplinary clinical departments was designed by Recherché Axée sur la Tolérance des Biothérapies (RATIO) to prospectively collect data on severe and opportunistic infections in people receiving TNF-α antagonists over a 1-year period. There were 10 cases of L. pneumophila infections; 6 of the patients were treated with adalimumab, 2 with etanercept, and 2 with infliximab. The median duration of therapy when infection occurred was 38.5 weeks. The relative risk of L. pneumophila infection in people receiving anti-TNF therapy was reported as 16.7-21.0 in comparison with the general population. However, this may be an overestimate as 9 out of 10 patients were receiving concomitant immunosuppressive therapy (prednisone, methotrexate, azothioprine, or sulfasalzine), except for one, who was receiving infliximab alone.²⁰ A recent case review of the incidence of legionellosis in patients receiving infliximab included 10 cases¹⁹ in addition to those reported by the French registry;²⁰ concomitant immunosuppressive therapy was being used in at least 8 out of 10 of those cases.¹⁹ A British study comparing rates of infection in rheumatoid arthritis patients receiving DMARDs therapy versus TNF inhibitors (etanercept, infliximab, adalimumab, and anakinra) found that the rate of serious infection was equal in both cohorts, but a higher rate of infection with intracellular microbes (Legionella, Listeria, and Salmonella) occurred in those using TNF inhibitors.²¹

While the exact relative risk of developing L. pneumophila during treatment with TNF inhibitors is difficult to predict, there seems to be a clear association in the literature. It is important for clinicians to be mindful of this association and to consider adding floroquinolone or macrolide antibiotics for coverage of Legionella (and other agents of atypical pneumonia) in patients on anti-TNF-α therapy who present with pulmonary symptoms.

Fungal Infections

In 2008, the FDA issued a ‘black box warning’ to alert clinicians of the risk of endemic mycoses in patients receiving anti-TNF-α therapy. The report included 240 cases of histoplasmosis in patients treated with infliximab, etanercept, or adalimumab. Most cases occurred in areas where the fungus is most prevalent. The most concerning point raised by this report was that in 21 patients, the signs of infection was unrecognized and antifungal therapy was delayed; 12 of those patients died.²² A recent review addressed challenges of diagnosing fungal infections in patients receiving TNF-α antagonists: atypical presentation and symptoms of infection mimicking the underlying disease. The higher incidence of Histoplasmosis capsulatum (H. capsulatum) compared to Blastomyces dermatididis or Coccidiodes spp. in patients taking TNF-α inhibitors is attributed to the wide geographic area of H. capsulatum, as well as the fact that infection with H. capsulatum is contained almost exclusively by cellmediated immunity.²³ Multiple cases of aspergillosis have also been associated with TNF-α antagnonists.²⁴

In patients who are starting treatment with TNF-α antagonists, there is no reliable method to predict the risk for acquiring fungal infections. However, patients should be counseled to avoid high-risk activities that may predispose them to exposure to the endemic mycosis in their geographic areas.²⁵ Patients who develop endemic fungal infection while receiving TNF-α inhibitors should immediately discontinue the biologic and initiate therapy with antifungal agents in concordance with the Infectious Diseases Society of America guidelines for treatment of these infections in immunocompromised hosts.²³

Conclusion

The risk of infection is always a concern with any immunosuppressive treatment, and such infections are documented with all biologic therapies. Of the TNF inhibitors, infliximab seems to carry the highest risk of infection. In comparison to infliximab, use of etanercept (HR: 0.64, 95% CI: 0.49-0.84), abatacept (HR: 0.68, 95% CI: 0.48-0.96), rituximab (HR: 0.81, 95% CI: 0.55-1.20), and adalimumab (HR: 0.52, 95% CI: 0.39-0.72) was associated with lower rates of hospitalized infections, although the authors attributed variability in patients’ risk of infection to factors other than treatment with biologics.²⁶ Additionally, a 3-year national French registry (RATIO) study comparing incidence of nontuberculosis opportunistic infections (45 cases in 43 patients) between TNF-α inhibitors found that risk factors were infliximab (OR: 17.6 [95% CI: 4.3-72.9]; p<0.0001) or adalimumab (OR: 10.0 [95% CI: 2.3 to 44.4]; p=0.002) versus etanercept.²⁷

Still, it is difficult to predict the true risk to patients commonly seen in the dermatologist’s clinic when: 1) Most reviews of biologics-associated opportunistic infections are comprised of patients being treated for conditions other than psoriasis and 2) Most cases of opportunistic infections associated with biologic therapy occur when additional systemic immunosuppressive therapy is being utilized. Variation in dates of approval for these medications also translates to variation in experience.

The overwhelming majority of evidence supports the idea that biologics are safe for the treatment of psoriasis. Grijalva et al. recently published the results of a US multi-institutional collaboration examining whether or not TNF-α antagonists are associated with an increased risk of serious infections requiring hospitalization in comparison to non-biologic therapy.²⁸ The cohorts studied included 10,484 RA, 2,323 inflammatory bowel disease, and 3,215 psoriasis and spondyloarthropathies. In total, 1,172 serious infections were identified, the majority of which (53%) included pneumonia and skin and soft tissue infections. The conclusion was that TNF-α inhibitors are in fact, not associated with an increased risk for hospitalization for serious infection.²⁸ These findings contradict a general, replicated pattern seen in previous studies evaluating the safety of TNF-α antagonists, i.e., that there is a higher rate of serious infection in patients taking anti-TNF-α therapy compared to patients using non-biologic therapy that decreases with time. Dixon and Felson’s editorial²⁹ addressed the question of why the time-dependent risk of serious infection was not seen in Grijalva’s report. The authors attribute this finding to the unique design of Grijalva’s study, i.e., comparing the risk of serious infections between new user cohorts, not between patients initiating treatment with anti-TNF-α therapy versus those receiving treatment with nonbiologic agents. In other words, the time-dependent risk may disappear when both cohorts are examined at the same point in their course of treatment.29 Of course, this finding has yet to be replicated, but it does warrant a re-evaluation of the safety of anti-TNF-α therapy. Most would agree that the benefits of biologics outweigh the risks and that clinical practice measures such as screening, prevention, and vigilance are effective in limiting the risk of potential opportunistic infections associated with immunotherapy.

References

1. Lebwohl M, Leonardi C, Griffiths CE, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (Part I of II): Results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol. 2011 Sep 17.
2. Dreiher J, Kresch FS, Comaneshter D, et al. Risk of Herpes zoster in patients with psoriasis treated with biologic drugs. J Eur Acad Dermatol Venereol. 2011 Sep 16.
3. Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009 Feb 18;301(7):737-44.
4. Failla V, Nikkels AF. Ustekinumab and herpes zoster. Dermatology. 2011;222(2):119-22.
5. Javed S, Kamili QU, Mendoza N, et al. Possible association of lower rate of postherpetic neuralgia in patients on anti-tumor necrosis factor-alpha. J Med Virol. 2011 Nov;83(11):2051-5.
6. Whitley RJ, Gnann JW, Jr. Herpes zoster in the age of focused immunosuppressive therapy. JAMA. 2009 Feb 18;301(7):774-5.
7. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011(2):CD008794.
8. Kaminska E, Patel I, Dabade TS, et al. Comparing the lifetime risks of TNF-alpha inhibitor use to common benchmarks of risk. J Dermatolog Treat. Epub 2011 Jul 14.
9. Sanchez-Moya AI, Dauden E. Incidence of tuberculosis infection in psoriatic patients on anti-TNF therapy: report of a case series with 144 patients. J Eur Acad Dermatol Venereol. 2011 Jun;25(6):730-3.
10. Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005 Jul;52(7):1986-92.
11. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004 May 1;38(9):1261-5.
12. Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009 Jul;60(7):1884-94.
13. Pena-Sagredo JL, Hernandez MV, Fernandez-Llanio N, et al. Listeria monocytogenes infection in patients with rheumatic diseases on TNF-alpha antagonist therapy: the Spanish Study Group experience. Clin Exp Rheumatol. 2008 Sep-Oct;26(5):854-9.
14. Kelesidis T, Salhotra A, Fleisher J, et al. Listeria endocarditis in a patient with psoriatic arthritis on infliximab: are biologic agents as treatment for inflammatory arthritis increasing the incidence of Listeria infections? J Infect. 2010 May;60(5):386-96.
15. Schett G, Herak P, Graninger W, et al. Listeria-associated arthritis in a patient undergoing etanercept therapy: case report and review of the literature. J Clin Microbiol. 2005 May;43(5):2537-41.
16. Nadarajah K, Pritchard C. Listeria monocytogenes septic arthritis in a patient treated with etanercept for rheumatoid arthritis. J Clin Rheumatol. 2005 Apr;11(2):120-2.
17. Rachapalli S, O’Daunt S. Septic arthritis due to Listeria monocytogenes in a patient receiving etanercept. Arthritis Rheum. 2005 Mar;52(3):987.
18. Gil C, Legido J, Cuenca C, et al. [Meningitis due to Listeria monocytogenes during adalimumab therapy]. Gastroenterol Hepatol. 2009 Oct;32(8):587-8.
19. Hofmann A, Beaulieu Y, Bernard F, et al. Fulminant legionellosis in two patients treated with infliximab for Crohn’s disease: case series and literature review. Can J Gastroenterol. 2009 Dec;23(12):829-33.
20. Tubach F, Ravaud P, Salmon-Ceron D, et al. Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006 Nov 15;43(10):e95-100.
21. Symmons DP, Silman AJ. The world of biologics. Lupus. 2006;15(3):122-6.
22. U.S. Food and Drug Administration. FDA requires stronger fungal infection warning for TNF blockers.
23. Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy. Drugs. 2009 Jul 30;69(11):1403-15.
24. Nedel WL, Kontoyiannis DP, Pasqualotto AC. Aspergillosis in patients treated with monoclonal antibodies. Rev Iberoam Micol. 2009 Sep 30;26(3):175-83.
25. Arnold TM, Sears CR, Hage CA. Invasive fungal infections in the era of biologics. Clin Chest Med. 2009 Jun;30(2):279-86, vi.
26. Curtis JR, Xie F, Chen L, et al. The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis. 2011 Aug;70(8):1401-6.
27. Salmon-Ceron D, Tubach F, Lortholary O, et al. Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis. 2011 Apr;70(4):616-23.
28. Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011 Dec 7;306(21):2331-9.
29. Dixon W, Felson DT. Is anti-TNF therapy safer than previously thought? JAMA. 2011 Dec 7;306(21):2380-1.

¹Memorial University of Newfoundland Faculty of Medicine, St. John’s, NL, Canada
²Nexus Clinical Research, St. John’s, NL, Canada

ABSTRACT

Early diagnosis of psoriatic arthritis (PsA) is essential for preventing disease progression and joint destruction. The majority of patients develop PsA years after the onset of their skin disease. Therefore, dermatologists are in a strategic position to make the diagnosis of PsA, and either manage it or refer the patient to a rheumatologist in order to prevent the potentially irreversible destruction of the affected joints. We will review the presentation and temporal relationship of psoriasis and PsA, the diagnosis, classification, and management, in addition to the role of the dermatologist in the early detection of PsA.

Key Words:
Distal interphalangeal joint (DIP), metatarsophalangeal joint (MTP), psoriasis, psoriatic arthritis, PsA

Psoriatic arthritis (PsA) is often described as a chronic, inflammatory arthropathy affecting the distal interphalangeal joints (DIP) of the hands, metatarsophalangeal joints (MTP)
of the feet, and spine in association with psoriasis.1 One to three percent of the world population has been diagnosed with psoriasis.²

Estimates of the prevalence of PsA within the psoriasis population range from 6%-39%.3 The Psoriasis Foundation 2001 Benchmark Survey estimated the prevalence of PsA in patients with psoriasis to be as high as 23%.⁴ PsA is often under diagnosed or misdiagnosed, and therefore, statistics may be misrepresented.

Clinical Presentation

There appears to be great variability in the case definition for PsA. One such definition, proposed by Moll and Wright, defines PsA as “an inflammatory arthritis associated with
psoriasis and usually with a negative serological test for rheumatoid arthritis.”⁵ Due to the broad spectrum of PsA there has been a need to create subgroups (Table 1).

Characteristic features of psoriatic arthritis include: swelling, erythema, warmth, and inflammation of the affected joint. PsA can present with asymmetrical joint distribution,
involving more joints over time and progressing as an oligoarticular/polyarticular disease. Almost any joint can be involved including peripheral (e.g., the DIPs) and/ or axial joints (e.g., spine and sacroiliac joints). PsA can also manifest with involvement of periarticular structures such as tenosynovitis (inflammation of the tendon sheath), dactylitis or “sausage digit” (inflammation of entire digit), and enthesitis (insertion of the tendon).⁴

As with other sero-negative spondylarthropathies, there can also be extra-articular manifestations of PsA. These features may include inflammation of the eye, mucous
membranes, urinary system, and cardiovascular system (i.e., iritis, conjunctivitis, aortic dilation, and urethritis).⁶

There does not appear to be a difference in the prevalence of psoriasis between the sexes,⁷ however, the onset of disease seems to be earlier in women.⁸ The onset of psoriasis is bimodal with a median age of onset at 29.1 years.⁹ Those with early disease can have a greater body surface area involved, unstable psoriasis, frequent relapses, and a higher incidence of guttate psoriasis and nail involvement.^9,10

Patients with later onset tend to have a more stable course and less severe disease, but more frequent palmoplantar pustulosis.^9,10

The temporal sequence of disease onset can vary, making the diagnosis of PsA difficult. As high as 75%-80% of psoriasis patients will present with cutaneous manifestation 5-10 years prior to the onset of joint complaints.4,11 There can exist a flare in arthritis with or without a coinciding flare of psoriasis.4

The majority of patients with PsA have mild or moderate cutaneous manifestation,12 and 80%-90% of this population have nail lesions.^12,13 However, 46% of patients with psoriasis (no affected joints) have nail involvement.¹³ The extent and severity of both skin and joint disease correlate closely with the severity of psoriatic nail involvement, however this association is more commonly found in the DIP arthritis form of PsA.¹⁴

Differential Diagnosis

Distinguishing PsA from other inflammatory conditions can be challenging since the clinical features may overlap. The differential diagnosis may include: rheumatoid arthritis (RA), reactive arthritis, inflammatory bowel disease (IBD) and ankylosing spondylitis, to name a few. (See Table 2.)

To further complicate matters, other rheumatologic conditions such as osteoarthritis, soft tissue rheumatism, septic arthritis, and true RA can coexist with psoriasis. In addition, psoriasis has been found to occur with higher frequency in patients with IBD and ankylosing spondylitis.^15,16,17

The presence of such confounding variables stresses the importance of a full history and physical examination that includes serological, radiological, and perhaps genetic investigations to aid in the diagnosis.

Making the Diagnosis

There exist several PsA classification criteria in the literature. The Classification criteria for Psoriatic Arthritis (CASPAR) are newly developed criteria for the diagnosis of PsA. They are simple to use, have a high specificity of 98.7%, and a sensitivity of 91.4% for the diagnosis of PsA.18

CASPAR Criteria

A patient must have inflammatory articular disease (joint, spine, or entheseal) with 3 or more of the following 5 criteria:

1. Current OR personal history of psoriasis, OR family history of psoriasis (1st or 2nd degree relative). Psoriasis is defined as skin or scalp disease.
2. Psoriatic nail disease including: onycholysis, pitting, hyperkeratosis on current physical exam
3. Negative for rheumatoid factor (by any method except latex)
4. History of or current dactylitis recorded by a rheumatologist
5. Radiographic evidence of juxta-articular new bone formation, appearing as ill defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot.

Based on these criteria and established clinical features of PsA, a basic workup for a new patient in your office with psoriasis should include a history, physical examination, laboratory investigations, and review of treatment options as summarized below.

History

• Current OR personal history of psoriasis, OR family history of psoriasis
• Swelling of joints
• Pain or tenderness in joints
• Morning stiffness >30 minutes
• Functional capacity in activities of daily living (changes in ability to function at home and at work and impact on quality of life), etc.

Physical Examination

• Nails: evidence of onycholysis, pitting, hyperkeratosis, oil-drop sign, and nail crumbling
• Skin: see Table 1.

Musculoskeletal

• Signs of joint inflammation such as swelling, effusion, synovial thickening, erythema, decrease in range of movement
• Other manifestations: DIP joint involvement, enthesis, dactylitis, spondylitis and sacroiliitis, eye symptoms (i.e., iritis), etc.
• See Table 1 for other characteristic findings for PsA.

Diagnostic Investigations

• Laboratory tests should include: complete blood count, erythrocyte sedimentation rate, C-reactive protein, Rh factor, and routine renal and liver function tests.
• Plain radiographs: these can be normal in the early stages of disease. However, juxta-articular new bone formation, periarticular osteopenia, and later stages may demonstrate “pencil in cup” erosive disease in the hands or feet.

Treatment

When treating the cutaneous and joint manifestations, as in PsA, each aspect of the disease must be considered. The 2 may be treated independently, although a number of
systemic therapies may benefit both. Treatment options that can improve both PsA and psoriasis include:

1. Traditional systemic agents

• Cyclosporine (3-5mg/kg PO daily)
• Methotrexate (doses ranging from 15-25mg PO/IM weekly)

2. Biologic agents (with indication for PsA)

• Etanercept (50mg SC bi-weekly)
• Infliximab (5mg/kg IV at week 0, 2, 6 and then every8 weeks)
• Adalimumab (40mg SC every 2 weeks)

However, some may help one while adversely affecting the
other. Drugs that can induce disease exacerbation include:²⁰

1. Drugs that treat arthritis, but may worsen psoriasis

• Gold
• Systemic corticosteroids
• Hydroxychloroquine

2. Drugs that treat psoriasis, but may worsen arthritis

• Acitretin
• Efalizumab

The Role of the Dermatologist

The recognition and early treatment of PsA is analogous to that of acne. We are aware of the importance of early recognition of acne and the urgency in treating it aggressively in order to induce remission and prevent further damage. The destruction of the joints in PsA follows the same principle: treat early to prevent the damage. The dermatologist who monitors a psoriatic patient can detect PsA at its earliest stage.

A study by Zanolli and Wikle concluded that a large portion of patients with psoriasis presenting to a dermatologist for treatment were recognized to have coexisting joint complaints; and the prevalence of PsA is greater than that identified by a nondermatologist.²¹

The prevalence of psoriasis is greater than PsA, and psoriasis typically precedes the joint complaints.^4,11,22 Therefore, the dermatologist is in a unique position to screen patients with
psoriasis for PsA by maintaining a high index of suspicion and close follow-up. In limited cases, consultation with a rheumatologist may be necessary to make the diagnosis of PsA.

A screening questionnaire could be designed for patients presenting to the dermatologist for the first time with psoriasis. The Psoriasis and Arthritis Screening Questionnaire (PASQ)²³ that was developed by our group was created using the CASPAR criteria as its framework. This questionnaire does not replace a proper history, but reminds us to consider the diagnosis of PsA in any patient with symptoms of psoriasis, regardless of the severity of the cutaneous
manifestations.

Conclusion

The dermatologist is in a strategic position for early diagnosis, intervention, and appropriate management of the patient with PsA at its onset. The skin and joint involvement
in PsA can significantly affect a patient’s function and quality of life, and may increase cardiovascular morbidity and mortality.²⁴ These effects, in turn, may have significant impact on the family and society in general. Early diagnosis and effective therapy for PsA can prevent the progression of joint damage, and possibly induce a remission of the disease.

References

1. Stern RS. The epidemiology of joint complaints in patients with psoriasis. J Rheumatol 12(2):315-20 (1985 Apr).
2. Myers WA, Gottlieb AB, Mease P. Psoriasis and psoriatic arthritis: clinical features and disease mechanisms. Clin Dermatol 24(5):438-47 (2006 Sep-Oct).
3. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 53(4):573 (2005 Oct).
4. Qureshi AA, Husni ME, Mody E. Psoriatic arthritis and psoriasis: need for a multidisciplinary approach. Semin Cutan Med Surg 24(1):46-51 (2005 Mar).
5. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 3(1):55-78 (1973).
6. Weinstein GD, Gottlieb AB, editors: Therapy of Moderate to Severe Psoriasis, 2nd ed. New York: Marcel Dekker, (2003).
7. Lebwohl M. Psoriasis. Lancet 361(9364):1197-204 (2003 Apr 5).
8. Myers W, Opeola M, Gottlieb AB. Common clinical features and disease mechanisms of psoriasis and psoriatic arthritis. Curr Rheumatol Rep 6(4):306-13 (2004 Aug).
9. Ferrandiz C, Pujol RM, Garcia-Patos V, et al. Psoriasis of early and late onset: a clinical and epidemiologic study from Spain. J Am Acad Dermatol 46(6):867-73 (2002 Jun).
10. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 13(3):450-6 (1985 Sep).
11. Alenius GM. Psoriatic arthritis-new insights give new options for treatment. Curr Med Chem 14(3):359-66 (2007).
12. Cohen MR, Reda DJ, Clegg DO. Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies. J Rheumatol 26(8):1752-6 (1999 Aug).
13. Gladman DD, Anhorn KA, Schachter RK, et al. HLA antigens in psoriatic arthritis. J Rheumatol 13(3):586-92 (1986 Jun).
14. Williamson L, Dalbeth N, Dockerty JL, et al. Extended report: nail disease in psoriatic arthritis–clinically important, potentially treatable and often overlooked. Rheumatology (Oxford) 43(6):790-4 (2004 Jun).
15. Yates VM, Watkinson G, Kelman A. Further evidence for an association between psoriasis, Crohn’s disease and ulcerative colitis. Br J Dermatol 106(3):323-30 (1982 Mar).
16. Hellgren L. Association between rheumatoid arthritis and psoriasis in total populations. Acta Rheum Scand 15:316-26 (1969).
17. Brockbank J, Gladman D. Diagnosis and management of psoriatic arthritis. Drugs 62(17):2447-57 (2002).
18. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 54(8):2665-73 (2006 Aug).
19. Gladman DD. Clinical Manifestations and diagnosis of psoriatic arthritis. In: UpToDate online 2007 version 15.3.
20. Soriano ER, McHugh NJ. Therapies for peripheral joint disease in psoriatic arthritis. A systematic review. J Rheumatol 33(7):1422-30 (2006 Jul).
21. Zanolli MD, Wikle JS. Joint complaints in psoriasis patients. Int J Dermatol 31(7):488-91 (1992 Jul).
22. Thumboo J, Uramoto K, Shbeeb MI, et al. Risk factors for the development of psoriatic arthritis: a population based nested case control study. J Rheumatol 29(4):757-62 (2002 Apr).
23. Kraishi M, Heale C, Landells I, et al. The Psoriasis and Arthritis Screening Questionnaire (PASQ): a sensitive and specific tool to diagnose psoriatic arthritis patients with high correlation to the CASPAR criteria. Accepted for presentation at the 83rd Annual Conference of the Canadian Dermatology Association, June 27-July 2, 2008, Montréal, QC.
24. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 296(14):1735-41 (2006 Oct 11).

Early treatment should provide control of inflammation – control of pain, swelling and stiffness, and help prevent development of joint deformity and damage. Both skin and joint manifestations need attention.

Manage the joints to minimize or prevent joint destruction

Control of inflammation prevents joint destruction. At the same time, avoiding unnecessary stress on affected joints will also help prevent joint destruction. Maintaining normal range of movement in the joints is important.

Control of pain and stiffness

Nonsteroidal anti-inflammatory medications such as aspirin, ibuprofen, naproxen, indomethacin, or the newer cox-2 selective inhibitors such as celecoxib, rofecoxib, or valdecoxib help to control pain and stiffness. If the inflammation is mild, these medications may be sufficient.

In Addition

In addition to these medications, rest during acute attacks of inflammation is important, and regular exercise to maintain joint function is important.

For more severe inflammation, Disease Modifying Anti-Rheumatic Drugs (DMARDs) are indicated. Read more about these drugs in the next sections in Medical Treatments.

Methotrexate has been used for the treatment of cancer for many years. It was found to be effective in psoriasis and psoriatic arthritis in the 1960s. It is also used for a number of other forms of arthritis, including rheumatoid arthritis where it has an indication. Although there are not many studies demonstrating the efficacy of methotrexate in psoriatic arthritis, it is the drug of choice in this disease, particularly when both skin and joint manifestations are active. It is also the drug of choice when there is a significant joint involvement, even if the skin disease is mild. That is because in the clinical setting, methotrexate appears to work very well.

Mechanism of action

The exact mechanism of action of methotrexate is unknown, but it is an antimetabolite, and therefore interferes with cell proliferation. It inhibits skin proliferation and affects the inflammatory changes in the joints. Methotrexate works well to suppress the signs and symptoms of inflammation in the joints, and also controls psoriasis. It is not yet clear whether it actually prevents progression of joint damage.

Mode of administration

It is given orally at a dose of 15-25 mg once a week, either by mouth or by injection. Methotrexate is provided as a tablet containing 2.5 mg, therefore 6-10 tablets are required once a week, either all together or in divided doses 12 hours apart within a 24-hour period. When a dose higher than 17.5 mg per week is required, one often switches to an injectable form, given either intramuscularly or subcutaneously. This can be self injected, just like an insulin needle in a patient with diabetes. Folic acid supplementation is given as well, to reduce the frequency and severity of some of the side effects. Methotrexate starts working within a few weeks. It usually works well, and some patients have been able to reduce the dose. However, most patients require continued administration of the drug.

Although methotrexate is widely used for the treatment for psoriatic arthritis, there is not a labeled indication for its use in this condition.

Side effects

Side effects of methotrexate include mouth sores, hair loss (with high doses), suppression of the bone marrow leading to low blood, potential effect on the liver. To avoid these last two side effects, blood work is performed at regular intervals. People taking methotrexate should avoid drinking alcohol. People taking methotrexate should have blood tests performed at regular intervals. These include hematology and biochemistry. Initially we check the blood more often, until we arrive at a stable dose of methotrexate. Generally blood tests should be performed at 4-6 week intervals. If the liver function tests are raised more than twice the normal range methotrexate is usually stopped. Sometimes the liver test abnormality arises from the use of concomitant anti-inflammatory medications and those may need to be stopped.

Use in pregnancy

Women who are contemplating pregnancy should not take methotrexate, as it is an abortive agent. It is recommended that both men and women be off methotrexate for 3 months before conception.

Surgery

It is also recommended that people taking methotrexate stop the drug during the week of an operative procedure.

Sulfasalazine is the only drug that was developed specifically for arthritis and combines a sulfa drug with acetylsalicylic acid. Sulfasalazine is a favorite drug for inflammatory arthritis in Europe, and has been used for rheumatoid arthritis since the 1960s. It has been used for psoriatic arthritis since the 1970s. There are several clinical trials using sulfasalazine, showing a modest improvement over placebo. However, in individuals who cannot take methotrexate, it is the drug of choice. It does not have a specific indication for psoriatic arthritis.

Mechanism of action

Sulfasalazine helps control symptoms and signs of inflammation, and may help the skin, but there is not enough information on its effect on the psoriasis. The exact mechanism of action is unknown.

Mode of administration

Sulfasalazine is provided as a tablet of 500 mg, and usually 4 a day (2gm) is necessary. The effect is usually noted within 8-12 weeks. However, some patients require a dose of 3-4 gm per day.

Side effects

People with an allergy to sulfa drugs should not take sulfasalazine. Some patients taking sulfasalazine develop an allergic reaction manifesting with a sever rash. The major side effect of sulfasalazine is diarrhea, which usually disappears with use, and suppression of the bone marrow to cause a low white count and thus predisposition to infection. Hematological blood tests (to check the white blood cell count) should be performed at regular intervals (2-3 months) in people taking sulfasalazine. The drug is stopped when side effects are noticed and the white count usually returns to normal.

Use in pregnancy

There have been successful pregnancies on sulfasalazine. However, it is recommended that women who are on sulfasalazine and are contemplating pregnancy discuss this with their physicians.