key: cord-0834864-erxjii1h authors: Wollina, Uwe; Fioranelli, Massimo; Goldust, Mohamad; Lotti, Torello title: Psoriatic Arthritis and COVID‐19 Pandemic: Consequences in Medical Treatment? date: 2020-06-01 journal: Dermatol Ther DOI: 10.1111/dth.13743 sha: 6b6e43a967cad4bc1a0ba28456f960e28826ae79 doc_id: 834864 cord_uid: erxjii1h The COVID‐19 pandemic has a strong negative impact on human society world‐wide. Patients with immune‐mediated disease may be prone to an increased risk of infection and/ or more severe course. We review the available data for patients with psoriatic arthritis (PSA) and systemic treatments. Current treatment options are summarized. Based upon the experience with COVID‐19 the following problems are addressed: (a) Can systemic treatment reduce comorbidities of PsA that are also comorbidities for COVID‐19? Does systemic medical treatment pose an increased risk of infection with SARS‐CoV‐2? Does systemic drug therapy have an impact on the risk of pulmonary fibrosis ‐ a factor with strong negative impact on COVID‐19 outcome? Small molecules, inhibitors of tumor necrosis factor alfa, interleukin and JAK inhibitors are considered. The data are inhomogeneous for the multiple drugs used in PsA. Although the risk for severe upper airway tract infections during clinical controlled trials was mostly in the range of placebo, these data have been obtained before the COVID‐19 pandemic and should be interpreted with caution. Some biologics demonstrated an anti‐fibrotic activity in vitro and in animal disease models. None of the biologics is indicated during an active infection with fever. In non‐symptomatic PsA patients, systemic drug therapy can be continued. This article is protected by copyright. All rights reserved. Psoriatic arthritis (PsA) is the most important extracutaneous manifestation of psoriasis. PsA is characterized by arthritis, enthesitis, dactylitis and axial involvement. Diagnosis of PsA is often delayed what has a negative effect on long-term joint damage and resulting functional disability. Historically, Moll and Wright (1973) defined PsA an inflammatory arthritis in association with psoriasis of skin and nails but absence of rheumatoid factor (seronegative arthritis). 1 Currently, the CASPAR criteria are the most widely accepted (Table I) . 2 However, CASPAR criteria have some weakness in diagnosis early PsA, where radiological signs may be missing. 3 Dermatologists play a role in early recognition of PsA, since they are familiar with psoriasis and extracutaneous manifestations and since they outnumber specialized rheumatologists. Therefore, dermatologists should also have a detailed insight in the treatment options for PsA and their possible adverse events. 4 We used a PUBMED research for "Psoriasis arthritis" AND "COVID-19" AND "Treatment" for English and German articles. This article is protected by copyright. All rights reserved. The COVID-19 pandemic which is caused by SARS-CoV-2 warrants re-consideration of our treatment options in skin disease and related conditions. Multiple lines of evidence support an evolutionary origin of SARS-CoV-2 from bats. It has been shown, that interactions between SARS-CoV-2 spike protein and receptor angiotensin-converting enzyme 2 (ACE2) is crucial for virus entry into host cells. 5 COVID-19 is characterized by respiratory clinical symptoms such as dry cough, fever, and dyspnea which can progress to an acute respiratory distress syndrome (ARDS) with pneumonia and pulmonary fibrosis due to a cytokine storm. ARDS is cause of death in about 50%. Older age was associated with greater risk of ARDS and death, likely to impaired immune response. 6 Significant comorbidities that are risk factors for a more severe course of COVID-19 are hypertension, diabetes and cardiovascular diseases. 7 PsA patients as well as patients with psoriasis are known to have comorbidities like cardiovascular disease, metabolic syndrome, obesity, diabetes mellitus, dyslipidemia, inflammatory bowel disease. These features show a clear overlap to comorbidities in COVID-19. 8 On the other hand, medical treatment may influence the risk of infection and the course of the infections as well. The aim of treatment is achieving a complete remission or alternatively minimal disease activity. There is a wide range of medical treatment options available. The European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations for treatment suggest a step-up strategy. 9, 10 The first step in medical treatment are non-steroidal anti-inflammatory drugs, followed by single disease modifying drugs (DMARDs). If failed, then combinations of standard DMARDs are This article is protected by copyright. All rights reserved. recommended followed biologic drugs. Initially intra-or peri-articular corticosteroids are able to improve mono-or milder oligoarthritis. 11 Methotrexate low dose once a week followed by folic acid orally 5 mg the next day is the most frequently used DMARD. Available data argue for a marked reduction in disease activity in PsA patients with polyarticular arthritis. 12 Sulfasalazine and leflunomide is have lost importance in recent clinical practice, mainly because more effective treatment has become available. 13 Tumor necrosis factor-alfa (TNFa) inhibitors are licensed for PsA. These include adalimumab, certolizumab, etanercept, golimumab and infliximab and their biosimilars. These compounds induce a significant improvement of arthritis, enthesitis, dactylitis, and psoriasis. 14, 15 Cytokine inhibitors with efficacy in PsA have been introduced more recently. They include ustekinumab, an IL-12/23 inhibitor, guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, secukinumab, a monoclonal antibody to IL-17A, and ixekizumab, a monoclonal antibody to IL-17A and IL-17AF, have demonstrated efficacy comparable to TNFainhibitors. [16] [17] [18] [19] [20] [21] Small molecules can be applied orally in contrast to biologics. Apremilast is a phosphodiesterase-4 inhibitor with lower efficacy but without the need of regular laboratory monitoring. 22 Another group of small molecules with activity in arthritis are Janus kinase (JAK) inhibitors. In a clinical placebo-controlled trial of patients with active PsA who had had an inadequate response to TNF inhibitors, tofacitinib was more effective in reducing disease activity. 23 Does Current Systemic Treatment Reduce the Risk of Comorbities for COVID-19? Cardiovascular comorbidities are common among patients with both psoriasis and PsA. 8, 24 This article is protected by copyright. All rights reserved. It has been speculated that modern treatment with small molecules and biologics might reduce the risk of major cardiovascular events. Since cardiovascular disease is a risk factor for COVID-19 and fatalities due to infection with SARS-CoV-2, a reduced cardiovascular risk might be a protective factor. Cardiovascular disease seems to be reduced in psoriasis by methotrexate, but not by apremilast. Major cardiovascular events are not reduced by TNFa inhibitors, IL-17 inhibitors, IL-12/23 inhibitors or apremilast during controlled trials. 25 In a recent large prospective cohort study using the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), the risk of major cardiovascular events under systemic treatment with methotrexate, adalimumab, etanercept, and ustekinumab has been analyzed in more than 7500 psoriasis patients. The mean follow-up time was about two years. The three biologics differed not significantly from methotrexate in case of incidence rates of major cardiovascular events. The lowest incidence was observed with etanercept, followed by methotrexate. 26 Similar data for PsA are not yet available. All our date from trials and real-world data originate from the pre-COVID-19 area. Therefore, they should be interpreted with caution. We know that TNFa-inhibitors increase the risk of tuberculosis with pulmonary tuberculosis, a prototype a severe respiratory bacterial infection. The risk for pulmonary tuberculosis is increased up to 25 times with this group of biologics, and therefore a strict pre-therapeutic screening for latent tuberculosis is a must. 27 This article is protected by copyright. All rights reserved. IL-17 antagonists increase the risk of pulmonary fungal infections, in particular with Candida spp. The risk is higher for ixekizumab (3.3 % of patients) than for ustekinumab (2.3%), secukinumab (1.7%) or TNFa receptor antagonist etanercept (0.8%). 28 Table II provides a summary on upper respiratory and severe infections seen with systemic medical therapy for PsA. [29] [30] [31] [32] [33] [34] [35] Does Systemic Medical Treatment of PsA Increase the Risk for COVID-19 Mortality? While propensity to airway infections is a measure for the risk to acquire an infection, including SARS-CoV-2, it does not directly the risk of severe COVID-19. Mortality of COVID-19 has been related to the development of pulmonary fibrosis. CT imaging demonstrates patchy ground glass opacities, thickening of interlobular or intralobular septa, and formation of fibrotic stripes. Fibrosis increases with severity of COVID-19 disease. 36, 37 Therefore, it seems important to avoid medical drugs that increase the potential risk of pulmonary fibrosis. Methotrexate-induced pneumonitis is a possible severe adverse event, but it is rare. Analyzing 104 patients with psoriasis or PsA, we haven't seen a single case of methotrexate-induced pneumonitis. 38 Interestingly this disease has not been reported in controlled clinical trials with methotrexate for rheumatoid arthritis since 2001. 39 The typical symptomatology shares with features with COVID-19 such as dry cough and dyspnea, fever, lymphopenia. The current understanding is, that viral disease such as Epstein-Barr virus infection can trigger methotrexate-induced pneumonitis. 40 In addition, risk factors of methotrexateinduced pneumonitis and COVID-19 are overlapping, i.e. age > 60 years, male gender, diabetes mellitus, renal dysfunction, and pre-existing lung disease. 41 After cessation of methotrexate and immunosuppressive treatment, symptoms may completely disappear. This article is protected by copyright. All rights reserved. IL-17A and IL-17A receptor have been shown to exert profibrotic activity in idiopathic pulmonary fibrosis. 42 Theoretically, IL-17 and IL-17 receptor antagonists/inhibitors should provide some protection against COVID-19 associated pulmonary fibrosis. In silica-induced pulmonary fibrosis IL-17A antagonists resulted in a shift toward a Th1-type immune response that induced autophagy. By this pathway, autophagic degradation of collagen was stimulated. 43 In different pulmonary fibrosis models, PDE4 inhibition had antifibrotic efficacy. PDE4 inhibitor roflumilast is FDA approved for chronic obstructive pulmonary disease (COPD). Nintedanib and pirfenidone are PDE4 inhibitors with antifibrotic activity. 44 Under these circumstances, it seems unlikely that apremilast increases the risk of pulmonary fibrosis. STAT3 phosporylation is involved in lung fibrosis. In vitro, JAK1/3 inhibitor tofacitinib demonstrated a dose-dependent inhibition of STAT3 phosphorylation. However, tofacitinib did not affect expression of IL-17A-induced smooth muscle actin (SMA) and extracellular matrix protein production. 42 Tofacitinib does not seem to be beneficial to reduce the risk of pulmonary fibrosis in case of COVID-19 but poses itself not a risk for fibrosis. In bleomycin-induced pulmonary fibrosis, TNFa levels are increased. In an animal models, TNFa inhibitors infliximab exerted a protective effect when given before intratracheal bleomycin instillation. 45 Conclusions COVID-19 pandemic has a strong impact on health system including dermatology and rheumatology. 46 Here we focus on PsA, a disorder seen by dermatologists and rheumatologists with treatment at is best as an interdisciplinary approach PsA like psoriasis shares a number of comorbidities with COVID-This article is protected by copyright. All rights reserved. 19 pandemic. 47, 48 Not only the disease itself but its medical treatment may change the risk for infection with SARS-CoV-2, which is responsible for COVID-19. The risks are at least two-fold: First, the possible increase of upper respiratory infections with SARS-CoV-2 which open the doors for COVID-19, and second the possibility of fostering lung fibrosis, a major factor in COVID-19 caused fatalities. PsA in contrast to rheumatoid arthritis does not pose a risk for pulmonary fibrosis. 49, 50 Our analysis of current medical treatment provides a non-uniform increase of URTI but no direct evidence for an increased risk of COVID-19. However, we have to be alerted that SARS-CoV-2 may behave differently and need to monitor our patients carefully under this view. Psoriatic arthritis Classification criteria for psoriatic arthritis: development of new criteria from a large international study Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis Psoriatic arthritis Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis Comorbidities associated with psoriatic arthritis: Review and update European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis A randomized placebo-controlled trial of methotrexate in psoriatic arthritis Psoriatic arthritis Tumor necrosis factor inhibitors in psoriatic arthritis The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and metaanalysis Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis A review of ixekizumab in the treatment of psoriatic arthritis Apremilast: A novel oral treatment for psoriasis and psoriatic arthritis Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors Systemic psoriasis therapies and comorbid disease in patients with psoriasis: A review of potential risks and benefits Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study The risk of tuberculosis related to tumour necrosis factor antagonist therapies: A TBNET Consensus Statement Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data Safety results of ixekizumab with 1822.2 patient-years of exposure: an integrated analysis of 3 clinical trials in adult patients with psoriatic arthritis Ustekinumab safety in psoriasis, psoriatic arthritis, and Crohn's disease: An integrated analysis of phase II/III clinical development programs Serious infections in patients with self-reported psoriatic arthritis from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) treated with biologics Safety and efficacy of intravenous golimumab in patients with active psoriatic arthritis: Results through week twenty-four of the GO-VIBRANT study An integrated analysis of the safety of tofacitinib in psoriatic arthritis across phase III and long-term extension studies with comparison to realworld observational data Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2 A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version) Toxicity of methotrexate treatment in psoriasis and psoriatic arthritis -short-and long-term toxicity in 104 patients Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials Methotrexate-associated lymphoproliferative disorders in patients with rheumatoid arthritis: Clinicopathologic features and prognostic factors Methotrexate-associated pneumonitis and rheumatoid arthritis-interstitial lung disease: Current concepts for the diagnosis and treatment Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury Protective effect of infliximab, a tumor necrosis factor-alfa inhibitor, on bleomycin-induced lung fibrosis in rats Priorities for global health community in COVID-19 pandemic Management of dermato-rheumatic syndromes The COVID-19 outbreak and rheumatologic skin diseases. Dermatol Thera. 2020; e13357 The lung in rheumatoid arthritis: Focus on interstitial lung disease Do anti-TNF blockers increase the risk of lung involvement in patients with ankylosing spondylitis or psoriatic arthritis? A systematic review This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.