German S3‐Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm – Part 2: Treatment monitoring and specific clinical or comorbid situations

Abstract

For chapters 1 (Notes on use/Disclaimer), 3 (Funding), 4 (Scope and purpose of this guideline), 5 (Population and health questions covered by the guideline) and 6 (Targeted users of this guideline), see long version of the guideline. All documents are available in an up-to-date version on the following website: https://debm.charite.de Guideline text and recommendations This chapter is based on the related chapter in previous versions of this guideline [1, 2]. An existing systematic review and meta-analysis was updated, details of which can be found in the Guideline Development Report. Recommendations [3–6] Treatments are usually categorized as non-steroidal anti-inflammatory drug (NSAIDs)/COX-2 inhibitors (e.g., diclofenac, etoricoxib), conventional synthetic disease modifying anti rheumatic drugs (csDMARDs; e.g., MTX), targeted synthetic disease modifying anti rheumatic drugs (tsDMARDS; e.g., apremilast) and biological disease modifying anti rheumatic drugs (bDMARDs; e.g., TNF-antagonists). Head-to-head trials allowing direct comparison between the different groups or between the individual drugs are extremely rare. Indirect comparisons, e.g., network meta-analyses, are limited by the low number of trials for psoriatic arthritis. See Table 3 for an overview of randomized controlled trial (RCT) data on psoriatic arthritis. The role of NSAIDs is usually in the relief of symptoms of psoriatic arthritis for patients with mild and non-erosive articular as well as para-articular, entheseal involvement. Treatment of NSAIDs should be limited to the lowest required dosage for the shortest period as needed [8]. Methotrexate is recommended, taking the label, the efficacy on skin and peripheral joints, the safety profile and the available long-term experience in the treatment of rheumatic joint disorders into to account [8]. Biological DMARDs For inadequately responding patients after at least one synthetic DMARD, we recommend using biological DMARDs as monotherapy or in combination with synthetic DMARDs in patients with moderate-to-severe psoriasis with active joint involvement (PsA). Previously, guidelines have given a preference to TNF alpha antagonists over other bDMARDs. In the guideline group’s view, a preference for inhibitors of TNF treatments for PsA is no longer mandatory, since ustekinumab (enthesitis) and the IL-17A antibody treatments might be equally effective; however more data are needed for its real-life long-term efficacy, safety and co-medication. The treatment with a biological DMARD can be performed in monotherapy or in combination with a conventional synthetic DMARD. Considering the evidence on skin and joint involvement and the experience of the expert group, apremilast is primarily suggested for patients with moderate-to-severe psoriasis and concomitant psoriatic arthritis with an inadequate response to at least one csDMARD, in whom biological treatments are not appropriate. Local injection of glucocorticoids can be recommended in patients with active mono- or oligoarthritis, dactylitis with enthesitis or tendosynovitis. Systemic usage of glucocorticoids should not be standard for treatment of psoriatic arthritis, but if needed, e.g., during flares, “systemic steroids at the lowest effective dose may be used with caution” [9]. Tapering of glucocorticoids should be done slowly and stepwise when feasible. A narrative review of the existing literature and an assessment of the approval status of psoriasis therapies for Crohn’s disease and ulcerative colitis were conducted. Existing guidelines were consulted [10-12]. Likely due to an overlap in the pathophysiology and genetic background of psoriasis and Crohn’s disease, the risk of psoriasis patients developing Crohn’s disease is approximately two- to threefold higher compared to the general population [13, 14]. The IL-17A antibody secukinumab and the IL-17RA antibody brodalumab have failed in studies in Crohn’s disease, with some patients experiencing worsening of their disease during treatment [15, 16]. Cases of newly onset Crohn’s disease and ulcerative colitis have been observed during treatment of psoriasis patients with IL-17 inhibitors. The observed signal is, however, low, and it is presently unclear if the rate exceeds the rate expected in a psoriasis population [17]. (For further information see additional background text in the long version.) In contrast, ustekinumab, adalimumab, infliximab, and certolizumab are all targeted therapies approved not only for the treatment of psoriasis, but also for the treatment of Crohn’s disease and, in the case of adalimumab, infliximab and ustekinumab, ulcerative colitis; dosages may vary between psoriasis and inflammatory bowel disease (IBD). Notably, the anti-TNF fusion protein etanercept failed in clinical trials in Crohn’s disease [18]. There is an ongoing phase II/III clinical development program for the IL-23p19 inhibitors guselkumab and risankizumab in Crohn’s disease and ulcerative colitis. In the case of risankizumab, positive clinical effects have been published for the induction and long term treatment of patients with Crohn’s disease [19, 20] and are supported by immunological findings in the intestinal mucosa of patients with Crohn’s disease receiving the drug [21]. There are several published case reports on the successful use of guselkumab in patients with Crohn’s disease [22, 23]. Due to their intestinal side effect profile with a relatively frequent induction of abdominal pain, loose stools and diarrhea, fumarates should not be used in patients with inflammatory bowel disease (IBD). Severe gastrointestinal diseases are listed as contraindication in the prescription information of Fumaderm® and Skilarence®. Inhibition of PDE4 with apremilast has shown positive effects in a phase II trial with ulcerative colitis [24]. Methotrexate has limited efficacy in Crohn’s disease [25, 26] and probably even less in ulcerative colitis [27, 28], but there is a considerable body of experience and no signal for a worsening of these conditions. Acitretin may be considered neutral in patients with psoriasis and inflammatory bowel disease and has been used in the treatment of patients with inflammatory bowel disease that developed psoriasiform lesions (including cases of so called paradoxical psoriasis) during treatment with TNF antagonist [29]. Ciclosporin (CsA) is frequently used in the treatment of steroid-refractory ulcerative colitis and has demonstrated long term outcomes similar to those of infliximab [30]. In patients with psoriasis and active IBD or a history of IBD, we recommend preferentially using approved targeted therapies with a documented efficacy in these conditions: Crohn’s disease: anti-TNF (infliximab, adalimumab, certolizumab) and anti-IL-12/23p40 (ustekinumab). Ulcerative colitis: anti-TNF (infliximab, adalimumab) and anti-IL-12/23p40 (ustekinumab). If these first-choice treatments cannot be used, we suggest the following treatments to be considered as second choice targeted treatment options in patients with psoriasis and IBD: Crohn’s disease: anti-IL-23p19 (preferred risankizumab, guselkumab; also possible: tildrakizumab) Ulcerative colitis: anti-IL-23p19 (preferred risankizumab, guselkumab; also possible: tildrakizumab) If these first-choice treatments cannot be used, we suggest the following treatments to be considered as second choice oral treatment options in patients with psoriasis and IBD: Crohn’s disease: methotrexate. Active ulcerative colitis: ciclosporin (preferred), apremilast (also possible). This chapter is based on the related chapter in previous versions of this guideline [1, 2]. A systematic search was conducted, details of which can be found in the Guideline Development Report. (For further information see additional background text in the long version of the guideline.) Some studies have studied the possible association of the use of systemic therapies for psoriasis and incident cancer (in patients without previous history of cancer). A systematic review of RCTs and observational studies exploring the risk of cancer in psoriasis patients treated with biologics described an increased risk of non-melanoma skin cancer in those patients being treated with anti-TNFs. However, included studies lacked adjustment for highly relevant confounding factors such as prior phototherapy. Data on other cancers do not show a risk associated with exposure to drugs. However, the studies are likely to be underpowered to ascertain the risk of individual types of cancer [31]. Vaengebjerg et al. did not find increased risk of cancer in patients with psoriasis and psoriatic arthritis on biologics compared with other systemic therapies [32]. There are also some studies describing the risk of cancer associated with systemic therapy for other immune-mediated disorders, mainly rheumatoid arthritis, other rheumatic disorders and inflammatory bowel disease. Results in these disorders might not be appropriately extrapolated to psoriasis patients, as psoriatic patients receive less immunosuppressive therapy (specially corticosteroids) and the associated disorders are different [33]. Most studies are reassuring and did not find a relationship between exposure to anti-TNFs and risk of incident cancer in rheumatoid arthritis and psoriatic arthritis [34]. Luo et al., analyzing data from nine cohorts, described an increased risk of cancer in psoriatic arthritis patients treated with disease modifying antirheumatic drugs, which was not seen in patients receiving biologics. However, this increase was due to nonmelanoma skin cancer (NMSC) and included studies have not considered the likely effect of previous PUVA therapy [35]. Summary of Product Characteristics (SmPCs) of TNF inhibitors contain information regarding the risk of lymphoma/leukemia. However, these are rare events and data supporting this association are conflicting. So far, no such association have been shown for psoriasis patients [31]. Few studies provide information that is relevant for answering this question. Regarding patients with precancerous conditions (data available only for cervical dysplasia), a study using routine data of women with rheumatoid arthritis (RA), describe that initiation of therapy with a biological disease-modifying anti-rheumatic drug (bDMARD) was associated with an increased, but not statistically significant, risk of high-grade cervical dysplasia or cervical cancer compared to initiation of a nonbiological (nb)DMARD [36]. Conversely, a review analyzing 238 women with RA and a history of cervical carcinoma in situ, no genital cancer was observed in the TNF inhibitor (TNFi)-treated group over a median of 5.2 years of compared with of genital cancer in the group, during a median of years A systematic review of studies of patients with a history of cancer and to anti-TNF therapy for the risk of the of cancer or cancer compared to included nine studies with of were studies on The were with studies on describing the study did not find an increased risk of in patients treated with anti-TNFs compared to A based on routine of patients with rheumatoid arthritis and inflammatory bowel disease, and a previous described an increased risk of a second in patients treated with that was higher with longer use was also associated with an increased in a with RA and concomitant use of systematic review the risk of cancer in patients with immune-mediated diseases to included observational studies with after a cancer and with or cases of one and not to the was on psoriasis of cancer were similar receiving anti-TNF therapy or no but was higher patients receiving combination (For further information see additional background text in the long version of the guideline.) For patients with we recommend patients with a risk of In case of inadequate response to we suggest using in psoriasis patients with a previous history of patients with history of nonmelanoma skin see background suggest anti-TNF or ustekinumab can be used based on existing safety data on a with cancer suggest or anti can be used in psoriasis patients with a previous history of cancer the of long-term experience based on on a with a cancer This chapter is based on the related chapter in previous versions of this guideline [1, 2]. 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