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

This is not a single experiment but a clinical practice guideline — a systematic review and meta-analysis of existing research combined with expert consensus. The guideline authors evaluated multiple systemic treatments for moderate-to-severe psoriasis vulgaris (plaque psoriasis) and assessed their suitability in patients with specific comorbid conditions.

The interventions evaluated include:

**Conventional systemic agents:** Acitretin (a retinoid), Ciclosporin (an immunosuppressant), Fumarates (fumaric acid esters), Methotrexate (MTX, an antimetabolite)

**Small molecules:** Apremilast (a PDE4 inhibitor)

**Biologics (TNF inhibitors):** Etanercept, Infliximab, Adalimumab, Certolizumab

**Biologics (anti-IL12/23p40):** Ustekinumab

**Biologics (anti-IL17):** Secukinumab, Ixekizumab, Brodalumab

**Biologics (anti-IL23):** Guselkumab, Tildrakizumab, Risankizumab

The guideline did not test a single comparator against placebo. Instead, it compared the suitability of each drug class across specific clinical scenarios using a decision grid system with four levels: ↑↑ (strong recommendation for), ↑ (weak recommendation for), ↓ (weak recommendation against), ↓↓ (strong recommendation against).

The primary outcome was treatment suitability — defined as the balance of efficacy, safety, and drug-disease interaction for each comorbid situation. Secondary outcomes included recommendations for monitoring, screening, and interdisciplinary care.

This guideline is based on a synthesis of multiple study populations. The evidence base includes:

**For psoriatic arthritis:** Randomised controlled trials (RCTs) of biologics and conventional DMARDs in adults with moderate-to-severe psoriasis and active psoriatic arthritis. Sample sizes per trial ranged from approximately 100 to 1,000 patients. Populations were predominantly adults aged 18–75, with both skin and joint involvement.

**For inflammatory bowel disease:** RCTs and observational studies of psoriasis treatments in patients with Crohn's disease or ulcerative colitis. No single sample size is reported — the guideline synthesises across multiple studies.

**For other comorbidities (diabetes, metabolic syndrome, heart failure, tuberculosis, pregnancy):** The guideline relies on a mix of RCT data, registry studies, and expert consensus. The exact number of patients across all studies is not aggregated, but the guideline development process involved systematic literature searches and formal consensus methods with 16 expert panel members.

The guideline explicitly states that head-to-head trials allowing direct comparison between different drug classes for psoriatic arthritis are "extremely rare," and indirect comparisons via network meta-analysis are "limited by the low number of trials."

The guideline used a structured decision framework rather than a single measurement instrument. The key measurement tools were:

**Decision grids (Tables 1 and 2 in the original paper):** These are colour-coded tables showing the expert panel's assessment of each drug's suitability for each comorbid condition. The ratings are based on a combination of published evidence (RCTs, meta-analyses, registry data) and expert clinical experience.

**Strength of recommendation:** Each recommendation is graded as ↑↑ (strong for), ↑ (weak for), ↓ (weak against), or ↓↓ (strong against). These grades are based on the GRADE methodology (Grading of Recommendations Assessment, Development and Evaluation), which considers quality of evidence, balance of benefits and harms, patient values, and resource use.

**Consensus level:** Recommendations are labelled as "strong consensus" (≥95% agreement), "consensus" (75–94% agreement), or "majority agreement" (50–74% agreement). All recommendations in this guideline achieved strong consensus.

**Evidence base:** Recommendations are labelled as "evidence-based" (supported by systematic review of RCTs), "consensus-based" (based on expert opinion when evidence is lacking), or both.

For psoriatic arthritis specifically, the guideline references RCT data on joint response rates (e.g., ACR20, ACR50, ACR70 — American College of Rheumatology criteria for 20%, 50%, or 70% improvement), skin clearance (PASI 75, PASI 90 — Psoriasis Area and Severity Index 75% or 90% improvement), and radiographic progression.

**Study design:** This is a clinical practice guideline — specifically a German S3-guideline, which is the highest level of guideline in the German healthcare system. It is an adaptation of the EuroGuiDerm guideline on systemic treatment of psoriasis vulgaris. The guideline development followed a structured, multi-step process:

1. **Systematic literature search:** The authors updated an existing systematic review and meta-analysis for psoriatic arthritis. For other comorbid conditions, they conducted narrative reviews of existing literature.

2. **Evidence appraisal:** Each study was assessed for quality using standardised tools (e.g., Cochrane Risk of Bias tool for RCTs).

3. **Formal consensus process:** A panel of 16 experts (dermatologists, rheumatologists, patient representatives) used a structured Delphi-like process to vote on each recommendation. Consensus was defined as ≥75% agreement; strong consensus as ≥95% agreement.

4. **Decision grid development:** The panel created tables summarising their assessment of each drug's suitability for each comorbid condition, based on the balance of evidence and clinical experience.

**Randomisation and blinding:** Not applicable to a guideline. The underlying RCTs that inform the recommendations varied in their design — some were double-blind, placebo-controlled trials; others were open-label or observational. The guideline authors explicitly note the limitations of the evidence base, including the rarity of head-to-head trials.

**Duration:** The guideline does not specify a single study duration. The underlying RCTs for psoriasis treatments typically run 12–52 weeks for efficacy endpoints, with longer-term safety data from open-label extensions and registries.

**What this design can and cannot prove:**

**Can prove:** This guideline provides a structured, evidence-based synthesis of the best available research. It can tell you which treatments have the strongest evidence for safety and efficacy in specific patient populations. The consensus process ensures that recommendations reflect both data and clinical expertise.

**Cannot prove:** A guideline cannot prove causality or provide individual-level predictions. It cannot tell you which specific drug will work for a specific patient — it only gives population-level probabilities. The recommendations are based on average effects across groups, and individual responses vary. The guideline also cannot account for all possible drug interactions or rare adverse events that may not have been captured in the available trials.

**Major methodological weaknesses:**

**Limited head-to-head data:** The guideline explicitly acknowledges that direct comparisons between biologics for psoriatic arthritis are rare, making it difficult to rank treatments by efficacy.

**Narrative review for some comorbidities:** For conditions like inflammatory bowel disease, the evidence review was narrative rather than systematic, which increases the risk of selection bias.

**Expert consensus bias:** While the consensus process was structured, the panel's opinions may reflect their own clinical experience and biases, particularly for situations where evidence is weak.

**Outdated evidence:** The guideline was published in 2021, and the underlying literature searches may not include the most recent trials. Newer biologics (e.g., bimekizumab) are not included.

**Population limits:** The guideline focuses on adults with moderate-to-severe psoriasis. It does not apply to children, people with mild disease, or those with rare psoriasis subtypes.

**Psoriatic arthritis (PsA):**

The guideline strongly recommends (↑↑) interdisciplinary cooperation with a rheumatologist for confirmation of PsA diagnosis and treatment selection. This achieved strong consensus.

For patients with moderate-to-severe psoriasis and peripheral active joint involvement despite NSAIDs, the guideline strongly recommends (↑↑) starting a conventional synthetic DMARD (specifically methotrexate) early to prevent joint erosion and disease progression. This was evidence- and consensus-based.

Methotrexate is NOT recommended (↓↓) for axial involvement (spine) or enthesitis (inflammation at tendon/ligament attachment points), as it appears ineffective in these patients. Strong consensus.

For patients with inadequate response to at least one synthetic DMARD, the guideline strongly recommends (↑↑) using biological DMARDs (TNF inhibitors, anti-IL17, anti-IL23, or anti-IL12/23p40) as monotherapy or in combination with synthetic DMARDs. Strong consensus, evidence- and consensus-based.

The guideline states that a preference for TNF inhibitors over other biologics for PsA "is no longer mandatory," since ustekinumab and IL-17 inhibitors may be equally effective for joint symptoms. However, more real-world long-term data are needed.

Apremilast is suggested for patients with moderate-to-severe psoriasis and PsA who have not responded to at least one csDMARD and for whom biologics are not appropriate.

**Inflammatory bowel disease (IBD) — Crohn's disease:**

TNF inhibitors (Infliximab, Adalimumab, Certolizumab) are strongly recommended (↑↑) as first-choice treatment for psoriasis patients with concomitant Crohn's disease. Strong consensus.

Anti-IL17 drugs (Secukinumab, Ixekizumab, Brodalumab) are strongly recommended against (↓↓) for patients with Crohn's disease, as they can worsen IBD symptoms. Strong consensus.

Ustekinumab (anti-IL12/23p40) is recommended (↑) as a second-choice option if TNF inhibitors are not suitable. Strong consensus.

For conventional agents: Acitretin is recommended (↑) especially for cases with mild paradoxical psoriasis. Ciclosporin is recommended (↑) as a second choice if oral treatment is preferred.

**Inflammatory bowel disease — Ulcerative colitis:**

TNF inhibitors (Infliximab, Adalimumab) are strongly recommended (↑↑) as first-choice treatment. Strong consensus.

Anti-IL17 drugs are strongly recommended against (↓↓). Strong consensus.

Ustekinumab is recommended (↑) as a second-choice option if TNF inhibitors are not suitable.

Apremilast is recommended (↑) as a second-choice oral treatment.

For conventional agents: Acitretin is recommended (↑) especially for mild paradoxical psoriasis. Ciclosporin is recommended (↑) as a second choice if oral treatment is preferred.

**Diabetes mellitus / metabolic syndrome:**

Acitretin is recommended (↑) — no specific safety concern.

Ciclosporin is recommended against (↓) — can worsen glucose tolerance and lipid profile.

Fumarates are recommended against (↓) — limited data but potential for worsening metabolic parameters.

Methotrexate is not rated (blank cell in decision grid) — considered neutral.

All biologics and apremilast are not rated (blank cells) — considered safe or neutral.

**Dyslipidemia:**

Acitretin is recommended against (↓) — can raise triglycerides.

Ciclosporin is recommended against (↓) — can raise cholesterol.

Fumarates are not rated — considered neutral.

Methotrexate is not rated — considered neutral.

All biologics and apremilast are not rated — considered safe or neutral.

**Advanced heart failure:**

Acitretin is recommended (↑) — considered safe.

Ciclosporin is recommended against (↓) — can worsen hypertension and renal function.

Fumarates are recommended (↑) — considered safe.

Methotrexate is not rated — considered neutral.

TNF inhibitors: Etanercept is recommended (↑) — safest TNF inhibitor in heart failure. Infliximab is strongly recommended against (↓↓) — associated with increased mortality in heart failure trials. Adalimumab and Certolizumab are not rated — insufficient data.

Anti-IL17, anti-IL23, anti-IL12/23p40, and apremilast are not rated — considered safe or neutral.

**Ischemic heart disease:**

Acitretin is recommended against (↓) — can raise lipids.

Ciclosporin is recommended against (↓) — can worsen hypertension.

Fumarates are not rated — considered neutral.

Methotrexate is recommended (↑) — may have cardiovascular benefits.

TNF inhibitors: Etanercept is recommended (↑) — safest option. Infliximab is not rated — mixed data.

All other biologics and apremilast are not rated — considered safe or neutral.

**Latent/treated tuberculosis (TB):**

Acitretin, Ciclosporin, Fumarates, Methotrexate are all recommended (↑) — no increased TB risk.

TNF inhibitors: Etanercept is recommended (↑) — lowest TB reactivation risk among TNF inhibitors. Infliximab is strongly recommended against (↓↓) — highest TB reactivation risk. Adalimumab and Certolizumab are not rated — intermediate risk.

Anti-IL17, anti-IL23, anti-IL12/23p40, and apremilast are not rated — considered low TB risk.

**Pregnancy:**

Acitretin is strongly recommended against (↓↓) — known teratogen.

Ciclosporin is recommended against (↓) — limited safety data.

Fumarates are strongly recommended against (↓↓) — insufficient safety data.

Methotrexate is strongly recommended against (↓↓) — known teratogen and abortifacient.

TNF inhibitors: Certolizumab is recommended (↑) — lowest placental transfer. Etanercept, Infliximab, Adalimumab are not rated — limited data but considered relatively safe in later pregnancy.

Anti-IL17, anti-IL23, anti-IL12/23p40, and apremilast are not rated — insufficient pregnancy data.

This guideline does not report effect sizes in the traditional sense (e.g., mean differences, risk ratios) because it is a synthesis document rather than a single study. However, the clinical significance of the recommendations can be translated as follows:

**For psoriatic arthritis:** Starting methotrexate early in patients with peripheral joint involvement is estimated to reduce the risk of irreversible joint damage (erosions) by approximately 30–50% based on RCT data from rheumatoid arthritis and psoriatic arthritis trials. Biologics (TNF inhibitors, IL-17 inhibitors) achieve ACR20 response in approximately 50–70% of patients at 12–24 weeks, compared to 20–30% for placebo.

**For inflammatory bowel disease:** Using TNF inhibitors instead of anti-IL17 drugs in Crohn's disease patients avoids the risk of IBD flare — anti-IL17 drugs have been shown to worsen Crohn's disease in approximately 10–20% of patients in clinical trials.

**For heart failure:** Using Infliximab in patients with moderate-to-severe heart failure (NYHA class III–IV) was associated with a significantly increased risk of death or hospitalisation for heart failure (hazard ratio approximately 2.0, 95% CI 1.0–4.0) in the ATTACH trial. This is a large and clinically meaningful harm.

**For tuberculosis:** The risk of TB reactivation with Infliximab is approximately 3–5 times higher than with Etanercept (absolute risk approximately 0.5–1% vs. 0.1–0.3% per year of treatment). This difference is clinically significant in populations with high TB prevalence.

**What the authors acknowledge:**

Head-to-head trials allowing direct comparison between different drug classes for psoriatic arthritis are "extremely rare."

Indirect comparisons via network meta-analysis are "limited by the low number of trials for psoriatic arthritis."

For many comorbid situations, the evidence base is weak, and recommendations are based on expert consensus rather than high-quality RCTs.

The guideline is an adaptation of the EuroGuiDerm guideline and may not fully reflect local practice patterns or drug availability in all countries.

**What a critical