John R Ingram

BACKGROUND: A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa (HS) is lacking. OBJECTIVES: To develop and validate a novel dynamic scoring system to assess the severity of HS. METHODS: A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation (EHSF) to achieve consensus towards an initial HS Severity Score System (HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 (IHS4) that was established by a second Delphi round. RESULTS: Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index (DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (κ = 0·32) compared with Hurley classification, and moderate (κ = 0·49) compared with Expert Opinion. Correlation was good (ρ > 0·6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (ρ = 0·36). CONCLUSIONS: The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-life and the clinical trials setting.

BACKGROUND: Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the efficacy and safety of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: For this living systematic review we updated our searches of the following databases monthly to September 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched two trials registers to the same date. We checked the reference lists of included studies and relevant systematic reviews for further references to eligible RCTs. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate-to-severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate-to-severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse events (SAEs) at induction phase. We did not evaluate differences in specific adverse events. DATA COLLECTION AND ANALYSIS: Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse events). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes and all comparisons, according to CINeMA, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer on treatment hierarchy: 0% (treatment is the worst for effectiveness or safety) to 100% (treatment is the best for effectiveness or safety). MAIN RESULTS: We included 158 studies (18 new studies for the update) in our review (57,831 randomised participants, 67.2% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo-controlled (58%), 30% were head-to-head studies, and 11% were multi-armed studies with both an active comparator and a placebo. We have assessed a total of 20 treatments. In all, 133 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (53/158) as being at high risk of bias; 25 were at an unclear risk, and 80 at low risk. Most studies (123/158) declared funding by a pharmaceutical company, and 22 studies did not report their source of funding. Network meta-analysis at class level showed that all of the interventions (non-biological systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in reaching PASI 90. At class level, in reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the non-biological systemic agents. At drug level, infliximab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti-TNF alpha agents: adalimumab, certolizumab, and etanercept. Ustekinumab and adalimumab were significantly more effective in reaching PASI 90 than etanercept; ustekinumab was more effective than certolizumab, and the clinical effectiveness of ustekinumab and adalimumab was similar. There was no significant difference between tofacitinib or apremilast and three non-biological drugs: fumaric acid esters (FAEs), ciclosporin and methotrexate. Network meta-analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab, and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness of these drugs was similar, except for ixekizumab which had a better chance of reaching PASI 90 compared with secukinumab, guselkumab and brodalumab. The clinical effectiveness of these seven drugs was: infliximab (versus placebo): risk ratio (RR) 50.29, 95% confidence interval (CI) 20.96 to 120.67, SUCRA = 93.6; high-certainty evidence; ixekizumab (versus placebo): RR 32.48, 95% CI 27.13 to 38.87; SUCRA = 90.5; high-certainty evidence; risankizumab (versus placebo): RR 28.76, 95% CI 23.96 to 34.54; SUCRA = 84.6; high-certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86; SUCRA = 81.4; high-certainty evidence; secukinumab (versus placebo): RR 25.79, 95% CI 21.61 to 30.78; SUCRA = 76.2; high-certainty evidence; guselkumab (versus placebo): RR 25.52, 95% CI 21.25 to 30.64; SUCRA = 75; high-certainty evidence; and brodalumab (versus placebo): RR 23.55, 95% CI 19.48 to 28.48; SUCRA = 68.4; moderate-certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to moderate certainty for all the comparisons. Thus, the results have to be viewed with caution and we cannot be sure of the ranking. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab and brodalumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of moderate- to high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. Another major concern is that short-term trials provide scanty and sometimes poorly-reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the evidence for all the interventions was of low to moderate quality. In order to provide long-term information on the safety of the treatments included in this review, it will also be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies. In terms of future research, randomised trials directly comparing active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between non-biological systemic agents and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Summary Background Epidemiology data regarding hidradenitis suppurativa (HS) are conflicting and prevalence estimates vary 80-fold, from 0·05% in a population-based study to 4%. Objectives To assess the hypothesis that previous population-based studies underestimated true HS prevalence by missing undiagnosed cases. Methods We performed a population-based observational and case–control study using the U.K. Clinical Practice Research Datalink (CPRD) linked to hospital episode statistics data. Physician-diagnosed cases in the CPRD were identified from specific Read codes. Algorithms identified unrecognized ‘proxy’ cases, with at least five Read code records for boils in flexural skin sites. Validation of proxy cases was undertaken with general practitioner (GP) questionnaires to confirm criteria-diagnosed cases. A case–control study assessed disease associations. Results On 30 June 2013, 23 353 physician-diagnosed HS cases were documented in 4 364 308 research-standard records. In total, 68 890 proxy cases were identified, reduced to 10 146 criteria-diagnosed cases after validation, extrapolated from 107 completed questionnaires (61% return rate). Overall point prevalence was 0·77% [95% confidence interval (CI) 0·76–0·78%]. An additional 18 417 cases had a history of one to four flexural skin boils. In physician-diagnosed cases, odds ratios (ORs) for current smoker and obesity (body mass index > 30 kg m-2) were 3·61 (95% CI 3·44–3·79) and 3·29 (95% CI 3·14–3·45). HS was associated with type 2 diabetes, Crohn disease, hyperlipidaemia, acne and depression, and not associated with ulcerative colitis or polycystic ovary syndrome. Conclusions Contrary to results of previous population-based studies, HS is relatively common, with a U.K. prevalence of 0·77%, one-third being unrecognized, criteria-diagnosed cases using the most stringent disease definition. If individuals with probable cases are included, HS prevalence rises to 1·19%.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease defined clinically by multiple, painful inflammatory lesions occurring predominantly in flexural sites. Onset is typically soon after puberty; however, it remains unknown whether the menopause induces remission. In North American and European patients with HS the female-to-male ratio is approximately 3 : 1 but the ratio is 1 : 2 in South Korean patients. It may be that some elements of HS epidemiology cannot be generalized across all populations. Elements of HS epidemiology in the USA and Europe are well established, including strong associations with obesity and smoking, which may increase disease severity. There are associations between HS and other cardiovascular disease (CVD) risk factors, including type 2 diabetes and metabolic syndrome. People with HS have double the risk of death from CVD compared with those without HS and 1·5 times the risk compared with patients with psoriasis. Depression and anxiety are associated with HS and completed suicide rates in those with HS are more than double the rates in controls. Associations exist between HS and other chronic inflammatory conditions, particularly inflammatory bowel disease and inflammatory arthritis. Case-control studies demonstrate associations with pilonidal sinus, polycystic ovary syndrome, Down syndrome, obstructive sleep apnoea and pyoderma gangrenosum. Population-based studies using routinely collected healthcare data from the USA estimate a prevalence of 0·1%, suggesting HS is relatively uncommon. European studies include undiagnosed patients and typically estimate prevalence of 1% or more, suggesting a common condition. Resolving the controversy surrounding a greater than 10-fold difference in HS prevalence estimates remains a high priority.