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Background: Hand eczema is common and a cause of morbidity and occupational disability. When education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control chronic hand eczema, ultraviolet therapy or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted by UK dermatologists., Primary Objective: Compare alitretinoin and ultraviolet therapy as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment., Design: Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis, and an economic evaluation., Setting: UK secondary care dermatology outpatient clinics., Participants: Patients with severe chronic hand eczema unresponsive to at least 4 weeks of treatment with potent topical corticosteroids., Primary End Point: Natural logarithm of the Hand Eczema Severity Index + 1, 12 weeks post planned start of treatment., Randomisation: Participants randomised 1 : 1 by minimisation to alitretinoin or ultraviolet therapy for 12 to 24 weeks., Blinding: Blinded primary end-point assessor., Results: Intention-to-treat population: 441 (100.0%) participants; 220 (49.9%) alitretinoin and 221 (50.1%) ultraviolet therapy. At least one dose was received by 212 (96.4%) alitretinoin and 196 (88.7%) ultraviolet therapy participants., Primary Outcome: The unadjusted median (interquartile range) relative change in hand eczema severity index at 12 weeks was 30% (10-70%) of that at baseline for alitretinoin compared with 50% (20-100%) for ultraviolet therapy. There was a statistically significant benefit of alitretinoin compared with ultraviolet therapy at 12 weeks, with an estimated fold change or relative difference (95% confidence interval) = 0.66 (0.52 to 0.82), p  = 0.0003 at 12 weeks. There was no evidence of a difference at 24 or 52 weeks, with the estimated fold change (95% confidence interval) equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively., Primary Analysis Results Were Consistent for Secondary End Points: Fifty-nine per cent allocated to alitretinoin and 61% allocated to ultraviolet therapy achieved a clear/almost clear assessment during the trial period. Differential treatment compliance observed: 145 (65.9%) alitretinoin and 53 (24.0%) ultraviolet therapy participants confirmed compliance (≥ 80% received, no treatment breaks > 7 days during first 12 weeks). High levels of missing data were observed., Safety: One hundred and thirty-five reportable adverse events across 79 participants, 55 (25.0%) alitretinoin and 24 (10.9%) ultraviolet therapy. Four serious adverse events (two alitretinoin, two ultraviolet therapy). Four pregnancies reported (three alitretinoin, one ultraviolet therapy). No new safety signals were detected., Conclusion: As a first-line therapy, alitretinoin showed more rapid improvement and superiority to ultraviolet therapy at week 12. This difference was not observed at later time points. Alitretinoin is cost-effective at weeks 12 and 52. Ultraviolet therapy is cost-effective after 10 years, with a high degree of uncertainty. Hand eczema severity index may be a useful primary outcome measure for hand eczema trials; ALPHA results will inform future trials., Limitations: Treatment compliance was poor for ultraviolet therapy. Regular twice weekly treatment was not received by most patients. Assessment of long-term effects of randomised treatments was complicated by use of second-line treatments post treatment phase., Further Work: Further analysis of substudies and pilot data will provide valuable information for future studies. A clear need for better therapeutic approaches for severe chronic hand eczema remains. Future studies will need to further address long-term benefits of treatments given., Trial Registration: This trial is registered as ISRCTN80206075., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information.

The proinflammatory cytokine IL-36γ is highly expressed in epithelial cells and is a pivotal mediator of epithelial inflammation. In particular, IL-36γ is strongly associated with the inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36γ is expressed as an inactive precursor and must be processed by specific proteases to become bioactive. Our aim therefore was to identify protease/s capable of IL-36γ activation and explore the importance of this activation in psoriasis. Using a keratinocyte-based activity assay in conjunction with small-molecule inhibitors and siRNA gene silencing, cathepsin S was identified as the major IL-36γ-activating protease expressed by epithelial cells. Interestingly, cathepsin S activity was strongly up-regulated in samples extracted from psoriasis patients relative to healthy controls. In addition, IL-36γ-Ser18, identified as the main product of cathepsin S-dependent IL-36γ cleavage, induced psoriasiform changes in human skin-equivalent models. Together, these data provide important mechanistic insights into the activation of IL-36γ and highlight that cathepsin S-mediated activation of IL-36γ may be important in the development of numerous IL-36γ-driven pathologies, in addition to psoriasis.

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX)., Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology-European League Against Rheumatism (OMERACT-EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT-EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2-5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy., Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2-5): -0.7 (95% CIs -1.2 to -0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8., Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment., Trial Registration Number: NCT00767325., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: To explore whether changes in a composite (power Doppler/greyscale ultrasound (PDUS)) synovitis score, developed by the OMERACT-EULAR-Ultrasound Task Force, predict disease activity outcomes in rheumatoid arthritis (RA)., Methods: Patients with RA who were methotrexate inadequate responders starting abatacept were evaluated. Individual joint PDUS scores were combined in the Global OMERACT-EULAR Synovitis Score (GLOESS) for metacarpophalangeal joints (MCPs) 2-5, all joints (22 paired) and a reduced (9 paired) joint set. The predictive value of changes in GLOESS at week 1-16 evaluations for clinical status and response (Disease Activity Score (DAS)28 (C reactive protein, CRP) <2.6; DAS28(CRP) ≤3.2; DAS28(CRP) ≥1.2 improvement) up to week 24, and correlations between DAS28 and GLOESS were assessed., Results: Eighty-nine patients completed the 24-week treatment period. Changes in GLOESS (MCPs 2-5) from weeks 1 to 16 were unable to predict DAS28 outcomes up to week 24. However, significant improvements in GLOESS (MCPs 2-5) were observed at week 12 in patients with DAS28 ≥1.2 improvement at week 24 versus those who did not achieve that clinical response. In patients achieving DAS28 ≥1.2 improvement or DAS28 ≤3.2 at week 24, changes in GLOESS (22 and 9 paired joint sets) were greater in patients who already achieved DAS28 ≥1.2 at week 12 than in those who did not. No significant correlations were found between changes in DAS28 and GLOESS definitions at any time point., Conclusions: PDUS was not correlated with clinical status or response as measured by DAS28-derived criteria, and PDUS changes were not predictive of clinical outcome. The discrepancies require further exploration., Trial Registration Number: NCT00767325; Results.