Comparison of ALitretinoin with PUVA as the first-line treatment in patients with severe chronic HAnd eczema (ALPHA): study protocol for a randomised controlled trial.

INTRODUCTION: Hand eczema (HE) is one of the most common skin disorders and an important cause for morbidity and occupational disability. The 1-year prevalence of HE is estimated to be up to 10% and it is estimated that 5%-7% of those develop severe chronic HE. However, current clinical evidence is not compelling enough to guide clinical practice. In a survey among 194 UK dermatologists the most frequent first choice approaches were psoralen combined with ultraviolet A (UVA) treatment (PUVA), oral steroids and alitretinoin (AL). When asked which strategy was most efficient for long-term outcome 20% of clinicians indicated they did not know; 43% of clinicians reported AL and 30% reported PUVA. METHODS AND ANALYSIS: ALPHA is a multicentre, open, prospective, two-arm parallel group, randomised controlled trial comparing PUVA and AL with a planned sample size re-estimation. Between 500 and 780 participants will be randomised on a 1:1 basis. The physician's global assessment (PGA) will direct treatment after randomisation, non-responders will be treated according to usual clinical practice; providing valuable pilot data on second line therapeutic approaches to inform future trials.Assessments will be conducted up to 52 weeks post randomisation. The primary outcome measure is the Hand Eczema Severity Index at 12 weeks. Secondary outcome measures include modified Total Lesion Symptom Score, PGA, time to relapse, patient reported outcome measures and DNA extraction and assessment of genetic variants. A substudy on molecular inflammatory mediators will provide information on subgroup specific treatment responses. Photographs will be taken and HE severity assessed by a central review panel. ETHICS AND DISSEMINATION: Ethics approval was obtained from Leeds West Research Ethics Committee (14/YH/1259).Trial results will be disseminated at relevant clinical conferences and societies, published in peer-reviewed journals and through relevant patient groups. TRIAL REGISTRATION NUMBER: ISRCTN80206075.

Plucked hair follicles from patients with chronic discoid lupus erythematosus show a disease-specific molecular signature.

OBJECTIVE: When faced with clinical symptoms of scarring alopecia-the standard diagnostic pathway involves a scalp biopsy which is an invasive and expensive procedure. This project aimed to assess if plucked hair follicles (HFs) containing living epithelial cells can offer a non-invasive approach to diagnosing inflammatory scalp lesions. METHODS: Lesional and non-lesional HFs were extracted from the scalp of patients with chronic discoid lupus erythematosus (CDLE), psoriasis and healthy controls. RNA was isolated from plucked anagen HFs and microarray, as well as quantitative real-time PCR was performed. RESULTS: Here, we report that gene expression analysis of only a small number of HF plucked from lesional areas of the scalp is sufficient to differentiate CDLE from psoriasis lesions or healthy HF. The expression profile from CDLE HFs coincides with published profiles of CDLE from skin biopsy. Genes that were highly expressed in lesional CDLE corresponded to well-known histopathological diagnostic features of CDLE and included those related to apoptotic cell death, the interferon signature, complement components and CD8+ T-cell immune responses. CONCLUSIONS: We therefore propose that information obtained from this non-invasive approach are sufficient to diagnose scalp lupus erythematosus. Once validated in routine clinical settings and compared with other scarring alopecias, this rapid and non-invasive approach will have great potential for paving the way for future diagnosis of inflammatory scalp lesions.

Regression of Peripheral Subclinical Enthesopathy in Therapy-Naive Patients Treated With Ustekinumab for Moderate-to-Severe Chronic Plaque Psoriasis: A Fifty-Two-Week, Prospective, Open-Label Feasibility Study.

OBJECTIVE: To investigate whether sonographically determined subclinical enthesopathy in patients with moderate-to-severe psoriasis regresses with the use of ustekinumab therapy for skin disease. METHODS: Seventy-three patients with moderate-to-severe psoriasis, who were not treated with systemic therapy and did not have symptoms of psoriatic arthritis (PsA), and 23 healthy volunteers were screened by ultrasound for subclinical enthesitis. Subsequently, 23 patients with psoriasis whose ultrasound results showed inflammatory changes were treated with ustekinumab for 52 weeks. The evolution of sonographic abnormalities of the upper and lower limb entheses was assessed using an extensive gray-scale and power Doppler (PD) ultrasound protocol at weeks 0, 12, 24, and 52. For each parameter, a gray-scale or PD ultrasound score of >0 was determined to be abnormal, and a summative score based on the Glasgow Ultrasound Enthesitis Scoring System was calculated. RESULTS: Of all the patients with psoriasis screened using ultrasound, 49.3% had at least 1 inflammatory entheseal abnormality. Mean ± SD inflammation scores were higher in the patients with psoriasis compared with the healthy volunteers (9.9 ± 6.6 versus 1.0 ± 1.4). With treatment, the mean inflammation scores decreased significantly by 42.2% from week 0 to week 24 (-4.2 [95% confidence interval -6.3, -2.1]; P < 0.001) and by 47.5% by week 42 (-4.7 [95% confidence interval -7.1, -2.3]; P = 0.001). Entheseal structural abnormalities did not change significantly during treatment. CONCLUSION: Within 12 weeks of treatment, interleukin-12 (IL-12)/IL-23 inhibition for psoriasis appears to suppress subclinical enthesopathy, and the suppression is maintained through week 52. Further longitudinal studies are needed to determine whether therapy initiated for skin disease may prevent the development of PsA.

Development of classification criteria for discoid lupus erythematosus: Results of a Delphi exercise.

BACKGROUND: No classification criteria currently exist for discoid lupus erythematosus (DLE), which has led to problematic heterogeneity in both observational and interventional research efforts. OBJECTIVES: We sought to develop DLE classification criteria based on consensus of international expert opinion of relevant stakeholders in the field. METHODS: Using a Delphi consensus process and nominal group techniques, potential items for classification criteria were generated. Experts ranked items in terms of their appropriateness and ability to discriminate DLE from other diagnoses, and items were subsequently eliminated using consensus exercises. RESULTS: A final list of 12 clinical and histopathologic items was generated for potential inclusion into a set of DLE classification criteria through a formal ongoing validation process. LIMITATIONS: The participants are predominantly composed of DLE experts in North America and Europe. CONCLUSION: This work represents a key step toward the development of formal DLE classification criteria.

Halo naevi, vitiligo and diffuse alopecia areata associated with tocilizumab therapy.

We present a follow-up case report of a 33-year-old lady with juvenile onset arthritis who developed halo naevi while on treatment with tocilizumab. This case report describes the development of halo naevi, vitiligo and diffuse alopecia areata associated with tocilizumab therapy following infection with Methicillin-resistant Staphylococcus aureus (MRSA) and Panton-Valentine leukocidin positivity. This is the first case that describes these events and supports previous theories on cellular and humoral immunity as causative factors. The regression of melanocytes during treatment with tocilizumab could also implicate IL-6 and sIL-6R as future targets in the treatment of melanoma through its direct effect of melanocytic cytotoxicity, which supports previous studies.

Developing classification criteria for discoid lupus erythematosus: an update from the World Congress of Dermatology 2015 meeting.

Currently, no standardized classification criteria exist for cutaneous lupus erythematosus. With increased interest in studying cutaneous lupus erythematosus, specifically discoid lupus erythematosus, it is our aim to apply previously adopted methods from rheumatology to dermatologic diseases to develop feasible, validated, and standardized classification criteria useful in both academic and community practice. Here we report the progress to date to define discoid lupus erythematosus using clinical, histopathologic, and serologic features by means of a Delphi method-using a series of iterative questionnaires sent to expert stakeholders. We present specific updates from the World Congress of Dermatology 2015 meeting, at which a nominal group of expert stakeholders met to discuss the results of round 1 of the Delphi process to further clarify and harmonize specific classification items for inclusion into round 2.

A randomised, controlled trial of a 4% cutaneous emulsion of sodium cromoglicate in treatment of atopic dermatitis in children.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Sodium cromoglicate (SCG) is a chromone with anti-inflammatory, anti-itch and anti-allergic activity. This trial is a 12-week comparison (RCT) of a 4% SCG cutaneous emulsion with its vehicle in AD. MATERIALS AND METHODS: 208 children aged 2-12 years participated, 104 in each group. The primary endpoint was change in SCORAD score. Secondary endpoints included SASSAD score, topical steroid usage and global assessments. RESULTS: SCORAD was reduced by 28% (SCG group) and by 19% (vehicle): difference was statistically significant (p = 0.03) after 8 weeks and nearly significant (p = 0.09) after 12. A similar result occurred in SASSAD (p = 0.001 at 8 weeks). In subjects without major protocol deviations (SCG-64, vehicle-63), difference in SCORAD remained significant at 12 weeks (p = 0.04). Weight of topical steroids reduced in both groups: -0.60 ± 1.3 g/day (35%), SCG and -0.05 ± 1.1 g/day vehicle (p = 0.04). Treatment success, defined as investigator global opinion graded very or moderately effective, was significantly more frequent in SCG group (p = 0.025). Application site discomfort reported by 12.5% of subjects in SCG group and 16.5% in vehicle group. CONCLUSIONS: SCG 4% cutaneous emulsion provides an effective, well-tolerated, steroid-sparing treatment for AD in children.

Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools.

OBJECTIVE: Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head-to-head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments. METHODS: Data from the CONTEST study, a head-to-head comparison of 3 existing questionnaires, were used to identify items with a Youden index score of ≥0.1. These were combined using 4 approaches: CONTEST (simple additions of questions), CONTESTw (weighting using logistic regression), CONTESTjt (addition of a joint manikin), and CONTESTtree (additional questions identified by classification and regression tree [CART] analysis). These candidate questionnaires were tested in independent data sets. RESULTS: Twelve individual questions with a Youden index score of ≥0.1 were identified, but 4 of these were excluded due to duplication and redundancy. Weighting for 2 of these questions was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in 6 joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC curve analysis and discarded. The other 3 questionnaires were significant in all data sets, although CONTESTw was slightly inferior to the others in the validation data sets. Potential cut points for referral were also discussed. CONCLUSION: Of 4 candidate questionnaires combining existing discriminatory items to identify PsA in people with psoriasis, 3 were found to be significant on ROC curve analysis. Testing in independent data sets identified 2 questionnaires (CONTEST and CONTESTjt) that should be pursued for further prospective testing.

The link between enthesitis and arthritis in psoriatic arthritis: a switch to a vascular phenotype at insertions may play a role in arthritis development.

OBJECTIVE: Subclinical enthesopathy is recognised in both psoriasis and psoriatic arthritis (PsA). This study used ultrasonography with power Doppler (PD) to test the hypothesis that subclinical enthesopathy in PsA was associated with an 'inflammatory' or vascular phenotype compared to that seen in psoriasis. METHODS: 100 patients with a mean age of 46.3 years (SD 15) (42 with psoriasis and 58 with PsA) and 23 matched healthy controls (HC) from two centres were included. 1230 lower limb entheses were scanned by ultrasonographers blinded to clinical details. Both inflammatory and chronic features of enthesopathy were scored. RESULTS: Psoriasis patients (with or without arthritis) were more likely to express a vascular phenotype, with higher inflammation-related enthesopathy scores than HC (for inflammation p<0.0001, for chronicity p=0.02, for total ultrasound scores p<0.0001). The PsA patients had higher ultrasound enthesopathy scores than psoriasis patients (inflammation p=0.04, chronicity p=0.02) and HC (inflammation p<0.0001, chronicity p=0.003). When symptomatic entheses were excluded, PsA patients still had higher PD scores than psoriasis patients (p=0.003). Doppler positivity in at least one entheseal site was observed more frequently in PsA (21/58, 36.2%) versus psoriasis (4/42, 9.5%; p=0.002). CONCLUSIONS: This study shows that the ultrasound appearances of subclinical enthesitis in psoriasis differ from the subclinical enthesitis in PsA, with PsA patients having more PD. This is suggestive of a more inflammatory or vascular process in PsA, and offers potentially novel insights into the progression from skin to joint disease in psoriasis.

Psoriasis patients with nail disease have a greater magnitude of underlying systemic subclinical enthesopathy than those with normal nails.

OBJECTIVE: Enthesopathy is a major feature of psoriatic arthritis (PsA), which is supported by imaging studies. Given that nail disease often predates PsA and that the nail is directly anchored to entheses, the authors asked whether nail involvement in psoriasis equates with a systemic enthesopathy. METHODS: Forty-six patients with psoriasis (31 with nail disease) and 21 matched healthy controls (HC) were recruited. 804 entheses of upper and lower limbs were scanned by an ultrasonographer blinded to clinical details. RESULTS: Psoriasis patients had higher enthesitis scores than HC (median (range) 21 (0-65) vs 11 (3-39), p=0.005). Enthesopathy scores were higher in patients with nail disease (23 (0-65)) than in patients without nail disease (15 (5-26), p=0.02) and HC (11 (3-39), p=0.003). Inflammation scores of patients with nail disease (13 (0-34)) were higher than patients without nail disease (8 (2-15), p=0.02) and HC (5 (0-19), p<0.001). Modified nail psoriasis severity index scores were correlated to both inflammation (r(2)=0.45, p=0.005) and chronicity scores (r(2)=0.35, p=0.04). No link between the psoriasis area and severity index and enthesitis was evident. CONCLUSION: The link between nail disease and contemporaneous subclinical enthesopathy offers a novel anatomical basis for the predictive value of nail psoriasis for PsA evolution.

Clinical and pharmacogenetic influences on response to hydroxychloroquine in discoid lupus erythematosus: a retrospective cohort study.

The recommended systemic therapy of choice for discoid lupus erythematosus (DLE) is the 4-aminoquinolone antimalarial hydroxychloroquine. There is limited published information on the likelihood of clinical response and, in particular, what factors influence outcome. We conducted a multicenter observational and pharmacogenetic study of 200 patients with DLE treated with hydroxychloroquine. The primary outcome was clinical response to hydroxychloroquine. We investigated the effects of disease attributes and metabolizing cytochrome P450 (CYP) polymorphisms on clinical outcome. Although the majority of patients responded to hydroxychloroquine, a significant proportion (39%) either failed to respond or was intolerant of the drug. Cigarette smoking and CYP genotype did not have any significant influence on response to hydroxychloroquine. Moreover, multivariate analysis indicated that disseminated disease (odds ratio (OR): 0.21; 95% confidence interval (CI): 0.08-0.52; P<0.001) and concomitant systemic lupus erythematosus (SLE; OR: 0.06; 95% CI: 0.01-0.49; P = 0.009) were significantly associated with lack of response to hydroxychloroquine. These findings suggest that baseline lupus severity and SLE are predictors of response to hydroxychloroquine. A prospective study is now required to further investigate the relationship between disease activity and response to hydroxychloroquine. This will have the potential to further inform the clinical management of this disfiguring photosensitive disease.

Linear pitting and splinter haemorrhages are more commonly seen in the nails of patients with established psoriasis in comparison to psoriatic arthritis.

BACKGROUND: Recently the role of several ligament and tendon insertions around the nail matrix and nail plate have been identified as possible contributory factors that explain the higher prevalence of nail involvement in psoriatic arthritis (PsA). The purpose of this study was to determine whether such anatomical factors might also be associated with different patterns of nail involvement in skin psoriasis and PsA. METHODS: A total of 173 patients were recruited: 121 PsA cases and 52 psoriasis cases. All patients had a standardised assessment of the nails for lesions including pitting, splinter haemorrhages and onycholysis. RESULTS: The overall modified Nail Psoriasis Severity Index scores did not differ between the two groups (psoriasis mean 8.5, SD 7.1; PsA mean 8.3, SD 9.4). In the nail matrix, linear pitting appeared to be more common in skin psoriasis (OR 0.27, 95% CI 0.18-0.41). There were no significant differences in the distribution of nail plate abnormalities other than splinter haemorrhages which were more commonly seen in psoriasis cases (OR 0.23, 95% CI 0.14-0.39). CONCLUSION: The pattern of nail disease in psoriasis and PsA differed with respect to the frequency of linear pitting and splinter haemorrhages, with both features occurring more often in psoriasis.

Low-dose UVA1 phototherapy for proximal and acral scleroderma in systemic sclerosis.

Previous studies report the benefit of UVA1 phototherapy in treating acrosclerosis in patients with systemic sclerosis. We carried out a retrospective study to examine the effectiveness of UVA1 phototherapy in scleroderma affecting acral and proximal sites in patients with this disease. Patients with systemic sclerosis (diffuse type, n=5; limited type, n=3) underwent low-dose UVA1 radiation (30-40 J/cm(2)) thrice weekly. In all patients skin lesions improved, demonstrated by a fall in the modified Rodnan skin score ranging from 8 to 18 points in diffuse systemic sclerosis and 6 to 10 points in limited disease. This study would suggest that UVA1 phototherapy is effective for scleroderma affecting proximal and acral sites in patients with systemic sclerosis.

Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy.

OBJECTIVES: Dermatologists and rheumatologists have differed in their use of serial liver biopsy and liver function tests (LFT) to monitor the risk of hepatic fibrosis in long-term MTX therapy. It is judged safe to monitor LFT only in RA. Whilst there are few studies in PsA to justify this approach, it is widely used in rheumatology practice. The study aimed to assess prevalence of hepatic fibrosis in both psoriasis and PsA patients on long-term MTX therapy. METHODS: A prospective study of 54 patients with psoriatic disease had a liver biopsy according to dermatology guidelines on long-term MTX treatment with full assessment of risk factors. Previously, monitoring these patients was in accordance with ACR guidelines with 3-monthly LFT. RESULTS: MTX treatment duration was a mean of 6.9 years, with a mean cumulative dose of 4396 mg. There were no cases of advanced fibrosis or of cirrhosis and mild early fibrosis in 11 (22%) patients. The presence of early mild changes was related to the number of risk factors that the patient had for hepatic fibrosis [also the risk factors for non-alcoholic steatohepatitis (NASH)]. Pro-collagen 3 N-terminal peptide (PIIINP) was unhelpful in PsA and frequently elevated despite normal liver biopsy. CONCLUSIONS: Despite other risk factors for NASH, monitoring for hepatic fibrosis using serial liver function and ACR guidelines tests alone as in RA appears safe in psoriasis and PsA. Liver biopsy ought to be considered to assess the liver if LFT are persistently elevated. PIIINP is misleading in active PsA.