Developing classification criteria for skin-predominant dermatomyositis: the Delphi process.

BACKGROUND: The European League Against Rheumatism/American College of Rheumatology classification criteria for inflammatory myopathies are able to classify patients with skin-predominant dermatomyositis (DM). However, approximately 25% of patients with skin-predominant DM do not meet two of the three hallmark skin signs and fail to meet the criteria. OBJECTIVES: To develop a set of skin-focused classification criteria that will distinguish cutaneous DM from mimickers and allow a more inclusive definition of skin-predominant disease. METHODS: An extensive literature review was done to generate items for the Delphi process. Items were grouped into categories of distribution, morphology, symptoms, antibodies, histology and contextual factors. Using REDCap™, participants rated these items in terms of appropriateness and distinguishing ability from mimickers. The relevance score ranged from 1 to 100, and the median score determined a rank-ordered list. A prespecified median score cut-off was decided by the steering committee and the participants. There was a pre-Delphi and two rounds of actual Delphi. RESULTS: There were 50 participating dermatologists and rheumatologists from North America, South America, Europe and Asia. After a cut-off score of 70 during the first round, 37 of the initial 54 items were retained and carried over to the next round. The cut-off was raised to 80 during round two and a list of 25 items was generated. CONCLUSIONS: This project is a key step in the development of prospectively validated classification criteria that will create a more inclusive population of patients with DM for clinical research. What's already known about this topic? Proper classification of patients with skin-predominant dermatomyositis (DM) is indispensable in the appropriate conduct of clinical/translational research in the field. The only validated European League Against Rheumatism/American College of Rheumatology criteria for idiopathic inflammatory myopathies are able to classify skin-predominant DM. However, a quarter of amyopathic patients still fail the criteria and does not meet the disease classification. What does this study add? A list of 25 potential criteria divided into categories of distribution, morphology, symptomatology, pathology and contextual factors has been generated after several rounds of consensus exercise among experts in the field of DM. This Delphi project is a prerequisite to the development of a validated classification criteria set for skin-predominant DM.

Validity and sensitivity to change of laser Doppler imaging as a novel objective outcome measure for cutaneous lupus erythematosus.

OBJECTIVES: The objectives of this study were to assess the reliability of a novel objective outcome measure, laser Doppler imaging (LDI), its validity against skin biopsy histology and other clinical instruments, including localized cutaneous lupus disease area and severity index (L-CLASI) and visual analogue scale (VAS) score of photographs, and its responsiveness to clinical change with therapy. METHODS: A prospective observational cohort study was conducted in 30 patients with active cutaneous lupus erythematosus (CLE). At baseline and 3 months, disease activity was assessed using L-CLASI and a high resolution LDI system by two assessors. Skin biopsy was scored as 0 = non-active, 1 = mild activity and 2 = active. Photographs were assessed by two clinicians using 100 mm VAS. Inter-rater reliability was analyzed using Bland-Altman limits of agreement. Correlation between histology and LDI, L-CLASI and VAS and sensitivity to change of LDI with physician subjective assessment of change (PSAC) at 3 months were analyzed using Kendall's tau-a. RESULTS: Of 30 patients with CLE, 28 (93%) were female, mean (SD) age 48.4 (11.5) y, 25 (83%) were Caucasians, 25 (83%) had concurrent systemic lupus erythematosus and 16 (53%) were smokers. CLE subtypes were acute = 9, subacute = 8 and chronic = 13. Inter-rater agreement for LDI was fair but for VAS score of photographs was poor. In 20 patients with biopsy, correlation with histology was better for LDI (tau-a = 0.53) than L-CLASI (tau-a = 0.26) (difference = 0.27; 90% CI 0.05-0.49) or VAS score of photographs (tau-a = 0.17) (difference = 0.36; 90% CI 0.04-0.68). There was a moderate correlation between PSAC score and change in LDI (tau-a = 0.56; 90% CI 0.38-0.74; p < 0.001, n = 15). CONCLUSION: LDI provides a reliable, valid and responsive quantitative measure of inflammation in CLE. It has a better correlation with histology compared to clinical instruments. LDI provides an objective outcome measure for clinical trials.

Use of optical coherence tomography for the diagnosis of preclinical lesions of circumscribed palmar hypokeratosis.

Circumscribed hypokeratosis of palms and soles is a rare dermatosis, usually affecting women. Diagnosis is mainly based on the clinical characteristics, including the clinical appearance and anatomical site of the skin lesions and on the demographic features of the affected patients, usually middle-aged to elderly women. Skin biopsy may be performed to confirm clinical diagnosis. Optical coherence tomography (OCT) is a technique that has been undergone substantial development in dermatology in recent years, and its use in clinical practice has been growing progressively. Several dermatological conditions have been studied with this tool, but to our knowledge, it has not been used to investigate this form of hypokeratosis. We report a case of circumscribed palmar hypokeratosis for which diagnosis was confirmed by OCT, which was performed as the patient was reluctant to undergo skin biopsy because of its invasiveness. We highlight the potential use of OCT in obtaining a virtual skin biopsy to confirm clinical diagnosis and identify preclinical skin lesions amenable to early treatment.

Treatment of severe, chronic hand eczema: results from a UK-wide survey.

Treatment of severe hand eczema (HE) that is resistant to topical potent corticosteroid treatment is challenging. In 2013, we surveyed 194 UK dermatologists to obtain information about their usual treatment pathways to inform the choice of the comparator in a trial of alitretinoin in severe HE (ALPHA trial); the results indicated that the treatment approaches favoured by UK dermatologists differ. Psoralen combined with ultraviolet A (PUVA) and alitretinoin were identified as the most frequent first-line treatment options for hyperkeratotic HE, whereas oral corticosteroids were identified as the most frequent first-line treatment for vesicular HE, followed by PUVA and alitretinoin. In terms of potential adverse effects of long-term or repeated use, oral steroids and ciclosporin A were reported to cause most concern. There is uncertainty about which treatment gives the best short and long-term outcomes, because of a lack of definitive randomised controlled trials evaluating the effectiveness of different treatment pathways in severe HE.

Redefining cutaneous lupus erythematosus: a proposed international consensus approach and results of a preliminary questionnaire.

There is currently no uniform definition of cutaneous lupus erythematosus (CLE) upon which to base a study population for observational and interventional trials. A preliminary questionnaire was derived from and sent to a panel of CLE experts which demonstrated consensus agreement that (1) there is a need for new definitions for CLE (2) CLE is distinct from systemic lupus erythematosus and that a CLE grouping scheme should remain apart from current systemic lupus erythematosus schema (3) current CLE grouping schemes are inadequate around communication, prognostic information and to meet the needs of researchers, clinicians, patients and payers.

Brief report: responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus.

OBJECTIVE: The immunopathogenesis of systemic lupus erythematosus (SLE) is heterogeneous, and responses of skin to rituximab are variable. This study was undertaken to determine the phenotype of rituximab-responsive disease. METHODS: Eighty-two patients with SLE who were receiving rituximab were prospectively studied. Of these patients, 32 had significant skin involvement before or after treatment. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index 2004. Cutaneous lupus subtype was classified by a dermatologist as acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), chronic cutaneous lupus erythematosus (CCLE), or other skin diseases, with supportive photographs or biopsies where necessary. RESULTS: Of 26 patients with skin disease at baseline, 9 (35%) had a beneficial mucocutaneous response to rituximab at 6 months, with good responses in ACLE (6 of 14 patients [43%]), and poor responses in CCLE (0 of 8 patients) (P = 0.034). Clinical response was associated with anti-RNP negativity (P = 0.024) and anti-Ro negativity (P = 0.031). Flares of SCLE and CCLE occurred in 12 patients who either had no skin disease or had ACLE at baseline (i.e., a switch in subtype). Concomitant antimalarials or conventional immunosuppressants were not associated with response or flare rate. Posttreatment biopsies confirmed typical active SLE histology in lesions occurring during B cell depletion. CONCLUSION: Our findings indicate that the clinical response to rituximab in cutaneous manifestations of SLE depends on subtype. None of the CCLE patients responded, and new CCLE lesions were observed during B cell depletion, suggesting that initiation and activity of these lesions is not B cell dependent. Flares of a range of skin diseases after B cell depletion may indicate a change in immune regulation following B cell-targeted therapy.

Safety and efficacy of calcipotriol plus betamethasone dipropionate gel in the treatment of scalp psoriasis in adolescents 12-17 years of age.

BACKGROUND: Plaque psoriasis has a relatively high prevalence in adolescence, resulting in a significant impact on quality of life, including social interactions. OBJECTIVES: The primary objective was to assess the safety of once-daily application of fixed-combination calcipotriol plus betamethasone dipropionate gel in adolescent scalp psoriasis. Assessment of efficacy was a secondary objective. METHODS: This phase II, multicentre, single-arm, open-label, 8-week trial included patients aged 12-17 years with moderate-to-very severe scalp psoriasis according to Investigator's Global Assessment (IGA) (≥ 10% of the scalp area affected). RESULTS: Seventy-eight patients received treatment. Twenty-seven patients (35%) reported a total of 64 adverse events (AEs); most were mild (33/64) or moderate (22/64) in severity and there were no serious AEs. No cases of hypercalcaemia were reported, and the mean changes from baseline to end of treatment in albumin-corrected serum calcium (0·00 mmol L(-1)), 24-h urinary calcium excretion (-0·03 mmol per 24 h) and urinary calcium-to-creatinine ratio (-0·12 mmol g(-1)) were not considered clinically relevant. At the end of treatment 66 patients (85%) were clear or almost clear according to IGA. There was an 80% improvement in mean Total Sign Score from baseline to end of treatment. In total, at the end of treatment, 87% of patients rated their scalp psoriasis as clear or very mild, and 75 (96%) had no or mild pruritus compared with 14 (18%) at baseline. CONCLUSIONS: Once-daily calcipotriol plus betamethasone dipropionate gel is well tolerated and efficacious for scalp psoriasis in adolescents.

Multiple halo naevi associated with tocilizumab.

Tocilizumab, a humanized monoclonal antibody directed against the interleukin (IL)-6 receptor, is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). We describe a case of multiple halo naevi occurring in a patient with a history of JIA treated with tocilizumab. IL-6 is a key cytokine in the setting of cancer through its effects on angiogenesis and inhibition of adaptive anti-tumour immunity. IL-6 also plays a role in melanocyte function, and increased levels have been noted in vitiligo skin, where it is a paracrine inhibitor of melanocytes. Tocilizumab may therefore lead to the development of halo naevi secondary to subsequent activation of adaptive immunity. Alternatively, as tocilizumab results in increased serum IL-6 levels, the epidermal cytokine profile is altered. Increased levels of IL-6 may therefore have a direct inhibitory effect on melanocytes, where access by tocilizumab may be limited due to differential size difference.

Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study).

BACKGROUND: Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown. OBJECTIVES: To compare three PsA screening questionnaires in a head-to-head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard. METHODS: This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria. RESULTS: In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis. CONCLUSION: Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.

Sequential use of biologics in moderate-to-severe plaque psoriasis: case studies illustrating an individualized approach.

Biologics have added great value to the treatment of psoriasis; however, there is currently little guidance on which biologic to use and at what stage of disease, and even less guidance on how to switch therapy in the event of treatment failure or the occurrence of side-effects. Furthermore, drug switching may not always be essential in cases of biologic failure, and adding conventional systemics has a role in some patients. It is clear that we have limited data to support any particular policy in initiating and switching biologics in psoriasis, but a pragmatic approach to therapy is supported by the case reports described within this article. Specifically, the case studies include patients who were initiated on different biologics and subsequently switched to alternatives for a variety of reasons, such as unresponsiveness or a concomitant disease. As more evidence emerges from long-term studies and registry data, a clearer picture should emerge on how best to use biologics in different situations to aid successful treatment outcomes. Comparative studies are necessary before firm recommendations about sequential use can be made.

Immunohistochemistry of ultrastructural changes in scarring lupus erythematosus.

BACKGROUND: The various clinical types of lupus erythematosus (LE) show an essentially similar histological picture, and the subsets of LE cannot easily be distinguished by histology alone. However, there is an important clinical difference: lesions of discoid LE (DLE) cause scarring, particularly on the scalp, whereas lesions of subacute and acute LE heal without scarring. The focal thickening of the basement membrane zone (BMZ) in DLE lesions represents an important histopathological finding, and there is little known about the nature of these alterations at the BMZ level. AIM: To investigate BMZ alterations in the basement membrane zone (BMZ) in cutaneous LE (CLE) by immunohistochemistry. METHODS: Skin biopsies from 30 patients with CLE [DLE and subacute CLE (SCLE)] and from 10 controls were studied using antibodies to cytokeratin 5, cytokeratin 14, bullous pemphigoid (BP)180, BP230, plectin, laminin 5, collagen IV and collagen VII. Results. There was increased expression of components of the lamina lucida, lamina densa and anchoring fibrils in active DLE, whereas expression was normal in SCLE and control tissues, and in areas of scarring in DLE. In addition, higher expression of the hemidesmosome-associated antigens (BP230 and plectin) was found in active DLE. The expression of other antigens was similar in all tissues examined. CONCLUSIONS: These alterations in the BMZ suggest that the BMZ may react in a different way in active DLE than in SCLE, and that the BMZ may remodel in different ways. These immunohistochemical differences may provide a new method of histological differentiation between the various LE subtypes.

Photochemotherapy for systemic sclerosis: effect on clinical and molecular markers.

BACKGROUND: The cutaneous changes seen in systemic sclerosis (SSc) can result in considerable patient morbidity. AIM: We previously reported on the beneficial effect of psoralen ultraviolet A (PUVA) phototherapy in 13 patients with morphoea. We now report the findings of a study in which patients with SSc were treated with PUVA. METHODS: Twelve patients with SSc were treated with PUVA phototherapy. The effect on cutaneous disease activity was assessed using the modified Rodnan score, and the effect on serological and immunohistochemical growth factors and adhesion molecules was also measured. RESULTS: The median Rodnan score at baseline was 24.5 [interquartile range (IQR) 18.5-26.0]. The median number of treatments with PUVA was 24 exposures (IQR 20-26) with a median cumulative exposure of 68.3 J/cm(2) (IQR 28.6-139.8). Of the 12 patients, 11 responded well to phototherapy with a mean change in Rodnan score of 6.58 (36.98%) (P < 0.01, Wilcoxon signed ranks test). After treatment with PUVA there was a significant increase in circulating tumour necrosis factor-alpha levels in 8/12 patients (P = 0.03). In 7/12 patients there was an increase in E-selectin and vascular cell adhesion molecule, although this was not significant. CONCLUSIONS: PUVA treatment is associated with a significant improvement in cutaneous symptoms in patients with SSc as measured by the Rodnan score (P < 0.01). Specific lymphocyte markers, adhesion molecules and cytokines are also affected by this treatment, helping to clarify further the mechanism of action of PUVA treatment and our understanding of the primary pathological process.

A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus.

BACKGROUND: In a recent open pilot trial, R-salbutamol sulphate, a well-known molecule with anti-inflammatory effects, was tested successfully on patients with therapy-resistant discoid lupus erythematosus (DLE). OBJECTIVES: To compare the efficacy and safety of R-salbutamol cream 0.5% vs. placebo on DLE lesions in a multicentre, double-blinded, randomized, placebo-controlled phase II trial. METHODS: Thirty-seven patients with at least one newly developed DLE lesion were randomized - 19 to the R-salbutamol cream 0.5% and 18 to placebo - and treated twice daily for 8 weeks. Efficacy was evaluated through scores of erythema, scaling/hypertrophy and induration as well as pain and itching; general improvement scored by the investigator and global improvement scored by patients' assessment were also evaluated. RESULTS: The mean area under the curve of improvement for scaling/hypertrophy, pain, itching and global patient assessment was significantly better for the actively treated patients as compared with placebo (scaling/hypertrophy, P = 0.0262; pain, P = 0.0238; itching, P = 0.0135; global patient assessment, P = 0.045). Moreover, the percentage of patients without induration was significantly higher in the active group compared with the placebo group (P = 0.013), and a statistically significantly greater decrease in the size of the lesional area was also seen in the overall analysis of the R-salbutamol-treated patients (P = 0.0197). No serious adverse events were reported. CONCLUSIONS: Application of R-salbutamol cream 0.5% was safe and well tolerated. Statistically significant effects were seen on scaling/hypertrophy, induration, pain and itching as well as patient global assessment, suggesting that R-salbutamol could be a promising new topical therapy alternative for DLE.

Scar classification in cutaneous lupus erythematosus: morphological description.

BACKGROUND: Scarring represents the single most debilitating aspect of discoid lupus erythematosus (DLE) in patients with cutaneous lesions alone. Despite this, there have been no studies which have attempted to classify the types of scars seen in this chronic disease. OBJECTIVES: The aim was to classify the types of scars based on morphological description. PATIENTS AND METHODS: Forty-five patients with histologically confirmed DLE were included in the study. In the assessment of the types of scars, the scars were scored initially according to their anatomical localization. Each anatomical area was assessed for the types of scars which occurred in these areas. RESULTS: Scars in patients with DLE were initially classified morphologically into six types according to the site of the scar and then each type was classified into subtypes according to the morphology of the scar. Scars were seen in the majority of the patients and scarring affected mostly areas including the scalp, other hairy areas such as the eyebrows, nonhairy areas, mucosa, fatty layers of the skin and the nails. This study demonstrated that scars may not only produce textural changes but may also produce pigmentary changes. It is possible that other types of scars may yet occur in DLE but have not so far been detected. CONCLUSIONS: Early classification and identification of the types of scars in these patients may change management towards more aggressive therapy in those with continued disease activity, and it is possible that different types of scarring require different therapies.