Nailfold dermoscopy predicts the absence of a capillaroscopy sclerodermic pattern: The multicentre, prospective VASCUL-R trial.

BACKGROUND: Nailfold capillaroscopy is recommended to diagnose primary or secondary Raynaud's phenomenon (RP). Capillaroscopy is normal in primary RP, which is the most frequent. Screening for RP capillary anomalies with nailfold dermoscopy has been promising. OBJECTIVE: To determine whether normal nailfold dermoscopy-based on the absence of five criteria that define a sclerodermic pattern-is able to predict normal capillaroscopy with good positive-predictive value (PPV). METHODS: Prospective, 2-phase (monocentre and multicentre) study on patients at first consultation for RP undergoing nailfold video capillaroscopy (NVC) and nailfold dermoscopy by two different 'blinded' trained observers, respectively, a vascular specialist and a dermatologist, not familiar with capillaroscopy. The five criteria noted were as follows: disorganization, megacapillaries, low capillary density, avascular areas and haemorrhages. RESULTS: Based on 105 patients, the dermoscopy PPV for a normal NVC was 100% (p = 0.015), with 37.9% sensitivity, when no criterion was observed. Excluding haemorrhages, the PPV remained 100% (p < 0.0001), with sensitivity rising to 73.7% and 100% specificity. CONCLUSION: Normal nailfold dermoscopy with the absence of four easy-to-observe criteria predicts normal NVC with an excellent PPV.

Elastic fiber alterations and calcifications in calcific uremic arteriolopathy.

Calcific uremic arteriolopathy (CUA) is a severely morbid disease, affecting mostly dialyzed end-stage renal disease (ESRD) patients, associated with calcium deposits in the skin. Calcifications have been identified in ESRD patients without CUA, indicating that their presence is not specific to the disease. The objective of this retrospective multicenter study was to compare elastic fiber structure and skin calcifications in ESRD patients with CUA to those without CUA using innovative structural techniques. Fourteen ESRD patients with CUA were compared to 12 ESRD patients without CUA. Analyses of elastic fiber structure and skin calcifications using multiphoton microscopy followed by machine-learning analysis and field-emission scanning electron microscopy coupled with energy dispersive X-ray were performed. Elastic fibers specifically appeared fragmented in CUA. Quantitative analyses of multiphoton images showed that they were significantly straighter in ESRD patients with CUA than without CUA. Interstitial and vascular calcifications were observed in both groups of ESRD patients, but vascular calcifications specifically appeared massive and circumferential in CUA. Unlike interstitial calcifications, massive circumferential vascular calcifications and elastic fibers straightening appeared specific to CUA. The origins of such specific elastic fiber's alteration are still to be explored and may involve relationships with ischemic vascular or inflammatory processes.

Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis-associated Raynaud's phenomenon (SSc-RP) episodes than placebo. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial in patients with SSc-RP assessed the effect of 50-unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between-group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank-sum test. RESULTS: The intent-to-treat analysis included 46 BTA-treated patients and 44 placebo recipients. At 4 weeks after assigned treatment injections, the median number of daily RP episodes decreased comparably in the BTA and placebo groups (median change -1 episode/day [interquartile range (IQR) -1.5, 0 episodes/day] and -1 episode/day [IQR -2.5, 0 episodes/day], respectively) (P = 0.77 versus placebo). Moreover, change in Raynaud's Condition Score, quality of life assessed by Health Assessment Questionnaire disability index, and hand function assessed by shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Cochin Hand Function Scale from baseline to follow-up weeks 4, 12, and 24 did not differ significantly between groups. The BTA group experienced transient hand muscle weakness significantly more frequently (P = 0.003). CONCLUSION: Neither the primary nor secondary end points were reached, and our results do not support any beneficial effect of palmar BTA injections to treat SSc-RP.

Vasculitis and familial Mediterranean fever: Description of 22 French adults from the juvenile inflammatory rheumatism cohort.

Objective: The frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases. Methods: Patients with vasculitis were selected from patients followed for FMF in the French JIR-cohort. Results: Twenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications. Conclusion: This study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.

Nailfold capillaroscopy findings in cutaneous lupus erythematosus patients with or without digital lesions and comparison with dermatomyositis patients: A prospective study.

BACKGROUND: Differential diagnosis between cutaneous lupus erythematosus (CLE) and dermatomyositis (DM) may be challenging if digital lesions occur. OBJECTIVES: To compare nailfold capillaroscopy (NFC) findings in CLE patients with or without digital involvement, and to compare capillaroscopic findings between CLE patients with digital lesions and DM patients. METHODS: Prospective monocentric study including CLE and DM patients. NFC was performed and standardized items were recorded. RESULTS: Fifty-one CLE patients and 10 DM patients with digital lesions were included. A scleroderma pattern was found in 6 patients (12%): in 5 out of 17 patients with digital lesions, compared with only 1 out of 34 patients without digital lesions (p = 0.01). In multivariate analysis, CLE digital lesions and digital ulcerations were statistically associated with scleroderma pattern. CLE digital lesions were significantly associated with architectural disorganization (p = 0.0003) and capillary rarefaction (p = 0.0038). A scleroderma pattern was significantly more frequent in DM patients (80%) than in CLE patients with digital lesions (30%, p = 0.018). Capillaroscopic findings were not significantly different between CLE patients with digital lesions and DM patients. CONCLUSION: Although scleroderma pattern is more frequent in DM patients than in CLE patients with digital lesions, NFC cannot formally distinguish CLE from DM.

Systemic sclerosis is associated with lower limb vascular stiffness and microvascular impairment: results from a prospective study.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease characterized by microangiopathy. Peripheral arterial disease, increasingly studied during SSc, is responsible for digital ulcers, associated with a high risk of amputation. The aim of our study was to assess the frequency of lower limb arterial impairment in SSc patients by measuring ankle-brachial index (ABI), toe pressure (TP), and toe-brachial index (TBI). METHODS: Systemic sclerosis patients were included prospectively during 1 year in Tenon and Saint-Antoine Hospitals, Paris. Clinical and biological data were recorded. For each patient, ABI, TP, and TBI were measured and an arterial duplex ultrasonography was prescribed in case of abnormal results. RESULTS: Eighty-six patients were included (94% women, median age 62 years). Only 24% of them had no lower limb hemodynamic vascular abnormalities; 44% had an isolated microvascular abnormality (normal ABI and TBI<0.75); 31% had at least a macrovascular injury associated or not with microvascular impairment (abnormal ABI) and 12.6% had a TP<50 mmHg. During follow-up, there was a trend towards association of low TBI with more major adverse event (all-cause mortality, non-fatal stroke, non-fatal myocardial infarction, and lower limb ischemic manifestations) than normal TBI. CONCLUSION: By measuring ABI and TP, we showed that 76% of SSc patients had hemodynamic arterial lower limb abnormalities related to macro- and/or microvascular impairment and that 28% had vascular stiffness. In SSc patients, ABI is not an accurate tool to detect lower limb arterial disease, likely due to underlying micro- and macrovascular changes. Key Points • The presence of lower limb macro-and/or microvascular involvement was detected in 76% of SSc patients. • In SSc patients, ABI is not an accurate tool to detect lower limb arterial disease, likely due to underlying microvascular changes and frequent arterial stiffness.

Individual Burden of Psoriasis (I-BOP): Building and Validation of a New Scoring Tool for Patients with Psoriasis.

BACKGROUND: Psoriasis impacts independently of its severity on patients' lifestyle and quality of life (QoL). AIM: To build a tool for assessing the patient-reported psoriasis burden. METHODS: An expert group created a questionnaire using a standardized methodology building questionnaires assessing quality of life issues. The questionnaire was translated from French into a cultural and linguistically validated US English version. RESULTS: A conceptual questionnaire of 54 questions was created. The confirmatory analyses resulted in a 10-feature questionnaire divided into 4 internally consistent domains with a Cronbach's alpha coefficient of 0.9. It was reproducible and highly reliable. It correlated well with the Dermatology Life Quality Index (DLQI), Perceived Stress Scale (PSS), and SF-12 mental and SF12 physical scores. CONCLUSION: This tool allows for the first time to assess the burden of psoriasis patients. Its use may allow improving medical and nonmedical patient care, thus improving their daily life.

Leg Ulcers in Sickle-Cell Disease: Treatment Update.

Significance: Sickle-cell leg ulcers (SCLUs) are a severe, chronic, and recurrent complication of sickle-cell disease (SCD). There are no official recommendations for treatment. Recent Advances: Only a few studies with a high level of evidence have been conducted to evaluate treatment of SCLUs. However, several studies have been conducted with a high level of evidence to evaluate the efficacy of treatments in venous leg ulcers, and SCLUs could benefit from these treatments, especially when a venous incompetence or an edema is associated. Pathophysiology of SCLUs includes a vasculopathy related to chronic hemolysis and an endothelial dysfunction, which could be therapeutic approaches to SCLU treatment. Critical Issues: Therapeutic approaches to SCLUs can target SCD on the one hand and skin healing and associated aggravating factors on the other. A review of the literature found only case series and six randomized controlled trials; some offered encouraging results, but most had serious biases. Clinical trials specifically targeting SCLUs are difficult to realize because of the small number of affected patients, in comparison with patients with leg ulcers from other causes. Future Direction: Treating SCLUs remains a challenge. Data in the literature are currently insufficient to offer clear treatment guidelines because of several biases in controlled studies. New studies are under way to assess the efficacy of topical treatments and describe the microbiome of SCLUs. Prevention of SCLU recurrence should be assessed in future clinical trials because the high risk of recurrence is an unsolved critical issue.

Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature.

BACKGROUND: We have limited data on the treatment of calcinosis cutis associated with systemic sclerosis and dermatomyositis. OBJECTIVE: To assess the efficacy and tolerance of available treatments for calcinosis cutis based on previously published studies. METHODS: We performed a systematic review of studies published in Medline, Embase, and the Cochrane library during 1980-July 2018. The strength of clinical data was graded according to the modified Oxford Centre for Evidence-Based Medicine levels of evidence. RESULTS: In all, 30 studies (288 patients) were included. Eleven therapeutic classes, surgery, and physical treatments were identified as potential treatment options for calcinosis cutis. On the basis of results of a small randomized controlled trial and 4 retrospective studies, low-dose warfarin should not be used for calcinosis cutis (level IB evidence). The results of several studies suggest diltiazem and bisphosphonates might be useful treatment options (level IV). Considering biologic therapies, rituximab has shown promising results in treating both dermatomyositis and systemic sclerosis, whereas tumor necrosis factor inhibitors might be useful for treating juvenile dermatomyositis (level IV). Intralesional sodium thiosulfate might be a promising alternative (level IV). LIMITATIONS: Few included studies had a high level of evidence. CONCLUSION: This study highlights the efficacy and tolerance profiles of available treatments for calcinosis cutis, with a focus on level of evidence.

Persistent deficiency of mucosal-associated invariant T cells during dermatomyositis.

OBJECTIVES: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are important for antibacterial immunity and may have regulatory roles. MAIT cells are decreased during SLE. However, their frequencies and phenotype have not been investigated in DM. We studied MAIT cell frequencies and phenotype in DM patients with active and inactive disease (after treatment). METHODS: Peripheral blood flow cytometry analysis of MAIT cells was compared between DM (n = 22), SLE (n = 10), psoriasis (n = 7) and atopic dermatitis (n = 5) patients, and healthy controls (n = 19). RESULTS: A dramatic decrease of circulating MAIT cell frequency was observed in active DM and SLE patients compared with healthy controls and other inflammatory skin diseases [active DM: median = 0.25% (interquartile range 0.19-0.6%), P < 0.0001; active SLE: median = 0.61 (0.55-0.77), P < 0.0001 vs healthy controls: 2.32% (1.18-4.45%)]. MAIT cells from active DM patients had an abnormal phenotype including increased expression of CD25 and cytotoxic T-lymphocyte-associated protein 4 that correlated with their low frequency in the blood. CONCLUSION: In DM, peripheral blood MAIT cells are dramatically reduced and have an activated/exhausted phenotype that may be linked to increased activation-induced cell death.

Localization, Morphologic Features, and Chemical Composition of Calciphylaxis-Related Skin Deposits in Patients With Calcific Uremic Arteriolopathy.

Importance: Calcific uremic arteriolopathy (CUA), a rare, potentially fatal, disease with calcium deposits in skin, mostly affects patients with end-stage renal disease who are receiving dialysis. Chemical composition and structure of CUA calcifications have been poorly described. Objectives: To describe the localization and morphologic features and determine the precise chemical composition of CUA-related calcium deposits in skin, and identify any mortality-associated factors. Design, Setting, and Participants: A retrospective, multicenter cohort study was conducted at 7 French hospitals including consecutive adults diagnosed with CUA between January 1, 2006, and January 1, 2017, confirmed according to Hayashi clinical and histologic criteria. Patients with normal renal function were excluded. For comparison, 5 skin samples from patients with arteriolosclerosis and 5 others from the negative margins of skin-carcinoma resection specimens were also analyzed. Main Outcomes and Measures: Localization and morphologic features of the CUA-related cutaneous calcium deposits were assessed with optical microscopy and field-emission-scanning electron microscopy, and the chemical compositions of those deposits were evaluated with µ Fourier transform infrared spectroscopy, Raman spectroscopy, and energy dispersive radiographs. Results: Thirty-six patients (median [range] age, 64 [33-89] years; 26 [72%] female) were included, and 29 cutaneous biopsies were analyzed. Calcific uremic arteriolopathy and arteriolosclerosis skin calcifications were composed of pure calcium-phosphate apatite. Calcific uremic arteriolopathy vascular calcifications were always circumferential, found in small to medium-sized vessels, with interstitial deposits in 22 (76%) of the samples. A thrombosis, most often in noncalcified capillary lumens in the superficial dermis, was seen in 5 samples from patients with CUA. Except for calcium deposits, the vessel structure of patients with CUA appeared normal, unlike thickened arteriolosclerotic vessel walls. Twelve (33%) patients died of CUA. Conclusions and Relevance: Calcific uremic arteriolopathy-related skin calcifications were exclusively composed of pure calcium-phosphate apatite, localized circumferentially in small to medium-sized vessels and often associated with interstitial deposits, suggesting its pathogenesis differs from that of arteriolosclerosis. Although the chemical compositions of CUA and arteriolosclerosis calcifications were similar, the vessels' appearances and deposit localizations differed, suggesting different pathogenetic mechanisms.

Circulating follicular helper T cells are increased in systemic sclerosis and promote plasmablast differentiation through the IL-21 pathway which can be inhibited by ruxolitinib.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases. However, there are no data about cTfh cells and their interaction with B cells in SSc. The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc. METHODS: Using flow cytometry, we analysed cTfh cells from 50 patients with SSc and 32 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells were performed for functional analysis. IgG and IgM production were measured by ELISA. RESULTS: We observed that cTfh cell numbers are increased in patients with SSc compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from patients with SSc present an activated Tfh phenotype, with high expression of BCL-6, increased capacity to produce IL-21 in comparison with healthy controls. In vitro, cTfh cells from patients with SSc had higher capacity to stimulate the differentiation of CD19+CD27+CD38hi B cells and their secretion of IgG and IgM through the IL-21 pathway than Tfh cells from healthy controls. Blocking IL-21R or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells' capacity to stimulate the plasmablasts and decreased the Ig production. CONCLUSIONS: Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc.

Cutaneous Arteriolosclerosis Is Not Specific to Ischemic Hypertensive Leg Ulcers.

BACKGROUND: The histological characteristic of hypertensive leg ulcers (HLU) is the presence of "arteriolosclerosis." The pertinence of performing a skin biopsy to diagnose HLU is questionable, as cutaneous arteriolosclerosis may be related to patient comorbidities. The objective here was to evaluate the frequency of arteriolosclerosis in skin leg biopsies performed in patients without ulcer and in control patients with HLU. METHODS: We performed a retrospective study between January 2013 and July 2014. Patients were included if they had undergone a deep skin biopsy on the lower limbs, in the absence of any leg ulcer. Controls were patients with typical HLU. RESULTS: Fifty-eight patients and 6 controls were included. Hypertension was present in 25 patients (43%). Arteriolosclerosis, defined as fibrous endarteritis, was present in 35 out of 58 patients (60%) and in all of the controls. No hyalinosis or hyperplastic proliferative arteriolosclerosis was observed in the patients or controls. Only age was an independent factor associated with the presence of cutaneous arteriolosclerosis (p &x#3c; 0.0001). CONCLUSION: Cutaneous arteriolosclerosis is significantly and independently associated with age. Thus, skin biopsy seems not to be necessary for the diagnosis of HLU but only for a differential diagnosis.

Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study.

BACKGROUND: Changing from one antimalarial (AM) agent to another is often recommended in cutaneous lupus erythematosus (CLE) when the first AM agent is ineffective or poorly tolerated. OBJECTIVE: To evaluate the effect on cutaneous response of a switch from hydroxychloroquine to chloroquine, or the reverse, after failure of the first AM agent. METHODS: We conducted a retrospective observational study between 1997 and September 2015. The overall cutaneous response rate and reasons for failure of the switch were assessed for up to 48 months. Kaplan-Meier survival curves were used to assess the risk for failure of the second AM agent. RESULTS: A total of 64 patients with CLE (78% were women) were included; for 48 patients, the switch was for inefficacy, and for 16, it was for adverse events. Median follow-up was 42 months (range, 3-171). Of the patients changed because of inefficacy, 56% were responders at month 3; however, the response decreased over time, with a median duration before failure of the second AM agent of 9 months (95% confidence interval, 6-24). For patients switched because of adverse events, the second AM agent was well tolerated in 69% of cases. LIMITATIONS: Retrospective design and subjective evaluation of cutaneous response. CONCLUSION: A change of AM agent should be considered in patients with CLE when the first AM agent is ineffective or poorly tolerated.

Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.

Importance: Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking. Objective: To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study. Design, Setting, and Participants: STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. We extracted data for patients with skin involvement at anti-TNF initiation. Main Outcomes and Measures: Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop ≥2 points from baseline but >1 at last follow-up). Results: Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred in 35% of cases, mostly during anti-TNF or concomitant treatment tapering. Conclusions and Relevance: Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered.