Anti-SAE autoantibody in dermatomyositis: original comparative study and review of the literature.

OBJECTIVE: Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM. METHODS: Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature. RESULTS: Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003). CONCLUSION: Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672.

UBA1 Variations in Neutrophilic Dermatosis Skin Lesions of Patients With VEXAS Syndrome.

IMPORTANCE: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described. OBJECTIVE: To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies. RESULTS: All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients. CONCLUSIONS AND RELEVANCE: This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

Psychometric validation of a patient-reported outcome questionnaire (Qualipsosex) assessing the impact of psoriasis and psoriatic arthritis on patient perception of sexuality.

ABSTRACT: Psoriasis (Pso) and psoriatic arthritis (PsA) frequently have a negative impact on patients' sexual health. We have developed a specific questionnaire assessing the impact of Pso and PsA on patient perception of sexuality: the QualipsoSex Questionnaire (QSQ). The aim of the present study was to further validate this questionnaire by checking its psychometric properties including validity, reliability, and responsiveness.A cross sectional observational study with a longitudinal component for responsiveness and test-retest reliability was performed in 12 centers in France including 7 dermatologists and 5 rheumatologists. Psychometric properties were examined according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) check-list.At baseline, 114 patients had Pso and 35 patients had PsA including 17 peripheral arthritis, 4 axial disease, 13 patients with both axial disease and peripheral arthritis and one patient with an undifferentiated phenotype. The mean Pso Area and Severity Index score was 12.5. Genital organs were involved in 44.7% of Pso cases. Internal consistency, construct validity, and reliability were good with Cronbach's α coefficient, measure of sampling adequacy and intraclass correlation coefficient respectively at 0.87, 0.84, and 0.93. The QSQ also demonstrated acceptable sensitivity to change.The QSQ has demonstrated good psychometric properties fulfilling the validation process relative to the recommendations of the COSMIN check list. The QSQ is simple to score and may hopefully be valuable in clinical practice and in clinical trials.

Histiocytoid Sweet Syndrome Is More Frequently Associated With Myelodysplastic Syndromes Than the Classical Neutrophilic Variant: A Comparative Series of 62 Patients.

Histiocytoid Sweet syndrome (H-SS) is a histological variant of Sweet syndrome (SS) differing from classical neutrophilic SS (N-SS) by a dermal infiltrate mainly composed of lymphocytes and histiocytoid myeloperoxidase-positive cells. We aimed to report a large series of H-SS and compare the frequency and type of hematological malignancies associated to H-SS and N-SS. We included 62 patients with a coding histopathologic diagnosis of SS prospectively registered between 2005 and 2014 in the database of our Department of Pathology. Overall, 22 (35.5%) and 40 (64.5%) patients had a histological diagnosis of H-SS and N-SS, respectively. Median age, sex ratio, and cutaneous lesions were similar in the 2 groups. The frequency of extra-cutaneous manifestations was similar (50% vs 37.5%, P = 0.42). Recurrent forms were significantly more frequent in H-SS than in N-SS patients (21% vs 2.5%, P = 0.01). A hematological malignancy was diagnosed in 22 patients, 12 (55.5%) with H-SS and 10 (25%) with N-SS (P = 0.019). Hematological malignancy was of myeloid origin in 8/22 (36.3%) H-SS and 5/40 (12.5%) N-SS patients (P = 0.02), and of lymphoid origin without myeloid component in 4/22 (18.1%) H-SS and 4/40 (10%) N-SS patients (P = 0.35), respectively. One N-SS patient had a hematological malignancy of mixed (myeloid and lymphoid) phenotype. A myelodysplastic syndrome (MDS) was diagnosed in 7/22 (31.8%) H-SS and 1/40 (2.5%) N-SS patients (P < 0.001). Hematological disease was diagnosed before (in 8 H-SS and 3 N-SS patients) or at the time of the occurrence of the cutaneous lesions (in 1 H-SS and 7 N-SS patients). However, in 3 H-SS patients, all with MDS, cutaneous lesions preceded the hematological disease by ≤6 months. In conclusion, H-SS was associated with MDS in one third of patients but also with lymphoid malignancies, and cutaneous lesions could precede the hematological diagnosis in patients with MDS. A complete hematological assessment is mandatory at diagnosis, and monitoring blood cell counts should be recommended for at least 6 months after the diagnosis of H-SS.

Development of monoclonal gammopathy under biotherapy in psoriasis: a French multicenter retrospective study.

BACKGROUND: Biotherapies or targeted therapies are fairly new treatments indicated for moderate to severe psoriasis. The side effects appear to be mainly infectious or cancerous. The role of biotherapies in the development of a pre-cancerous condition, monoclonal gammopathy of undetermined significance (MGUS), has recently been debated in the literature. OBJECTIVES: To evaluate the incidence of MGUS in psoriasis patients treated with biotherapy. MATERIALS AND METHODS: This study was a French multicenter retrospective study carried out through the French multicenter study group RESOPSO. Data on the results of serum protein electrophoreses performed before and within at least six months after the start of the biotherapy were collected. Demographic data, medical history, and psoriasis treatment history were specified. RESULTS: Four hundred and forty three patients were eligible for inclusion. Of these, three presented with monoclonal gammopathy for which the assessment was in favor of MGUS. The average treatment period was 19.7 months. Six patients presented with MGUS prior to the treatment. These patients' immunoglobulin levels remained stable, with an average remission of 24 months. Only psoriatic rheumatism appeared to be statistically linked to MGUS. CONCLUSION: The incidence and frequency of MGUS in psoriasis patients treated with biotherapy do not appear to increase relative to the general population.

Relationship between cutaneous polyarteritis nodosa (cPAN) and macular lymphocytic arteritis (MLA): Blinded histologic assessment of 35 cPAN cases.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a skin medium vessel neutrophilic arteritis with livedo, nodules, and ulcerations. Macular lymphocytic arteritis (MLA) is a small arteritis with erythematous or pigmented macules and typical histologic features (a lymphocytic infiltrate, concentric fibrin ring, no disruption of the internal elastic lamina). OBJECTIVE: We sought to assess the frequency of clinical and histologic features of MLA in patients with cPAN. METHODS: This was a monocentric retrospective analysis of patients given the diagnosis of cPAN with blinded assessment of skin biopsy specimens. RESULTS: All 35 patients included had an infiltrated livedo, nodules, or both. Ulceration was rare. Erythematous or pigmented lesions were present in 54% of patients. Predominantly lymphocytic arteritis, a paucity of neutrophils, concentric fibrin ring, and absence of internal lamina elastic disruption were present in 60%, 20%, 18%, and 23% of patients, respectively. Median follow-up was 11 years. None of the patients had systemic involvement, and 57% had a complete remission. The incidence of complete remission was not different between patients having a predominant lymphocyte infiltrate or few neutrophils. LIMITATIONS: This was a retrospective, monocentric study without a control group of patients with MLA. CONCLUSIONS: Our data do not favor the classification of cPAN and MLA as distinct entities.

Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience.

OBJECTIVES: Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. METHODS: We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. RESULTS: Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose ≥30 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. CONCLUSION: TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis.

Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin.

The aim of the research described here was to investigate the expression of Toll-like receptors (TLRs) in normal human keratinocytes, to study its modulation by proinflammatory cytokines, and to characterize the function of the latter within the epidermis. Our results demonstrate that normal human keratinocytes may present an intra-cytoplasmic expression of TLR2, TLR3, and TLR4. Exposure of keratinocytes to IFN-gamma and TNF-alpha increased intra-cytoplasmic expression and led to partial translocation at the cell surface. Keratinocyte activation by TLR2, TLR3, and TLR4 ligands led to the nuclear translocation of NF-kappab and the release of proinflammatory cytokines TNF-alpha and IL-8. In immunochemistry analysis, psoriatic skin showed a strong over-expression of TLR2 in the epidermis compared with normal skin. Our results thus demonstrate large TLR expression in keratinocytes and the functionality of TLRs 2, 3, and 4. TLR2 over-expression in psoriatic skin provides new insights into TLR implication in the pathogenesis of psoriasis, through inappropriate stimulation by infectious or endogen ligands.

Infliximab for severe hidradenitis suppurativa: transient clinical efficacy in 7 consecutive patients.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic and debilitating disorder. Despite its significant prevalence, few reports of therapeutic studies are available. Recent case studies have reported the efficacy of antitumor necrosis factor monoclonal antibodies in treating the condition. In the study presented here, we assessed the safety and efficacy of infliximab in a series of patients with severe HS. METHODS: We reviewed all consecutive patients with severe HS and treated with infliximab between October 2004 and December 2005. They were evaluated using the Sartorius severity score, a physician and patient overall assessment, and the Skindex-29 quality-of-life index. A substantive response was defined as marked or moderate overall improvement assessed by both physician and patient. RESULTS: Seven patients were reviewed. All received at least 3 infusions of infliximab (5 mg/kg) in weeks 0, 2, and 6, and 5 patients received a fourth infusion at week 10. At week 6, a substantive improvement was seen in 5 patients. With the other 2 patients, any improvement was minimal or nonexistent. At week 10, there was a substantive response in 2 of the 5 patients. Adverse events occurred in 3 patients: abdominal pain caused by colon cancer, a multifocal motor neuropathy with conduction block, and a severe allergic reaction. LIMITATIONS: We have reported on only 7 patients. All had severe and chronic disease. CONCLUSION: The efficacy of infliximab in patients with severe HS seems transient and is associated with significant toxicity. Prospective randomized studies are required to better assess the benefit-risk ratio of antitumor necrosis factor agents for this indication.