Omalizumab in the treatment of bullous pemphigoid resistant to first-line therapy: a French national multicentre retrospective study of 100 patients.

BACKGROUND: Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available. RESULTS: Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity [median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001] and CR [median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001] were achieved significantly faster. CONCLUSIONS: We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.

Anti-BP180 IgG antibody ELISA values correlate with adverse pregnancy outcomes in pemphigoid gestationis.

BACKGROUND: Adverse pregnancy outcomes (APO) occur in 35% of patients with pemphigoid gestationis (PG). No biological predictor of APO has been established yet. OBJECTIVES: To assess a potential relationship between the occurrence of APO and the serum value of anti-BP180 antibodies at the time of PG diagnosis. METHODS: Multicentre retrospective study conducted from January 2009 to December 2019 in 35 secondary and tertiary care centres. INCLUSION CRITERIA: (i) diagnosis of PG according to clinical, histological and immunological criteria, (ii) ELISA measurement of anti-BP180 IgG antibodies determined at the time of PG diagnosis with the same commercial kit and (iii) obstetrical data available. RESULTS: Of the 95 patients with PG included, 42 had one or more APO, which mainly corresponded to preterm birth (n = 26), intrauterine growth restriction (IUGR) (n = 18) and small weight for gestational age at birth (n = 16). From a ROC curve, we identified a threshold of 150 IU ELISA value as the most discriminating to differentiate between patients with or without IUGR, with 78% sensitivity, 55% specificity, 30% positive and 91% negative predictive value. The threshold >150 IU was confirmed using a cross-validation based on bootstrap resampling, which showed that the median threshold was 159 IU. Upon adjusting for oral corticosteroid intake and main clinical predictors of APO, an ELISA value of >150 IU was associated with the occurrence of IUGR (OR = 5.11; 95% CI: 1.48-22.30; p = 0.016) but not with any other APO. The combination of blisters and ELISA values higher than 150 IU led to a 2.4-fold higher risk of all-cause APO (OR: 10.90; 95% CI: 2.33-82.3) relative to patients with blisters but lower values of anti-BP180 antibodies (OR of 4.54; 95% CI 0.92-34.2). CONCLUSION: These findings suggest that anti-BP180 antibody ELISA value in combination with clinical markers is helpful in managing the risk of APO, in particular IUGR, in patients with PG.

Bullous pemphigoid: Three main clusters defining 3 outcome profiles.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic. OBJECTIVE: To investigate different clinical and biological profiles of BP. METHODS: We conducted a retrospective 2-center study including all BP patients seen between January 1, 2015, and February 28, 2021. We performed hierarchical clustering on principal components. RESULTS: Three clusters were identified. Patients in cluster 1 (n = 155) were older than those in clusters 2 (n = 89) and 3 (n = 35; P < .0001), more frequently presented pauci-bullous BP (n = 63 [41%] vs 14 [16%] and 2 [6%], respectively; P < .0001) and had anti-BP230 antibodies in 87% of cases. More than 100 blisters were observed in 14 patients (40%) from cluster 3, versus 3 (2%) from cluster 1 and 0 (0%) from cluster 2 (P < .0001). Frequency of mucosal involvement was higher in cluster 3 (n = 32 [91%, including epiglottis in 40%] vs 11 [7%] and 34 [38%]; P < .0001). In clusters 2 and 3, 70% and 74% of patients had antibodies targeting only BP180. Those in cluster 3 received more lines of systemic treatment and experienced more relapses. LIMITATIONS: Retrospective study without immunoelectron microscopy. CONCLUSION: We identified 3 different BP clusters, including one corresponding to severe BP180+ BP230- BP with features common to mucous membrane pemphigoid.

Real-life impact of immunologic tests to predict relapse after treatment cessation in patients with bullous pemphigoid: A French multicenter retrospective study.

BACKGROUND: A high level of anti-BP180 antibodies on enzyme-linked immunosorbent assay and a persistent positive direct immunofluorescence at the end of treatment (immunologic tests, [ITs]) are predictors of relapse after treatment cessation (TC) in patients with bullous pemphigoid. OBJECTIVE: To evaluate the real-life impact of the immunologic-based decision of TC on the 3- and 6-month relapse rates after TC in bullous pemphigoid. METHODS: Retrospective multicentric study included patients followed almost 6 months after TC. Patients were classified according to whether the TC decision was in accordance with the results of ITs performed during the 3 months before TC, despite the results of ITs or without ITs performed. RESULTS: We included 238 patients. Three months after TC, 36 patients showed relapse: 14 of 95 patients with TC in accordance with IT results (14.7%); 5 of 21 with TC despite ITs (23.8%); and 17 of 122 with TC without ITs (13.9%; P = .5). Six months after TC, the relapse rate was 18.9%, 28.6%, and 18.9% (P = .56), respectively, in the 3 groups. LIMITATIONS: The retrospective design and the limited follow up. CONCLUSION: In real-life practice, in bullous pemphigoid, the 3- and 6-month relapse rates were not significantly reduced with TC decision based on results of ITs as compared with a classic clinical-based decision.

Oral forms of secondary syphilis: An illustration of the pitfalls set by the great imitator.

INTRODUCTION: Syphilis is reemerging in certain populations, such as in men who have sex with men in particular. Oral manifestations are not uncommon and can render diagnosis difficult, particularly if occurring in isolation. MATERIALS AND METHODS: We recovered clinical data for all patients receiving a diagnosis of secondary syphilis who were referred to the National Reference Center for Syphilis in Paris, France, from January 2000 to July 2019. We selected patients presenting oral symptoms only and analyzed their general characteristics, time to diagnosis, and clinical presentations. RESULTS: Secondary syphilis was diagnosed in 206 patients, 38 of whom (18%) presented oral manifestations, which were isolated in 14 patients (37%). The main oral manifestations were subacute erosive or ulcerative lesions (55%), mucous patches on the tongue (53%), and nodular (10%) and leukokeratotic lesions (5%). Mean time to diagnosis was 4.5 months, but was significantly longer for patients with isolated oral symptoms (8.8 vs 1.8 months; P = .02). CONCLUSION: Oral presentations of secondary syphilis are frequent and challenging for diagnosis, even in patients with epidemiologic risk factors. Clinicians confronted with subacute oral lesions in such patients should bear in mind the possibility of this contagious, curable, and sometimes severe disease.

Transient abdominal telangiectasia of the newborn.

We report 20 newborns who developed, at a median age of 7 days, large abdominal patches of radially arranged purplish telangiectasia in a bilateral and symmetrical pattern in relation to the midline, creating a "butterfly wing" pattern. Clinical examination was normal in 13 newborns, six newborns had abdominal distention, and one newborn had poor weight gain due to inadequate breastfeeding. Most lesions spontaneously resolved within 3 months and did not reoccur for 19 newborns. Transient abdominal telangiectasia of the newborn (TATN) appears to be a distinctive entity that has not been previously described.

Comparison of 3 type VII collagen (C7) assays for serologic diagnosis of epidermolysis bullosa acquisita (EBA).

BACKGROUND: Serologic diagnosis of epidermolysis bullosa acquisita (EBA) relies on the detection of circulating autoantibodies to type VII collagen (C7). OBJECTIVE: We sought to compare the diagnostic performances of a commercialized enzyme-linked immunosorbent assay (ELISA) using C7 noncollagenous (NC) domains (C7-NC1/NC2 ELISA) and indirect immunofluorescence (IIF) biochip test on NC1-C7-expressing transfected cells (IIFT), with a full-length-C7 ELISA developed in our laboratory. METHODS: C7-NC1/NC2 ELISA, IIFT, and full-length-C7 ELISA were run on 77 nonselected consecutive EBA sera. RESULTS: C7-NC1/NC2 ELISA, IIFT, and full-length-C7 ELISA were positive, respectively, for: 30%, 27%, and 65% of the 77 sera; 43%, 32%, and 80% of 44 sera labeling the salt-split-skin (SSS) floor (F) by IIF (SSS/F(+)); 9%, 22%, and 47% of 32 SSS/F(-) sera; 28%, 28%, and 58% of classic EBA; 41%, 41%, and 82% of inflammatory EBA; and 18%, 0%, and 55% of mucous-membrane-predominant EBA. Significant differences for all sera were found between: the 2 ELISAs for the 77 sera, SSS/F(+) and SSS/F(-) sera, and IIFT versus full-length-C7 ELISA. LIMITATIONS: The retrospective design was a limitation. CONCLUSION: C7-NC1/NC2 ELISA and IIFT sensitivities for serologic diagnoses of EBA were low. Full-length-C7 ELISA was significantly more sensitive and could serve as a reference test.

Non eosinophilic chronic stricturing esophagitis: Lessons from thirty eight cases.

BACKGROUND AND AIMS: The endoscopic workup of dysphagia can lead to the diagnosis of atypical esophagitis, with thickened esophageal mucosa, strictures, mucosal exudates, furrows, and sloughing. While these aspects suggest eosinophilic esophagitis, pathology might not report the presence of eosinophils, but rather chronic inflammation, with spongiosis, parakeratosis, and lymphocytic infiltrate. We aimed to report the management of this disease and assess the prevalence of associated dermatological conditions. METHODS: We retrospectively evaluated the medical records of our patients with non-eosinophilic stricturing esophagitis for clinical, endoscopy, and pathology data. Patients were evaluated by a dermatologist. A blood immunoassay and skin biopsy were performed if needed. RESULTS: Thirty-eight patients (twenty-six women) were included in the study. The median age at onset of symptoms was 56.5 years, with a median duration of symptoms of two years. Thirty-five patients presented with dysphagia at diagnosis and eighteen with weight loss. At endoscopy, a single esophageal stenosis was diagnosed in 19 patients, localized in the upper third in 22 patients. Thirty patients received endoscopic treatment (dilatation in 29/38 and local triamcinolone injection in 11/38 patients). In 21 patients, oral, skin or vulvo-anal lesions were found on dermatological examination. Nineteen patients received systemic treatment, including corticosteroids, immunosuppressive drugs and plasmapheresis. Five patients developed esophageal squamous cell carcinoma. CONCLUSION: The management of non-eosinophilic chronic stricturing esophagitis is challenging, because of a low contribution of esophageal biopsies and the refractory nature of the strictures. In our experience, a dermatological evaluation helped in 55% of cases to introduce a systemic treatment, leading to limit the use of endoscopic dilatation. Endoscopic follow-up is needed, considering the significant risk of esophageal squamous cell carcinoma.

Which first-line treatment for cutaneous sarcoidosis? A retrospective study of 120 patients.

Sarcoidosis is a systemic disease that affects the skin in about 25% of patients. The treatment of cutaneous sarcoidosis is guided by the extent of lesions, associated symptoms and organ involvement. To evaluate rates of response to various potential first-line treatments for cutaneous sarcoidosis during the year following treatment initiation. This retrospective multicentre study included 120 patients with cutaneous sarcoidosis. Treatment response was assessed retrospectively from the patients' medical records. Univariate logistic regression analysis, with an estimation of unadjusted odds ratios (OR) and their 95% CI ,was performed to identify factors associated with complete cutaneous remission (CR), followed by multivariate logistic regression analysis. At one year, 43 of the 120 (36%) included patients had CR. The best response rates were obtained with oral corticosteroids (12/21, 57%), followed by a combination of hydroxychloroquine and topical steroids (6/13, 46%). In multivariate analysis, lupus pernio was the only predictor of a poor cutaneous response. We suggest the use of a combination of hydroxychloroquine and topical steroids as an optimal first-line treatment for cutaneous sarcoidosis, given the known adverse effects of systemic corticosteroids.

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.

Gliptin Accountability in Mucous Membrane Pemphigoid Induction in 24 Out of 313 Patients.

Mucous membrane pemphigoids (MMPs) and bullous pemphigoid (BP) are autoimmune bullous diseases that share physiopathological features: both can result from autoantibodies directed against BP180 or BP230 antigens. An association has been reported between BP and intake of gliptins, which are dipeptidyl peptidase-IV inhibitors used to treat type 2 diabetes mellitus. Clinical and immunological differences have been reported between gliptin-induced BPs and classical BPs: mucosal involvement, non-inflammatory lesions, and target BP180 epitopes other than the NC16A domain. Those findings accorded gliptins extrinsic accountability in triggering MMP onset. Therefore, we examined gliptin intrinsic accountability in a cohort of 313 MMP patients. To do so, we (1) identified MMP patients with gliptin-treated (challenge) diabetes; (2) selected those whose interval between starting gliptin and MMP onset was suggestive or compatible with gliptin-induced MMP; (3) compared the follow-ups of patients who did not stop (no dechallenge), stopped (dechallenge) or repeated gliptin intake (rechallenge); (4) compared the clinical and immunological characteristics of suggestive-or-compatible-challenge patients to 121 never-gliptin-treated MMP patients serving as controls; and (5) individually scored gliptin accountability as the trigger of each patient's MMP using the World Health Organization-Uppsala Monitoring Center, Naranjo- and Begaud-scoring systems. 17 out of 24 gliptin-treated diabetic MMP patients had suggestive (≤12 weeks) or compatible challenges. Complete remission at 1 year of follow-up was more frequent in the 11 dechallenged patients. One rechallenged patient's MMP relapsed. These 17 gliptin-treated diabetic MMP patients differed significantly from the MMP controls by more cutaneous, less buccal, and less severe involvements and no direct immunofluorescence IgA labeling of the basement membrane zone. Multiple autoantibody-target antigens/epitopes (BP180-NC16A, BP180 mid- and C-terminal parts, integrin α6ß4) could be detected, but not laminin 332. Last, among the 24 gliptin-treated diabetic MMP patients, five had high (I4-I3), 12 had low (I2-I1) and 7 had I0 Begaud intrinsic accountability scores. These results strongly suggest that gliptins are probably responsible for some MMPs. Consequently, gliptins should immediately be discontinued for patients with a positive accountability score. Moreover, pharmacovigilance centers should be notified of these events.

Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy.

In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.