[Anti-IL-5 in severe asthma associated with eosinophilic granulomatosis with polyangiitis. Real-life study]. / Anti-IL-5 dans l'asthme sévère associé à une granulomatose éosinophilique avec polyangéite. Étude en vie réelle.

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of necrotizing vasculitis affecting small vessels and typically characterized by severe glucocorticoid (GC)-dependent eosinophilic asthma. While mepolizumab, which is indicated at a dose of 100mg/4weeks in severe eosinophilic asthma, has been shown to be an effective treatment for EGPA-related asthma at a dose of 300mg/4weeks, it was only recently approved at this dose. METHODS: This retrospective, single-center, observational study was conducted to investigate over a 5-year period (2014-2019) the effect of mepolizumab 100mg/4weeks at 12months in patients with EGPA and glucocorticoid-dependant severe asthma. Response to treatment was defined as reduction in daily dose of oral corticosteroids to at most 5mg/day or reduction in annual exacerbation by at least 50%. RESULTS: Thirty patients were included, of whom twenty-three were treated (two were not fully evaluable). Among the 21 evaluable treated patients, 13 (62%) had responded at 12months. At baseline, non-responders had lower FEV1 levels and lower blood eosinophil levels than responders. CONCLUSIONS: Mepolizumab at a "severe asthma" dose (100mg/4weeks) is effective in treatment of GC-dependent severe asthma in most patients with EGPA.

Off-label use of biologics for the treatment of refractory and/or relapsing granulomatosis with polyangiitis.

OBJECTIVE: To describe the efficacy and safety of off-label use of biologics for refractory and/or relapsing granulomatosis with polyangiitis (GPA). METHODS: We conducted a French retrospective study including GPA patients who received off-label biologics for refractory and/or relapsing disease after failure of conventional immunosuppressive regimens. RESULTS: Among 26 patients included, 18 received infliximab (IFX), 2 adalimumab (ADA) and 6 abatacept (ABA). Biologics were initiated in median as 4th-line therapy (IQR 3-6) for relapsing and/or refractory disease in 23 (88%) and/or significant glucocorticoid-dependency in 8 cases (31%). At biologics initiation, median (IQR) BVAS and prednisone dose in anti- TNF-α and ABA recipients were 7 (3-8) and 2 (1-6), and 20 (13-30) mg/day and 20 (15-25) mg/day, respectively. Clinical manifestations requiring biologics were mainly pulmonary and ENT manifestations in 58% each. Anti-TNF-α and ABA were continued for a median duration of 8 months (IQR 6-13) and 11 months (IQR 6-18) respectively. Anti-TNF-α recipients showed remission, partial response and treatment failure in 10%, 30% and 60% at 6 months, and 25%, 20% and 55% at 12 months, respectively. ABA recipients showed remission, partial response and treatment failure in 17%, 33% and 50% at 6 months and 17%, 33% and 50% at 12 months. One patient treated with IFX experienced life-threatening reaction while one patient treated with ABA experienced a severe infection. CONCLUSION: This real-life study suggests that off-label use of anti-TNF-α and abatacept shows efficacy in less than 50% of refractory and/or relapsing GPA.

[Update on treatments and innovations in systemic auto-immune diseases]. / Actualités thérapeutiques et innovations dans les maladies systémiques et auto-immunes.

Many new drugs, sometimes promising, are now available to treat systemic auto-immune diseases. Treatment strategies and objectives are different according to each auto-immune disease. Major advances have been obtained in vasculitides treatments. In systemic lupus erythematosus, many drugs have been evaluated, targeting one of the multiple pathogenic mechanisms of the disease. Unfortunately, new drugs remain rare on the market and no major advances have been obtained. In systemic sclerosis, symptomatic treatments improved outcomes but effective drugs targeting all disease manifestations are missing. Autologous hematopoietic stem cell transplantation could be one of the future innovative treatment of systemic sclerosis despite the occurrence of adverse events.

Combined pulmonary fibrosis and emphysema in systemic sclerosis: A syndrome associated with heavy morbidity and mortality.

BACKGROUND: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) primarily due to tobacco smoking has been reported in connective tissue disease, but little is known about its characteristics in systemic sclerosis (SSc). METHODS: In this retrospective multi-center case-control study, we identified 36 SSc patients with CPFE, and compared them with 72 SSc controls with interstitial lung disease (ILD) without emphysema. RESULTS: Rate of CPFE in SSc patients with CT scan was 3.6%, and 7.6% among SSc patients with ILD. CPFE-SSc patients were more likely to be male (75 % vs 18%, p < 0.0001), smokers (83 % vs 33%, p < 0.0001), and to have limited cutaneous SSc (53 % vs 24% p < 0.01) than ILD-SSc controls. No specific autoantibody was significantly associated with CPFE. At diagnosis, CPFE-SSc patients had a greater decrease in carbon monoxide diffusing capacity (DLCO 39 ± 13 % vs 51 ± 12% of predicted value, p < 0.0001) when compared to SSc-ILD controls, whereas lung volumes (total lung capacity and forced vital capacity) were similar. During follow-up, CPFE-SSc patients more frequently developed precapillary pulmonary hypertension (PH) (44 % vs 11%, p < 10-4), experienced more frequent unscheduled hospitalizations (50 % vs 25%, p < 0.01), and had decreased survival (p < 0.02 by Kaplan-Meier survival analysis) as compared to ILD-SSc controls. CONCLUSIONS: The CPFE syndrome is a distinct pulmonary manifestation in SSc, with higher morbidity and mortality. Early diagnosis of CPFE by chest CT in SSc patients (especially smokers) may result in earlier smoking cessation, screening for PH, and appropriate management.

Concordance of Time-of-Flight MRA and Digital Subtraction Angiography in Adult Primary Central Nervous System Vasculitis.

BACKGROUND AND PURPOSE: 3D-TOF-MRA and DSA are 2 available tools to demonstrate neurovascular involvement in primary central nervous system vasculitis. We aimed to compare the diagnostic concordance of vessel imaging using 3D-TOF-MRA and DSA in patients with primary central nervous system vasculitis. MATERIALS AND METHODS: We retrospectively identified all patients included in the French primary central nervous system vasculitis cohort of 85 patients who underwent, at baseline, both intracranial 3D-TOF-MRA and DSA in an interval of no more than 2 weeks and before treatment initiation. Two neuroradiologists independently reviewed all 3D-TOF-MRA and DSA imaging. Brain vasculature was divided into 25 arterial segments. Concordance between 3D-TOF-MRA and DSA for the identification of arterial stenosis was assessed by the Cohen κ Index. RESULTS: Thirty-one patients met the inclusion criteria, including 20 imaged with a 1.5T MR unit and 11 with a 3T MR unit. Among the 25 patients (81%) with abnormal DSA findings, 24 demonstrated abnormal 3D-TOF-MRA findings, whereas all 6 remaining patients with normal DSA findings had normal 3D-TOF-MRA findings. In the per-segment analysis, concordance between 1.5T 3D-TOF-MRA and DSA was 0.82 (95% CI, 0.75-0.93), and between 3T 3D-TOF-MRA and DSA, it was 0.87 (95% CI, 0.78-0.91). CONCLUSIONS: 3D-TOF-MRA shows a high concordance with DSA in diagnostic performance when analyzing brain vasculature in patients with primary central nervous system vasculitis. In patients with negative 3T 3D-TOF-MRA findings, the added diagnostic value of DSA is limited.

[Congestive heart failure: Treatment with ultrafiltration]. / Insuffisance cardiaque congestive : place de l'ultrafiltration.

INTRODUCTION: The prevalence rate of congestive heart failure is approximately 2% in high-income countries. The aim of this study was to assess the overall benefit of ultrafiltration therapy in patients with acute or persistent congestive heart failure. METHODS: We conducted a health technology assessment following the EUnetHTA guidelines, with systematic literature review from bibliographic medical databases, independent experts and manufacturer interviews. RESULTS: Thirteen clinical trials and five meta-analyses were examined. In the most recent one, 608 patients were included, of which 304 received ultrafiltration therapy and 304 received intravenous loop diuretics. Ultrafiltration therapy seems to be more beneficial regarding the fluid removal and the body weight reduction, (mean difference respectively 1.44kg, IC95% [0.29; 2.59], P-value=0.01 and 1.28L [0.43; 2.12], P-value=0.003). No difference has been showed in overall mortality, renal function, hospital readmission or safety. Medico-economic studies are incomplete and contradictory. CONCLUSION: Ultrafiltration therapy seems to be effective, most likely for patients ineligible or resistant to intravenous diuretics. But most topics remain uncertain, mainly impact on overall mortality, safety and cost-effectiveness. Given these knowledge-gaps, the generalization of ultrafiltration therapy should be examined cautiously, and conditional upon a large-scale systematic evaluation.

[Pathophysiology of eosinophilic granulomatosis with polyangitis (Churg-Strauss)]. / Physiopathologie de la granulomatose éosinophilique avec polyangéite (Churg-Strauss).

Eosinophilic granulomatosis with polyangitis (EGPA) (formerly Churg-Strauss syndrome) is a rare small-sized vessel vasculitis belonging to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides. MPO-ANCA is present in only 31 to 38% of patients. In this review, we describe the pathophysiology of EGPA, which is characterized by a genetic predisposition, an environmental association, and a cellular dysfunction of eosinophils, neutrophils, and T and B cells.

[Severe alveolar haemorrhage related to a silicone embolism syndrome revealed by a chronic penis ulcer: A case report]. / Une hémorragie intra-alvéolaire sévère liée à un syndrome d'embolie siliconée révélée par une ulcération chronique du pénis : une observation.

INTRODUCTION: Silicone injections, in particular illegal injections, carried out in an aesthetic purpose, can cause serious complications, like silicone embolism syndrome. CASE REPORT: We present a 39-year-old man who presented with a severe acute respiratory distress syndrome related to an alveolar hemorrhage associated with a persistent penis ulcer and a genital lymphedema. It was the complications of silicone injections which revealed a severe personality disorder. Diagnosis of silicone embolism syndrome was made, a few years later, thanks to the histopathology study of a persistent penis ulcer with genital lymphedema. The outcome was favorable. CONCLUSION: A serious alveolar hemorrhage in a young patient should raise suspicion of silicone embolism syndrome, especially if there are cutaneous lesions compatible with injections.

Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Interleukin-1 receptor antagonist for refractory anti-MDA5 clinically amyopathic dermatomyopathy.

Autoantibodies targeting the melanoma-differentiation-associated gene-5 (MDA5)-encoded ribonucleic acid helicase are associated with clinically amyopathic dermatomyopathy (CADM). Marked systemic inflammation, skin ulcers and severe interstitial lung disease seem frequent. DM treatment consists of immunosuppressants and/or intravenous immunoglobulins, but evidence-based knowledge is lacking. Anakinra (an interleukin-1 receptor antagonist (IL-1RA)) use in this setting has never been reported. Herein, we report on a case of anakinra dramatic and rapid efficacy against general and extramuscular (e.g. calcinosis, arthritis, skin ulcers) in a patient with severe and refractory CADM. Unfortunately, short-term follow-up prevented efficacy evaluation against interstitial lung disease. IL-1RA could be a promising treatment for refractory CADM.

Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts.

OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.

Tobacco differentially affects the clinical-biological phenotypes of ANCA-associated vasculitides.

OBJECTIVES: To describe the clinical-biological phenotype of ANCA-associated vasculitides (AAV) according to tobacco consumption. METHODS: We conducted a descriptive study to describe that phenotype at diagnosis according to tobacco use. AAV patients entered in the French Vasculitis Study Group database with data on smoking habits were analysed. The clinical-biological phenotypes at diagnosis were compared according to current tobacco use (current smokers) or not (including previous and never smokers). RESULTS: AAV diagnoses were: granulomatosis with polyangiitis (GPA) for 583 (50%), eosinophilic granulomatosis with polyangiitis (EGPA) for 326 (28%) and microscopic polyangiitis (MPA) for 256 (22%). Among them, 973 patients (84%) never smoked, 116 (10%) were previous smokers and only 76 (6%) were current smokers. Current smokers were younger age (p=0.01), male gender (p=0.004), less frequently EGPA (p=0.017) and MPA (p=0.036), and had less frequent kidney involvement (p=0.10). Among GPA patients, current smokers, compared to non-current smokers, were younger age (p=0.02), male gender (p=0.08), more frequent skin involvement (p=0.03) and less frequent ENT involvement (p=0.06). Among EGPA patients, current smokers, compared to non-current smokers, were also younger (p=0.028) and had less frequent constitutional symptoms (p=0.02), arthralgias (p=0.04), renal involvement (p=0.025) and MPO-ANCA (p=0.02). Finally, analysis of MPA patients was impossible because only 6 (2%) were current smokers. CONCLUSIONS: These results suggest that tobacco use could differentially affect GPA and EGPA clinical-biological phenotypes, and support the role of environmental exposures in AAV development and its phenotype.

Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) treatment strategy is based on immunosuppressive agents. Little information is available concerning mycophenolic acid (MPA) and the area under the curve (AUC) in patients treated for AAV. We evaluated the variations in pharmacokinetics for MPA in patients with AAV and the relationship between MPA-AUC and markers of the disease. MPA blood concentrations were measured through the enzyme-multiplied immunotechnique (C(0), C(30), C(1), C(2), C(3), C(4), C(6) and C(9)) to determine the AUC. Eighteen patients were included in the study. The median (range) MPA AUC(0-12) was 50·55 (30·9-105·4) mg/h/l. The highest coefficient of determination between MPA AUC and single concentrations was observed with C(3) (P < 0·0001) and C(2) (P < 0·0001) and with C(4) (P < 0·0005) or C(0) (P < 0·001). Using linear regression, the best estimation of MPA AUC was provided by a model including C(30), C(2) and C(4): AUC = 8·5 + 0·77 C(30) + 4·0 C(2) + 1·7 C(4) (P < 0·0001). Moreover, there was a significant relationship between MPA AUC(0-12) and lymphocyte count (P < 0·01), especially CD19 (P < 0·005), CD8 (P < 0·05) and CD56 (P < 0·05). Our results confirm the interindividual variability of MPA AUC in patients treated with MMF in AAV and support a personalized therapy according to blood levels of MPA.

Progressive multifocal encephalopathy after cyclophosphamide in granulomatosis with polyangiitis (Wegener) patients: case report and review of literature.

Progressive multifocal encephalopathy (PML) is a rare demyelinating disorder targeting the central nervous system and resulting from JC virus reactivation. PML occurs in patients immunocompromised because of haematological malignancies, HIV infection or treatment with cytotoxic drugs. Herein, we describe PML occurring in 2 granulomatosis with polyangiitis (Wegener) patients treated with steroids and cyclophosphamide. The outcome was progressively favourable after immunosuppressant discontinuation for 1 patient and fatal for the other. Four previously reported GPA patients developed PML in the course of their disease. One of them improved gradually after immunosuppressant withdrawal. PML should be strongly suspected whenever unusual central neurological manifestations appear in this context. No effective treatment is available, but immunosuppressants should be discontinued if possible.

[100 essential drugs. An internal medicine approach]. / Les 100 médicaments essentiels. Une approche de médecine interne.

PURPOSE: Up to 4600 drugs in about 15,000 pharmaceutical forms are available in France which may be a source of misuse with increased occurrence of side effects and costs. While the World Health Organization is encouraging each developed country to work out its own list of essential drugs. The list provided in 2008 by the French Office for the safety of health products has had so far limited impact on practice, so it became obvious to a group of internists to work out a "wise list" of 100 essential medicines covering 95% of the disorders observed in France. METHODS: In June 2011, 10 internists agreed to each provide a list of 100 essential medicines, according to individual experience. In December 2011, a meeting of the participants provided a list as initial consensus and mandated five among them to make proposals for those areas neglected by too many participants or in which needless dispersion of medicines was stated. After internet-facilitated exchanges, an additional list was validated in mild-January 2012. RESULTS: Fifty-four drugs were included in the list of initial consensus (including nine selected by all 10 participants), and 46 in the additional list. So the final "wise list" included 100 drugs. In June 2012, 56 of these drugs were available as generics. This list was compared to those lists set out by five countries in the European Union. CONCLUSION: Generating such a list is feasible. Undoubtedly still non-comprehensive, this list will benefit from the expertise of 14 general practitioners who are currently working out a similar list across France. The final list will be submitted for validation by the French associations of generalist teachers and Internists.

[Severe cholestatic hepatitis revealing a DRESS syndrome]. / Hépatite cholestatique sévère révélant un Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

INTRODUCTION: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a drug-induced hypersensitivity syndrome, characterized by rash, hyereosinophilia and multiorgan failure, including cytolytic hepatitis. CASE REPORT: A 75-year-old man, treated with amoxicillin/clavulanic acid, presented with jaundice and disabling pruritus associated with severe cholestatic hepatitis, related to a DRESS syndrome. Because of the persistence of cholestasis and the severity of pruritus, a treatment with corticosteroids and plasma exchanges was initiated, allowing a rapid and complete remission. CONCLUSION: Amoxicillin/clavulanic acid, although rarely described in the literature, is a rare cause of DRESS syndrome. Severe cholestatic hepatitis associated with disabling pruritus may be one of the systemic manifestations, with a good prognosis using corticosteroids and plasma exchanges.

[The national plan for orphan rare diseases: nearly 10 years on]. / Le plan national maladies rares--bientôt 10 ans.

The management of orphan rare diseases has been the goal of two successive government plans since 2004. They allowed the management of these diseases to be handled initially through reference centers, then by specialized centers that were specifically created. The resulting benefits to patients, standardization of management protocols, dissemination of information through ORPHANET, and the development of both fundamental and clinical research have clearly justified the setting up of these plans. Other associated plans are expected to follow in the years to come.