P. Arlet

Hierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity.

The clinical phenotype and evolution of antisynthetase syndrome (ASS) are heterogeneous. This study was therefore undertaken to identify subgroups of ASS patients with similar clinico-biological features and outcomes. This retrospective multicentric study included 233 consecutive patients with three different anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS): anti-Jo1 (n=160), anti-PL7 (n=25) and anti-PL12 (n=48). To characterise ASS patients, bivariate, multiple correspondence (MCA), cluster and survival analyses were performed. Interstitial lung disease (ILD) and myositis were the most common ASS manifestations. However, their respective frequencies were correlated to anti-ARS specificity: ILD was more frequent (80% and 88% vs 67%, p=0.014) whereas myositis was less common (44% and 47% vs 74%, p<0.001) in patients with anti-PL7 and anti-PL12 compared to anti-Jo1. The MCA suggested that anti-PL7 and anti-PL12 phenotypes were close to one another and distinct from anti-Jo1. The clustering analysis confirmed these data, identifying subgroups strongly defined by the anti-ARS specificity and other clinical features. Cluster 1 (n=175, 86% of anti-Jo1) defined patients with the most diffuse phenotype, whereas patients from cluster 2 (n=48, 96% of anti-PL12 and anti-PL7) exhibited a disease more restricted to the lung. Patient survival was also conditioned by the anti-ARS specificity, and was significantly lower in patients with anti-PL7/12 rather than anti-Jo1 (p=0.012). Other factors associated with poor survival were mostly related to pulmonary involvement, including severe dyspnea (p=0.003) and isolated ILD (p=0.009) at diagnosis. In patients with ASS, the phenotype and the survival were correlated with the anti-ARS specificity.

Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study

Objective: Case reports have suggested that lipid-lowering drugs (LLDs), especially statins, could induce or reveal chronic muscle diseases. We conducted a study to evaluate the association between chronic muscle diseases and prior exposure to LLDs. Method: This was a retrospective study of chronic primary muscle disease cases newly diagnosed at the Toulouse University Hospitals between January 2003 and December 2004 among patients living in the Midi-Pyrénées area, France. All patients remained symptomatic for more than 1 year after drug withdrawal, or required drugs for inflammatory myopathy. Data on the patient’s exposure to LLDs and to other drugs were compared with that of matched controls (5/1) selected through the Midi-Pyrénées Health Insurance System database. Results: A total of 37 patients were included in the study. Of those, 21 (56.8%) suffered from dermatomyositis (DM) or polymyositis (PM), 12 (32.4%) from genetic myopathy, and 4 (10.8%) from an unclassified disease. The prevalence of exposure to statins was 40.5% in patients and 20% in controls (odds ratio (OR) 2.73, 95% confidence interval (CI) 1.21–6.14; p<0.01). There was a significant positive interaction between statins and proton pump inhibitors exposure (weighted OR 3.3, 95% CI 1.37–7.54; p = 0.02). Statin exposure rate was 47.6% among patients with DM/PM (OR 3.86, 95% CI 1.30–11.57; p<0.01). There was no difference between patients and controls for exposure to fibrates. Conclusion: Patients who developed chronic muscle diseases after the age of 50, including DM/PM, had a higher than expected frequency of prior exposure to statins. Further studies are needed to confirm this association and the role of proton pump inhibitors.

The Relapsing Polychondritis Disease Activity Index: Development of a disease activity score for relapsing polychondritis

OBJECTIVE The rarity of relapsing polychondritis (RP) has hindered the development of standardized tools for clinical assessment. Here, we describe the development of a preliminary score for disease assessing activity in RP, the Relapsing Polychondritis Disease Activity Index (RPDAI). METHODS Twenty-seven RP experts participated in an international collaboration. Selection and definition of items for disease activity were established by consensus during a 4-round internet-based Delphi survey. Twenty-six experts assessed the Physicians Global Assessment (PGA) of disease activity on 43 test cases on a 0-100 scale, yielding a total of 1118 PGA ratings. The weight of each item was estimated by multivariate regression models with generalized estimating equation, using PGA as the dependent variable. RESULTS Experts decided in consensus that the RPDAI should consider the 28-day period before each RPDAI assessment. Inter-rater reliability assessed by the intra-class correlation coefficient for the 1118 PGA ratings was 0.51 (CI95%: 0.41-0.64). The final RPDAI score comprised 27 items with individual weights ranging from 1 to 24 and a maximum theoretical RPDAI score of 265. Correlation between the RPDAI scores calculated based on the weights derived from the final multivariate model, and the 1118 PGA ratings was good (r=0.56, p<0.0001). CONCLUSION We have developed the first consensus scoring system to measure disease activity in relapsing polychondritis (see www.RPDAI.org for online scoring). This tool will be valuable for improving the care of patients with this rare disease.

Giant Cell Arteritis and Spinal Cord Compression: An Overlap Syndrome?

We describe 2 patients with spinal cord compression that occurred in the course of biopsy-proven giant cell arteritis (GCA). One case was due to an epidural tumorlike inflammatory lesion, the other to a concentric inflammatory thickening of the meninges. Both patients were highly corticodependent; they had low-titer anti-neutrophil cytoplasmic antibodies but no antimyeloperoxidase or antiproteinase 3 autoantibodies. The diagnosis was established by surgical biopsy. The histological pattern was reminiscent of Wegener granulomatosis. Both patients experienced relapse, despite high doses of corticosteroids, and experienced remission after the introduction of cyclophosphamide. Intravenous immunoglobulin perfusions were added for 1 patient. To our knowledge, spinal cord compression by a spinal pseudotumor or inflammatory meningitis has not been reported in the course of GCA. An overlap syndrome between GCA and Wegener granulomatosis is discussed.

Blood Concentrations of Hydroxychloroquine and Its Desethyl Derivative Correlate Negatively with the Percentage of CD45RO+ Cells among CD4+ Lymphocytes in Hydroxychloroquine-Treated Lupus Patients

Abstract:  The objective of the study was to investigate the influence of the blood concentrations of hydroxychloroquine ([HCQ]) and its derivative desethylhydroxychloroquine ([DHCQ]) on lymphocyte activation or differentiation in HCQ‐treated lupus patients. We studied the correlations between [HCQ], [DHCQ], and the frequency of various lymphocyte subsets in 58 HCQ‐treated lupus patients (mean HCQ dose: 4.93 ± 1.58 mg/kg/day; mean duration of the disease: 122 ± 64 months). [HCQ] and [DHCQ] were determined by high‐performance liquid chromatography (HPLC). Lymphocyte markers were studied by flow cytometry using monoclonal anti‐CD3, ‐CD4, ‐CD8, ‐CD25, ‐DR, ‐CD45RA,‐CD45RO, ‐CD19, ‐CD38, and ‐CD86 antibodies. sIL2‐R serum concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). [HCQ] and [DHCQ] were 599.9 ng/mL (median: 529.5; range: 55–1935) and 353.43 (median: 286 ng/mL; range: 118–1090). In a multiple regression analysis, [HCQ] and [DHCQ] were associated with the HCQ prescribed dose in mg/kg/day (P= 0.0002 and P= 0.03) and with compliance to the treatment (P= 0.004 and P= 0.03). We found a negative correlation between [HCQ], [DHCQ], and the CD45RO+ cell frequency among CD3+CD4+ cells (P= 0.03 and P= 0.007, respectively). Other lymphocyte subset markers (LSMs) and sIL2‐R concentrations were not significantly associated with [HCQ] or [DHCQ]. In the multiple regression analysis, CD45RO+ expression was negatively influenced by [HCQ] (P= 0.005), and positively influenced by smoking habits (P= 0.005) and age (P= 0.005). Similar results were found in the multivariate model including [DHCQ]. Disease activity and taking more than 10 mg/day of corticosteroids or an immunosuppressive drug did not influence CD45RO+ expression. Lupus patients had less CD3+CD4+CD45RO+ cells than controls (P= 0.03). In lupus patients, HCQ and DHCQ may alter the generation or the blood circulation of CD4+CD45RO+ lymphocytes in a concentration‐dependent pattern.

Fréquence et déterminants de l'insuffisance surrénalienne biologique dépistée par le test au Synacthène® à 250 μg lors du sevrage d'une corticothérapie prolongée. Étude chez 100 patients

PURPOSE The frequency of adrenal insufficiency after a prolonged, continuous course of oral high-dose corticosteroids is poorly documented. We evaluated it retrospectively in our internal medicine department. METHODS The patients were included between February 2000 and June 2007 and were administered a Synacthene 250 microg test (ST250) before tapering prednisone dose below 5mg per day. A non-responsive test was defined by a cortisol increase below 18 microg/dL, 60 min after stimulation. We also studied the risk factors associated with biological adrenal insufficiency by a multivariate logistic regression analysis. RESULTS Hundred patients were included (mean age: 61.5+/-16.3 years). Mean initial dose of corticosteroids was 65.5+/-112 mg/d. Forty-five patients failed to respond to the ST250. A normal ST250 was negatively associated with a duration of corticosteroids therapy longer than 19.5 months (OR=0.38 [0.15-0.94]; p=0.04) and positively with an age over 63.5 years (OR=2.5 [1.1-6.4]; p=0.05). Two patients experienced a clinical adrenal insufficiency crisis. CONCLUSION Biological adrenal insufficiency is very common after a prolonged course of oral high-dose corticosteroids. The risk does not seem to increase with age. The clinical benefit of a systematic ST250 at the time of corticosteroids withdrawal followed by hydrocortisone substitution if the test is non responsive remains unknown, and this practice is still a matter of debate.Purpose The frequency of adrenal insufficiency after a prolonged, continuous course of oral high-dose corticosteroids is poorly documented. We evaluated it retrospectively in our internal medicine department.

Which Adverse Events Are Related to Health Care during Hospitalization in Elderly Inpatients

Background: Adverse events result in longer hospital stays and increase costs and mortality. We aimed to assess incidence of adverse events occurring during hospitalization in a post-emergency unit and to describe their characteristics. Methods: All adverse events occurring in patients during their hospitalization in a post-emergency unit in a French university hospital (20 beds) were systematically and consecutively recorded from September 2009 to February 2011. Patients with adverse events were compared to up to three control patients, matched for date of admission +/- age in the same unit. Results: We identified 56 patients with 64 adverse events, giving an incidence of 3.0/100 patients admitted/year. Fifty-one adverse events were drug-related. Patients had a median age of 82.5 years with a male/female ratio of 1/1.4. They presented a median Charlson score of 1 and the median number of medications was 6. The drugs most frequently involved in drug-related events were nervous system drugs (47%) and anti-infectives (22%). In multivariate analysis, a Charlson score ≥ 2 was associated with the occurrence of adverse events (OR 0.4; 95% CI [0.21 - 0.80]). Conclusions: Systematic recording showed that adverse events were not rare in a post-emergency unit. Patients with comorbid conditions were less likely to present an adverse event, possibly because of greater precautions taken by the medical team.

Abatacept in relapsing polychondritis

Dear Editor, We read with great interest the open clinical trial of four relapsing polychondritis (RP) patients treated with abatacept by Peng and Rodriguez recently published in the Annals of the Rheumatic Diseases .1 Indeed, as the authors pointed out, there is rational to block T-cell pathway in this disease, though the biologic agents most used as second-line therapy after corticosteroids (CS) are proinflammatory cytokines blockers as tumor necrosis factor (TNF) inhibitors or tocilizumab.2 Of note, rituximab seems not efficient in this disease.3 Despite this rational, the study by Peng and Rodriguez is the first report of abatacept use in RP since we reported a first case in 2010.4 Results from this nice small clinical trial using abatacept subcutaneously at the dose of 125 mg weekly are mitigated: three patients experienced a considerable improvement on ear, nose and throat (ENT) …

Rituximab off-label use for immune diseases: assessing adverse events in a single-centre drug-utilization survey

Rituximab is an anti-CD20 autoantibody approved for rheumatoid arthritis. It induces deep and prolonged depletion of CD20-bearing lymphocytes. Rituximab is increasingly used off-label for autoimmune diseases (AIDs) in immunocompromised patients (ICP), whereas its safety is not well documented in this setting. We assessed off-label rituximab use in AIDs through a drug-utilization survey in Toulouse University Hospital (2834 beds) from January 2004 to December 2005. Patients who had received at least one rituximab infusion for AIDs were identified from the pharmacy department database. We used the World Health Organization definition for serious adverse events (SAEs) [1]. Patients taking >20 mg day−1 prednisone and/or an immunosuppressive drug at the time of first rituximab infusion were considered immunocompromised. All patients were followed 1 year after the first rituximab infusion. Thirty-seven patients (18 women), mean age 51.7 years (95% confidence interval ±17.6) were included in the study. Median disease duration was 87 months (range 1–396). Diagnostic groups were: autoimmune cytopenia (n = 19), autoimmune coagulation disorder (n = 5), cryoglobulinaemia (n = 7), Wegeners granulomatosis (n = 3), pemphigus (n = 2) and lupus erythematosus (n = 1). The mean daily corticosteroid dosage at the time of rituximab first infusion was 35.2 mg day−1 (median 30; range 0–60). There was 30 ICPs (81.1 ± 12.6%); 75.7% (±13.8) of the patients received a complete cycle of four 375 mg kg−1 day−1 infusions. Eight then had maintenance therapy. We estimated that the complete remission rate after rituximab was 20/37 (54 ± 16.1%) according to criteria used in major international publications. One patient had a partial response. Rituximab was the main contributor to complete remission in 14 patients (37.8 ± 15.6) who had no intensification of other therapies. Among 20 complete responders, three were treated again because of relapse between 12 and 13 months after the first infusion. SAEs occurred in 14/37 patients (37.8 ± 15.6%) (Table 1), including death in six with uncontrolled disease. Seven (18.9 ± 12.6%) had serious infections, of whom two had pneumocystosis. Six of these seven patients were immunocompromised and another had undergone splenectomy 3 months earlier. The estimated incidence rate of infectious SAEs was 20.7 (±14.5) per 100 patient-years in ICPs. Table 1 Serious adverse events (SAE) among 37 patients treated by Rituximab for AIDs To our knowledge, this is the first report of a systematic hospital-based safety survey of rituximab off-label utilization for AIDs. Incidence of SAE, especially infectious, was much higher than in another study including adult patients with various AIDs [2]. In this retrospective study, 1/3 of patients had rheumatoid arthritis, some had a short follow-up, and patients were included on a voluntary basis by their attending physician. We cannot exactly determine the contribution of rituximab to infectious SAEs, as SAEs occur in about 13.5 per 100 years in patients receiving chronic immunosuppressive therapy for various AIDs [3]. Given a large confidence interval, this may not be very different from the 20.7 (±14.5) per 100 years infection rate we have found. However, hypogammaglobulinaemia occurring in some patients [4], loss of IgM-only producing memory B cells that are crucial for defence against bacteria [5], alteration of antigen-presenting cell function due to B-cell depletion [6] and the possibility of delayed neutropenia [7] may worsen susceptibility to infection in previously immunocompromised patients exposed to rituximab. In conclusion, in this study SAEs were frequent among patients treated off-label by rituximab for AIDs. The infection rate was perhaps abnormally high. Benefit-to-risk ratio of rituximab off-label use for immune diseases in real life should be further systematically assessed.

Cryofibrinogénémie : étude monocentrique au CHU de Toulouse

PURPOSE Cryofibrinogenemia is an unknown disorder and studies dedicated to it are limited. The aim of our study was to report on the incidence, clinical manifestations and associated diseases in patients with isolated cryofibrinogenemia. METHODS This is a retrospective single-center study. Patients included in this study had a positive and isolated detection of cryofibrinogen between January 1st, 2011 and December 31st, 2012. Identification was possible through the database of the laboratory of immunology. RESULTS Two hundred and eighty-one consecutive orders of cryofibrinogenemia were identified. Seventy-three patients had a positive detection of cryofibrinogenemia. Among them, 12 had an isolated cryofibrinogenemia and sixty-one patients (84%) had concomitant cryofibrinogenemia and cryoglobulinemia. The mean age was 59±19years. Seven patients were female (58%). Cutaneous manifestations were present in half case. Peripheral nerve involvement was present in 5 cases (42%) and rheumatic manifestations in 4 patients (33%). A thrombotic event was reported in 7 patients (58%). Renal impairment was present in 7 patients. The median cryofibrinogen concentration was 254±304mg/L. Five patients had a secondary cryofibrinogenemia. The most often prescribed treatment was corticosteroids. CONCLUSION Cryofibrinogenemia is an unknown disorder. Testing for cryoglobulinemia is more frequent than for cryofibrinogenemia whereas clinical manifestations are similar. Detection of cryofibrinogen is positive in most of the cases, with an important prevalence of thrombotic events in this population. This study confirms the importance of conducting prospective studies on cryofibrinogenemia.