Xavier Puéchal

Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists.

Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohns disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-γ-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.

Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial

Objectives To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA). Methods Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40u2005mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7u2005mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1u2005mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT). Results Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia). Conclusions In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1u2005mg/kg of corticosteroids at 6u2005months. Clinical trial registration number NCT00305539.

Comparison of in vitro-specific blood tests with tuberculin skin test for diagnosis of latent tuberculosis before anti-TNF therapy

Introduction: Latent tuberculosis infection (LTBI) is detected with the tuberculin skin test (TST) before anti-TNF therapy. We aimed to investigate in vitro blood assays with TB-specific antigens (CFP-10, ESAT-6), in immune-mediated inflammatory diseases (IMID) for LTBI screening. Patients and methods: Sixty-eight IMID patients with (nu200a=u200a35) or without (nu200a=u200a33) LTBI according to clinico-radiographic findings or TST results (10 mm cutoff value) underwent cell proliferation assessed by thymidine incorporation and PKH-26 dilution assays, and IFNγ-release enzyme-linked immunosorbent spot (ELISPOT) assays with TB-specific antigens. Results: In vitro blood assays gave higher positive results in patients with LTBI than without (p<0.05), with some variations between tests. Among the 13 patients with LTBI diagnosed independently of TST results, 5 had a negative TST (38.5%) and only 2 a negative blood assays result (15.4%). The 5 LTBI patients with negative TST results all had positive blood assays results. Ten patients without LTBI but with intermediate TST results (6–10 mm) had no different result than patients with TST result ⩽5 mm (p>0.3) and lower results than those with LTBI (p<0.05) on CFP-10+ESAT-6 ELISPOT and CFP-10 proliferation assays. Conclusion: Anti-TB blood assays are beneficial for LTBI diagnosis in IMID. Compared with TST, they show a better sensitivity, as seen by positive results in 5 patients with certain LTBI and negative TST, and better specificity, as seen by negative results in most patients with intermediate TST as the only criteria of LTBI. In the absence of clinico-radiographic findings for LTBI, blood assays could replace TST for antibiotherapy decision before anti-TNF.

Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) enrolled in two prospective trials

The purpose of this study was to assess the outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in 2 prospective, randomized, open-label clinical trials (1994-2005), with or without Five-Factor Score (FFS)-defined poor-prognosis factors, focusing on survival, disease-free survival, relapses, clinical and laboratory findings, therapeutic responses, and factors predictive of relapse. Forty-four patients with FFS ≥ 1 were assigned to receive 6 or 12 cyclophosphamide pulses plus corticosteroids and the seventy-four with FFSxa0=xa00 received corticosteroids alone, with immunosuppressant adjunction when corticosteroids failed. Patients were followed (2005-2011) under routine clinical care in an extended study and data were recorded prospectively. Meanxa0±xa0SD follow-up was 81.3xa0±xa039.6 months. Among the 118 patients studied, 29% achieved long-term remission and 10% died. Among the 115 patients achieving a first remission, 41% experienced ≥1 relapses, 26.1xa0±xa026.8 months after treatment onset, with 57% of relapses occurring when corticosteroid-tapering reached <10xa0mg/day. Treatment achieved new remissions in >90%, but relapses recurred in 38%. Overall survival was good, reaching 90% at 7 years, regardless of baseline severity. Age ≥65 years was the only factor associated withxa0a higher risk of death during follow-up. The risk of relapse was higher for patients with anti-myeloperoxidase antibodies and lower for those with >3000 eosinophils/mm(3). Sequelae remained frequent, usually chronic asthma and peripheral neuropathy. In conclusion, EGPA patients survival rate is very good when treatment is stratified according to the baseline FFS. Relapses are frequent, especially in patients with anti-myeloperoxidase antibodies and baseline eosinophilia <3000/mm(3).

Effects of corticosteroids and immunosuppressors on idiopathic inflammatory myopathy related myocarditis evaluated by magnetic resonance imaging

Background: Cardiac involvement in idiopathic inflammatory myopathy has been recognised as an important prognostic factor, but treatment remains empirical. Objective: To investigate the effects of corticosteroids and immunosuppressors on myocarditis in patients with inflammatory myopathies. Methods: Patients with inflammatory myositis of recent onset who had not received treatment were evaluated for associated myocarditis by magnetic resonance imaging (MRI) and reinvestigated after treatment with high dose corticosteroids and immunosuppressors. Results: Four patients with histologically proven myositis were included. Two patients with polymyositis had cardiac clinical symptoms. Two other patients with dermatomyositis and diffuse cutaneous systemic sclerosis-polymyositis overlap syndrome were asymptomatic. In three cases the usual conventional screening tests were normal. For all patients an area of contrast enhancement and hypokinesia detected by cardiac MRI was markedly reduced after treatment with corticosteroids and immunosuppressors for 6 months. Conclusion: Treatment with intravenous methylprednisolone followed by prednisone and immunosuppressive therapy seems to be effective for treating myocardial involvement in patients with idiopathic inflammatory myopathies, either alone or presenting as overlap syndromes. Cardiovascular MRI is a non-invasive technique that may be a powerful tool for diagnosis and monitoring of myocardial inflammation in this setting.

Efficacy of anakinra, an IL1 receptor antagonist, in refractory Sweet syndrome

Sweet syndrome (SS) is a neutrophilic dermatosis characterised by fever, neutrophilia, tender erythematous skin lesions and a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis.1 The scarcity of the disease does not allow evaluation of drug responses in randomised controlled trials. This report describes for the first time the dramatic efficacy of a treatment with the interleukin 1 (IL-1) receptor antagonist in a patient presenting with refractory SS.nnA 55-year-old woman had, since 1998, recurrent fever, pulmonary involvement (alveolar lung condensations), elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) without evidence of an infectious or inflammatory disease. Skin lesions of the right flank were occasionally …

Treatment of Systemic Necrotizing Vasculitides in Patients Aged Sixty‐Five Years or Older: Results of a Multicenter, Open‐Label, Randomized Controlled Trial of Corticosteroid and Cyclophosphamide–Based Induction Therapy

To investigate a new therapeutic strategy, with rapid corticosteroid dose tapering and limited cyclophosphamide (CYC) exposure, for older patients with systemic necrotizing vasculitides (SNVs; polyarteritis nodosa [PAN], granulomatosis with polyangiitis [Wegneners] [GPA], microscopic polyangiitis [MPA], or eosinophilic GPA [Churg‐Strauss] [EGPA]).

Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors

The purpose of this study was to assess the long-term outcomes of patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS)-defined poor-prognosis factors (FFS=0) and enrolled in a prospective clinical trial. Patients were followed (2005-2012) under routine clinical care in an extended study and data were recorded prospectively. Long-term survival, disease-free survival (DFS), relapses, therapeutic responses and sequelae were analyzed. Mean±SD follow-up was 98.2±41.9months. After having initially received glucocorticoids (GC) alone, according to the study protocol, 82% (97/118) patients achieved remission but 18% (21/118) required ≥1 immunosuppressant(s) (IS) before 19/21 achieved remission. Two patients died before entering remission. After remission, 53% (61/116) patients relapsed 25.6±27.9months after starting treatment. The 5- and 8-year overall survival rates were 93% and 86%, respectively, with no difference between PAN and MPA, and between relapsers and nonrelapsers. DFS was shorter for MPA than PAN patients (P=0.02). Throughout follow-up, 47% of patients required ≥1 IS. At the last follow-up visit, 44% were still taking GC and 15% IS. The mean vasculitis damage index score was 1.9±1.9; the most frequent sequelae were peripheral neuropathy, hypertension and osteoporosis. For PAN or MPA patients without poor-prognosis factors at diagnosis and treated initially with GC alone, long-term survival was excellent. However, relapses remained frequent, requiring IS introduction for nearly half of the patients. To lower the frequencies of relapses and sequelae remains a challenge for FFS=0 PAN and MPA patients.

Whipple's disease

Whipples disease is a chronic, systemic infection caused by Tropheryma whipplei. Gene amplification, isolation and DNA sequencing of T whipplei have extended our knowledge of this pathogen, which is now recognised as a ubiquitous commensal bacterium. The spectrum of signs associated with T whipplei has now been extended beyond the classic form, which affects middle-aged men, and begins with recurrent arthritis followed several years later by digestive problems associated with other diverse clinical signs. Children may present an acute primary infection, but only a small number of people with a genetic predisposition subsequently develop authentic Whipples disease. This bacterium may also cause localised chronic infections with no intestinal symptoms: endocarditis, central nervous system involvement, arthritis, uveitis and spondylodiscitis. An impaired TH1 immune response is seen. T whipplei replication in vitro is dependent on interleukin 16 and is accompanied by the apoptosis of host cells, facilitating dissemination of the bacterium. In patients with arthritis, PCR with samples of joint fluid, saliva and stools has become the preferred examination for diagnosis. Immunohistochemical staining is also widely used for diagnosis. Treatment is based on recent microbiological data, but an immune reconstitution syndrome and recurrence remain possible. The future development of serological tests for diagnosis and the generalisation of antigen detection by immunohistochemistry should make it possible to obtain a diagnosis earlier and thus to decrease the morbidity, and perhaps also the mortality, associated with this curable disease which may, nonetheless, be fatal if diagnosed late or in an extensive systemic form.

European League Against Rheumatism Sjögren's Syndrome Disease Activity Index and European League Against Rheumatism Sjögren's Syndrome Patient‐Reported Index: A Complete Picture of Primary Sjögren's Syndrome Patients

The European League Against Rheumatism (EULAR) Sjögrens Syndrome (SS) Disease Activity Index (ESSDAI) and the EULAR SS Patient‐Reported Index (ESSPRI) were recently developed. We aimed to determine whether patients symptoms differed between patients with and without systemic involvement and if the disease‐specific indices correlated with each other in primary SS.