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Aging tendons or chronic tendinopathy are frequent conditions responsible for handicap in middle-aged and aging populations. Current therapies fail to relieve handicap. Medical treatment can sometimes be efficient, but surgical procedures often fail to restore tendon function. Cell therapy with platelets, based on tendon histological modifications and the capacity of such tissue to respond to growth factors, is an ever-expanding field of clinical research. In the current review, we compare the histological properties of normal tendons, aging tendons and chronic tendinopathy. We explain the natural healing process of such tendons and the rationale for using, or not, autologous growth factors. We review current clinical studies exploring the effect of concentrated autologous growth factor injection in chronic lesions and attempt to explain why, to date, all clinical studies have demonstrated no effect of such therapies.

Objective: Anakinra is effective in adult-onset Still's disease (AOSD) in the short term, but little is known regarding its efficacy over the long term. Our objective was to assess the long-term efficacy and safety of anakinra in AOSD., Methods: A nationwide survey was conducted between 2009 and 2010 to identify AOSD patients treated with anakinra. Collected data consisted of disease characteristics at diagnosis and at medication onset; anakinra efficacy, safety, and dose adaptation; and reasons for discontinuation, if applicable., Results: The study included 28 AOSD patients, with a mean age of 40.3 years and a mean disease duration at the start of anakinra of 9.3 years. All patients had previously failed to respond to steroids and disease-modifying antirheumatic drugs. All patients responded to anakinra, with a rapid and sustained decrease in steroid doses. At the last followup (mean 23 months), 16 patients were still being treated with anakinra: 4 had a partial response and 12 were in complete remission. Twelve patients had discontinued anakinra: 2 due to an insufficient response, 4 due to an AOSD flare after a period of complete remission, 2 due to side effects, and 1 due to a desire for pregnancy. In 3 patients, the drug discontinuation was possible because they achieved complete remission. Six additional patients experienced anakinra dose tapering, with sustained remission in 2 and relapse in the others. Anakinra was well tolerated and adverse events were rated as mild., Conclusion: Anakinra was consistently efficacious in AOSD and displayed good therapeutic maintenance. Anakinra dose tapering or discontinuation was associated with relapse in half of the patients., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Clinical joint examination (CJE) is less time-consuming than ultrasound (US) in rheumatoid arthritis (RA). Low concordance between CJE and US would indicate that the 2 tests provide different types of information. Knowledge of factors associated with CJE/US concordance would help to select patients and joints for US. Our objective was to identify factors associated with CJE/US concordance., Methods: Seventy-six patients with RA requiring tumor necrosis factor-α (TNF-α) antagonist therapy were included in a prospective, multicenter cohort. In each patient, 38 joints were evaluated. Synovitis was scored using CJE, B-mode US (B-US), and power Doppler US (PDUS). Joints whose kappa coefficient (κ) for agreement CJE/US was < 0.1 were considered discordant. Multivariate analysis was performed to identify factors independently associated with CJE/US concordance, defined as factors yielding p < 0.05 and OR > 2., Results: Concordance before TNF-α antagonist therapy varied across joints for CJE/US (κ = -0.08 to 0.51) and B-US/PDUS (κ = 0.30 to 0.67). CJE/US concordance was low at the metatarsophalangeal joints and shoulders (κ < 0.1). Before TNF-α antagonist therapy, a low 28-joint Disease Activity Score (DAS28) was associated with good CJE/B-US concordance, and no factors were associated with CJE/PDUS concordance. After TNF-α antagonist therapy, only the joint site was associated with CJE/B-US concordance; joint site and short disease duration were associated with CJE/PDUS concordance., Conclusion: Concordance between CJE and US is poor overall. US adds information to CJE, most notably at the metatarsophalangeal joints and shoulders. Usefulness is decreased for B-US when DAS28 is low and for PDUS when disease duration is short.

Introduction: Adipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA., Methods: In total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥ 5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion)., Results: Adiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively)., Conclusion: Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status.

Purpose: IL-8 and its murine equivalent keratinocyte chemoattractant (Kc), chemokines produced by chondrocytes, contribute to the pathophysiology of osteoarthritis. However, the mechanisms leading to their production are poorly known. We aimed to investigate whether mechanical (compression), inflammatory (IL-1β) and metabolic (visfatin) stresses may induce the release of Kc when applied on murine cartilage., Methods: Mouse cartilage explants were subjected to intermittent compression for 4, 6 and 24h. Primary cultures of immature murine articular chondrocytes were obtained by enzymatic digestion of articular cartilage from 6-days-old newborns mice. The effect of compression, IL-1β (10, 50, 100pg/mL) and of visfatin (5μg/mL) on the release of Kc was assessed by ELISA. IL-8 levels in conditioned media from human OA joint tissues (cartilage or synovium) were also assessed., Results: In comparison with non-compressed explants, loading increased Kc release of 3.2-, 1.9- and 2.0-fold at 4, 6 and 24h respectively (P<0.004, n=9). IL-1β triggered an increase of Kc release by primary cultured chondrocytes of 4.1-, 15.5- and 35.2-fold at 10, 50 and 100pg/mL of IL-1β respectively (P<0.05, n=4). Likewise, visfatin (5μg/mL) induced an increase in Kc release of 56.5±25.2 fold (P=0.002, n=6). IL-8 was released in conditioned media by synovium as well as by cartilage., Conclusion: We show for the first time that IL-8/Kc is highly responsive to mechanical, inflammatory and metabolic stresses, strengthening the hypothesis that IL-8/Kc could be added to the cytokines which may have a deleterious impact in osteoarthritis., (Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Obesity is one of the risk factors for hip or knee osteoarthritis (OA), since mechanical overload on weight-bearing joints activates chondrocytes and accelerates cartilage degeneration. Surprisingly, obesity and overweight also contribute to hand OA due to a systemic effect involving the pro-inflammatory and -degenerative role of some adipokines, secreted by adipose tissue, as well as some joint cells. Obesity-induced OA is now included in a larger phenotype termed "metabolic GA", since OA is associated with various parameters of the metabolic Ssyndrome (including type-2 diabetes) and excess cardiovascular mortality related to this disease. Early-onset OA should lead to suspect a potential metabolic syndrome. Weight loss strategies remain a valuable therapeutic approach to prevent OA and reduce its symptoms, and must be associated with physical activity to allow for optimal outcomes.

Introduction: The aim of this study was to evaluate, under real-life conditions, the safety and efficacy of tocilizumab in patients having failed anti-TNFα therapy for spondyloarthritis., Methods: French rheumatologists and internal-medicine practitioners registered on the Club Rhumatismes et Inflammations website were asked to report on patients given tocilizumab (4 or 8 mg/kg) to treat active disease meeting Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis, after anti-TNFα treatment failure. Safety and efficacy after 3 and 6 months were assessed retrospectively using standardised questionnaires., Results: Data were obtained for 21 patients, 13 with axial spondyloarthritis (46% men; median age, 42 years; disease duration, 11 years; HLA-B27-positive, 92.3%) and eight with peripheral spondyloarthritis (25% men; median age, 40 years; disease duration, 10 years; HLA-B27-positive, 62.5%). No patients with axial disease had at least a 20 mm decrease in the BASDAI, nor a BASDAI50 response or major ASAS-endorsed disease activity score improvements after 3 or 6 months; an ASAS-endorsed disease activity score clinically important improvement was noted at month 3 in five of 13 patients and at month 6 in one of four patients. A good DAS28 response was achieved in four patients with peripheral disease, including one in EULAR remission at month 3. Four patients were still taking tocilizumab at month 6, including one in EULAR remission and one with a good DAS28 response. Tocilizumab was well tolerated, with no serious adverse events. Initially elevated acute-phase reactants declined during tocilizumab therapy., Conclusion: In patients having failed anti-TNFα therapy, tocilizumab decreased acute-phase reactants but failed to substantially improve axial spondyloarthritis and was inconsistently effective in peripheral spondyloarthritis.

Objectives: To assess the effect of biotherapies vs placebo on fatigue in two situations: inadequate response to conventional treatments (IR-DMARD) and inadequate response to anti-TNF (IR-anti-TNF) in RA., Methods: A systematic review of the literature and meta-analysis were performed. We included randomized controlled trials (RCTs) assessing the effect of biotherapies vs placebo on fatigue, in combination with DMARDs. Fatigue was measured using the functional assessment of chronic illness therapy-fatigue (FACIT-F) or short-form 36 (SF-36) vitality scores at baseline and at Week 24. The results were in effect size (ES) for each biotherapy (or class of biotherapy) vs placebo. An ES of <0.5 was considered as small, between 0.5 and 0.8 as moderate and >0.8 as important., Results: From the 763 published studies, 10 RCTs were included in the analysis: seven involved IR-DMARD RA and three IR-anti-TNF. Among the 3837 included patients with established RA, 1227 patients were treated with an anti-TNF, 420 with rituximab, 258 with abatacept, 205 with tocilizumab and 1727 received placebo. The overall ESs of all biotherapies vs placebo on fatigue were small (ES = 0.45; 95% CI 0.31, 0.58) as well as for anti-TNFs (ES = 0.36; 95% CI 0.21, 0.51). The ESs were small in IR-DMARD RA (ES = 0.38; 95% CI 0.30, 0.46), similar between anti-TNF and non-anti-TNF agents and moderate in IR-anti-TNF RA (ES = 0.57; 95% CI 0.27, 0.86)., Conclusion: Few studies reported the impact of biotherapies on fatigue. The effect of biotherapies on fatigue in RA is small.

Objective: To examine blood B cell subsets in patients with rheumatoid arthritis (RA) prior to B cell depletion therapy and to assess their potential as predictors of clinical response to rituximab (RTX)., Methods: Blood B cell subsets were assessed by flow cytometry in 208 RA patients included in an RTX retreatment study (assessed prior to RTX treatment) and in 47 age-matched controls. Expression of BAFF receptor (BAFF-R) on B cells and serum B cell biomarkers was also measured. B cell subsets and BAFF-R expression were compared between RA patient and control populations. Univariate and multivariate analyses were performed to identify baseline factors associated with a European League Against Rheumatism response 24 weeks after 1 cycle of RTX., Results: Mean ± SD counts of both CD27- naive and CD27+ memory B cells were decreased in RA patients (188.6 ± 121.4/mm(3)) compared with controls (257.3 ± 154.1/mm(3)) (P = 0.001) and were partially restored in patients treated with methotrexate (MTX) plus anti-tumor necrosis factor compared with patients treated with MTX alone. Within the CD27+ memory B cells, the CD27+IgD- switched memory subtype was selectively decreased, irrespective of treatment. The frequency of CD27+ memory B cells correlated inversely with levels of several B cell activation biomarkers in RA. Serum BAFF level and BAFF-R expression was comparable in RA patients and controls. A low baseline CD27+ memory B cell frequency was associated with a greater clinical response to RTX (odds ratio 0.97 [95% confidence interval 0.95-0.99], P = 0.0015)., Conclusion: In B cell depletion therapy-naive RA patients, a low frequency of CD27+ memory B cells correlated with levels of serum B cell activation biomarkers and may predict response to RTX. These results suggest that low memory B cell frequency may be indicative of a B cell-driven RA subtype that is more sensitive to B cell depletion therapy., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Sjögren's syndrome (SS)-related peripheral neuropathy is responsible for disability, but no treatment has been shown to improve its outcome. In some cases, intravenous immunoglobulin (IVIG) therapy has been associated with some benefit. In this study, we investigated the effectiveness of IVIG in SS-related peripheral neuropathy., Methods: We assessed the efficacy and tolerance of IVIG in 19 patients with primary SS-related neuropathy without any necrotizing vasculitis in a retrospective national multicentric study. The evaluation of the response was assessed using the disability Modified Rankin Scale (MRS) and a global evaluation by the practitioner., Results: Eight patients (42%) exhibited a decrease of the MRS score corresponding to a clinical improvement, 10 patients (52%) exhibited a stable MRS score, and 1 patient (6%) showed an increase of MRS score. According to the global evaluation by the practitioner, 9 (47%) of the 19 patients were improved, 6 patients (31%) were stable, and 4 patients (21%) worsened. All the patients with sensorimotor (n = 5) or nonataxic sensory neuropathy (n = 4) were improved or stabilized. However, among the patients with ataxic neuropathy (n = 9), only 2 improved and 4 worsened. Ten of the 13 patients treated with corticosteroids could have had the prednisone dosage decreased from 15 mg/day (range 7.5-60) to 10 mg/day (range 5-20) with IVIG. Only 1 patient stopped the treatment after 1 dose because of a minor side effect and lack of initial efficacy., Conclusion: IVIG may be useful in the treatment of SS-associated sensorimotor neuropathies or nonataxic sensory neuropathy without any necrotizing vasculitis. The benefit of such therapy in the SS-related ataxic neuropathy seems less clear., (Copyright © 2011 by the American College of Rheumatology.)

Background: Crusted Norwegian scabies is an extremely rare hyperkeratotic variant of scabies infestation. We report herein a case of crusted scabies in a woman with severe rheumatoid arthritis (RA) treated by tocilizumab (TCZ), a monoclonal antibody blocking the interleukin-6 receptor., Observation: An 80-year-old female with severe RA developed erythroderma followed by hyperkeratosis, widespread scaling over the trunk, arms, hands and limbs, and crusted lesions on her scalp. She was on TCZ (8 mg/kg per month) with prednisone (20 mg/d). Several hypotheses were evoked (i.e., vasculitis, psoriasis or paraneoplasic syndrome) but a microscopic examination of the skin surprisingly demonstrated numerous scabies mites and eggs leading to the diagnosis of crusted (Norwegian) scabies. After repeated use of ivermectin and application of topical piperonyl butoxide cream, scabies disappeared. However, there had been outbreak of scabies among two individuals in the staff and two patients. TCZ was stopped after four infusions because of a severe infectious pneumonia and failure., Conclusion: Crusted scabies should be evoked in case of pruritus or erythroderma occurring under TCZ therapy and it may be explained by the interleukin-6 blockade., (Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: To examine whether serum B cell markers can predict response to rituximab, a B cell-depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA)., Methods: This rituximab re-treatment dose study (SMART [eSsai MAbthera sur la dose de Re-Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti-cyclic citrullinated peptide [anti-CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks., Results: There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti-CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6-7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02-4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2-16.2])., Conclusion: The presence of RF or anti-CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA., (Copyright © 2011 by the American College of Rheumatology.)

Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well. The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis. Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E(2) and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown. Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle. As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression.

Osteoarthritis is a whole joint disease including: cartilage, synovial tissue, subchondral bone, ligaments, muscles, and tendons. Cartilage is the main target tissue of the disease. Mechanical stress is a key regulator in osteoarthritis development and progression. Inflammation is a key regulator in osteoarthritis development and progression. The weight of genetic factors, mechanical stress, inflammation, and hormonal status is variable from a joint to another., (Copyright © 2010. Published by Elsevier Masson SAS.)

Angiosarcoma is a rare neoplasm comprising 1 to 2% of soft tissue sarcoma. This tumor has been associated with previous irradiation, exposure to toxins and the presence of foreign bodies. A case report of an epithelioid angiosarcoma that developed at the site of an arterial femoro-popliteal bypass using autologous vein is described. The initial presentation looked like a painful popliteal cyst. Chronic fibrosis secondary to the thrombosis could play a role in the tumorogenesis of this uncommon tumor. This case illustrates that sarcoma may be a late complication of vascular bypass and may have a rheumatologic presentation., (Copyright 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objectives: To evaluate different global ultrasonographic (US) synovitis scoring systems as potential outcome measures of rheumatoid arthritis (RA) according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) filter., Methods: To study selected global scoring systems, for the clinical, B mode and power Doppler techniques, the following joints were evaluated: 28 joints (28-joint Disease Activity Score (DAS28)), 20 joints (metacarpophalangeals (MCPs) + metatarsophalangeals (MTPs)) and 38 joints (28 joints + MTPs) using either a binary (yes/no) or a 0-3 grade. The study was a prospective, 4-month duration follow-up of 76 patients with RA requiring anti-tumour necrosis factor (TNF) therapy (complete follow-up data: 66 patients). Intraobserver reliability was evaluated using the intraclass correlation coefficient (ICC), construct validity was evaluated using the Cronbach alpha test and external validity was evaluated using level of correlation between scoring system and C reactive protein (CRP). Sensitivity to change was evaluated using the standardised response mean. Discriminating capacity was evaluated using the standardised mean differences in patients considered by the doctor as significantly improved or not at the end of the study., Results: Different clinimetric properties of various US scoring systems were at least as good as the clinical scores with, for example, intraobserver reliability ranging from 0.61 to 0.97 versus from 0.53 to 0.82, construct validity ranging from 0.76 to 0.89 versus from 0.76 to 0.88, correlation with CRP ranging from 0.28 to 0.34 versus from 0.28 to 0.35 and sensitivity to change ranging from 0.60 to 1.21 versus from 0.96 to 1.36 for US versus clinical scoring systems, respectively., Conclusion: This study suggests that US evaluation of synovitis is an outcome measure at least as relevant as physical examination. Further studies are required in order to achieve optimal US scoring systems for monitoring patients with RA in clinical trials and in clinical practice.

Objectives: To evaluate the reproducibility of clinical synovitis assessments in rheumatoid arthritis and the effect of variability on the Disease Activity Score-28 (DAS28)., Methods: Seven healthcare professionals from different cities examined the same patients with active non-early rheumatoid arthritis (RA; duration > 4 yrs), for whom a treatment change was being considered. There was no training session and the examination was to be performed as quickly as possible. The healthcare professionals assessed the 28 joints of the DAS28 in 7 patients (196 joints), then reexamined the same 28 joints in 4 of these 7 patients (112 joints), who had been rendered unrecognizable. Then 7 sonographers examined each of the 7 patients twice, using B-mode and power Doppler ultrasound (PD). The reference standards were presence of synovitis according to at least 50% of clinical examiners and 50% of sonographers. Agreement was assessed by Cohen's kappa statistic., Results: Intraobserver reliability ranged from 0.31 (least experienced research technician) to 0.77 (most experienced physician). Interobserver reliability ranged from 0.18 to 0.62. The largest difference between the lowest and the highest swollen joint counts in the same patient was 15, and the greatest variation in the DAS28 score was 0.92. Agreement between clinical and sonographic reference standards was 0.46, 0.37, and 0.36 for B-mode, PD, and both, respectively., Conclusion: Clinical inter- and intraobserver reliability is highly dependent on the examiner. Consequences on the DAS28 score can be substantial. Agreement with sonography is poor when both B-mode and PD are used but seems better, although low, when B-mode is used alone.

Objective: To evaluate the intraobserver and interobserver reproducibility of B-mode and power Doppler (PD) sonography in patients with active long-standing rheumatoid arthritis (RA) comparatively with clinical data., Methods: In each of 7 patients being considered for a change in their RA treatment regimen, 7 healthcare professionals examined the 28 joints used in the Disease Activity Score 28-joint count (DAS28). Then 7 sonographers examined each of the 7 patients twice, using previously published B-mode and PD grading systems. The clinical reference standard was presence of synovitis according to at least 4/7 examiners. The sonographic reference standard was at least grade 1 (ALG1) or 2 (ALG2) synovitis according to at least 4/7 sonographers. Interobserver reproducibility of sonography was assessed versus the sonographer having the best intraobserver reproducibility. Agreement was measured by Cohen's kappa statistic., Results: Intraobserver and interobserver reproducibility of B-mode and PD used separately was fair to good. Agreement between clinicians and sonographers at all sites using B-mode, PD, and both was 0.46, 0.37, and 0.36, respectively, for grade 1 synovitis; and 0.58, 0.19, and 0.19 for grade 2 synovitis. The number of joints with synovitis was smaller by physical examination (36.7%) than by B-mode with ALG1 (58.6%; p < 0.001). The number of joints with synovitis was higher by physical examination than by PD with both ALG1 (17.8%; p < 0.0001) and ALG2 (6.6%; p < 0.0001)., Conclusion: PD findings explain most of the difference between clinical and sonographic joint assessments for synovitis in patients with long-standing RA.

Objective: To report on the long-term followup of a cohort of patients with hepatitis C virus (HCV)-related vasculitis treated with rituximab with or without PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin., Methods: The study group comprised 32 HCV RNA-positive patients with HCV-related vasculitis: 20 patients were treated with rituximab and PEG-IFN alfa-2b (9 of whom had not previously received antiviral treatment and 11 of whom had experienced disease resistance to or relapse with antiviral treatment), and 12 antiviral-intolerant patients were treated with rituximab alone., Results: Treatment with rituximab and PEG-IFN alfa-2b plus ribavirin induced a complete clinical response and a partial clinical response in 80% and 15% of patients, respectively, a complete immunologic response and a partial immunologic response in 67% and 33% of patients, respectively, and a sustained virologic response in 55% of patients. Treatment with rituximab alone induced a complete clinical response and a partial clinical response in 58% and 9% of patients, respectively, and a complete immunologic response and a partial immunologic response in 46% and 36% of patients, respectively. B cell depletion was achieved in 96% of patients, and B cell recovery began after a median delay of 12 months. After a mean+/-SD followup period of 23+/-12 months, 22% of patients experienced a clinical relapse, and 34% of patients experienced an immunologic relapse. All relapses were associated with the absence of virologic control, and 78% of relapses were associated with B cell recovery. Six patients were re-treated with rituximab. All 6 of these patients had a complete clinical response, 50% had a complete immunologic response, and 50% had a partial immunologic response. Rituximab was well tolerated overall., Conclusion: Rituximab is an effective treatment of severe and/or refractory HCV-related vasculitis. Relapses were consistently associated with the absence of virologic control. The clinical and immunologic efficacy of rituximab after repeated infusion appeared to be the same as that observed after induction therapy.

B-cell-activating factor (BAFF) plays a key role in promoting activation of autoimmune B cells. This cytokine may be expressed in and secreted by salivary gland epithelial cells (SGEC) after stimulation with type I IFN or viral or synthetic dsRNA. Because this BAFF expression depends only in part on endosomal TLR and type I IFN, we investigated whether other dsRNA sensors could be implicated in BAFF expression. Using human SGEC, we confirmed the partial dependence of BAFF expression on TLR-3 by replicating the partial inhibition of BAFF expression observed upon endosomal inhibition using TLR-3 or Toll/IL-1R domain-containing protein inducing IFN-beta silencing mRNA, but not with TLR-7 silencing mRNA. Melanoma differentiation-associated gene 5 silencing mRNA had no effect on BAFF expression, but retinoic acid-inducible gene I silencing mRNA had a slight effect observed following infection with dsRNA reovirus-1. Inhibition of RNA-activated protein kinase (PKR) by 2-aminopurine completely abolished both BAFF mRNA and protein production after reovirus-1 infection and poly(I:C) stimulation through NF-kappaB and p38 MAPK pathways, with the latter implicated only after poly(I:C) stimulation. Thus, PKR is the dsRNA sensor implicated in BAFF induction in SGEC after dsRNA stimulation. In autoimmune diseases, PKR may be an interesting target for preventing BAFF following the induction of innate immunity.

Introduction: Cell stimulation leads to the shedding of phosphatidylserine (PS)-rich microparticles (MPs). Because autoimmune diseases (AIDs) are characterized by cell activation, we investigated level of circulating MPs as a possible biomarker in primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)., Methods: We measured plasma levels of total, platelet and leukocyte MPs by prothrombinase capture assay and flow cytometry in 43 patients with pSS, 20 with SLE and 24 with RA and in 44 healthy controls (HCs). Secretory phospholipase A2 (sPLA2) activity was assessed by fluorometry. Soluble CD40 ligand (sCD40L) and soluble P-selectin (sCD62P), reflecting platelet activation, were measured by ELISA., Results: Patients with pSS showed increased plasma level of total MPs (mean +/- SEM 8.49 +/- 1.14 nM PS equivalent (Eq), P < 0.0001), as did patients with RA (7.23 +/- 1.05 n PS Eq, P = 0.004) and SLE (7.3 +/- 1.25 nM PS Eq, P = 0.0004), as compared with HCs (4.13 +/- 0.2 nM PS Eq). Patients with AIDs all showed increased level of platelet MPs (P < 0.0001), but only those with pSS showed increased level of leukocyte MPs (P < 0.0001). Results by capture assay and flow cytometry were correlated. In patients with high disease activity according to extra-glandular complications (pSS), DAS28 (RA) or SLEDAI (SLE) compared with low-activity patients, the MP level was only slightly increased in comparison with those having a low disease activity. Platelet MP level was inversely correlated with anti-DNA antibody level in SLE (r = -0.65; P = 0.003) and serum beta2 microglobulin level in pSS (r = -0.37; P < 0.03). The levels of total and platelet MPs were inversely correlated with sPLA2 activity (r = -0.37, P = 0.0007; r = -0.36, P = 0.002, respectively). sCD40L and sCD62P concentrations were significantly higher in pSS than in HC (P < or = 0.006)., Conclusions: Plasma MP level is elevated in pSS, as well as in SLE and RA, and could be used as a biomarker reflecting systemic cell activation. Level of leukocyte-derived MPs is increased in pSS only. The MP level is low in case of more severe AID, probably because of high secretory phospholipase A2 (sPLA2) activity, which leads to consumption of MPs. Increase of platelet-derived MPs, sCD40L and sCD62P, highlights platelet activation in pSS.

Introduction: There is a suspicion of increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferations in patients with inflammatory arthritides receiving immunosuppressive drugs. We investigated the EBV load and EBV-specific T-cell response in patients treated with methotrexate (MTX) or anti-TNF therapy., Methods: Data for patients with rheumatoid arthritis (RA) (n = 58) or spondylarthropathy (SpA) (n = 28) were analyzed at baseline in comparison with controls (n = 22) and after 3 months of MTX or anti-TNF therapy for EBV load and EBV-specific IFNgamma-producing T cells in response to EBV latent-cycle and lytic-cycle peptides., Results: The EBV load and the number of IFNgamma-producing T-cells after peptide stimulation were not significantly different between groups at baseline (P = 0.61 and P = 0.89, respectively). The EBV load was not significantly modified by treatment, for RA with MTX (P = 0.74) or anti-TNF therapy (P = 0.94) or for SpA with anti-TNF therapy (P = 1.00). The number of EBV-specific T cells was not significantly modified by treatment, for RA with MTX (P = 0.58) or anti-TNF drugs (P = 0.19) or for SpA with anti-TNF therapy (P = 0.39). For all patients, the EBV load and EBV-specific T cells were significantly correlated (P = 0.017; R = 0.21). For most patients, short-term exposure (3 months) to MTX or anti-TNF did not alter the EBV load or EBV-specific T-cell response but two patients had discordant evolution., Conclusions: These data are reassuring and suggest there is no short-term defect in EBV-immune surveillance in patients receiving MTX or anti-TNF drugs. However, in these patients, long term follow-up of EBV-specific T-cell response is necessary and the role of non-EBV-related mechanisms of lymphomagenesis is not excluded.

Objectives: Inhibitor of differentiation 3 (Id3)-deficient mice show sicca symptoms, lymphocyte infiltration of exocrine glands and positive anti-Ro/SSA and anti-La/SSB antibodies, all hallmarks of primary Sjögren's syndrome (pSS). The impairment of Id3 in T cells and, possibly, in salivary glandular epithelial cells (SGECs) seems to be involved. This animal model prompted us to investigate the role of Id3 in human pSS., Methods: Quantitative Id3 expression in peripheral T cells, cultured SGECs and in total minor salivary glands was assessed by RT-PCR in pSS patients and controls. After Id3 sequencing, we investigated two single nucleotide polymorphisms (SNPs) (c.313G>A and g.-156A>G) in a case-control study of 212 Caucasian pSS patients and 168 controls., Results: Quantitative Id3 expression was not decreased in pSS patients nor in SGECs, in T cells or in minor salivary glands. As well, patients and controls did not differ in allele and genotype frequencies of Id3 SNPs (P = 0.67 and P = 0.71 for the c.313G>A and the g.-156A>G, respectively). Neither SNP was associated with a pattern of autoantibody secretion., Conclusion: Although the Id3-deficient mouse model represents an attractive model for human pSS, Id3 expression is not impaired in SGECs, peripheral T cells and in labial salivary glands in pSS patients and Id3-relevant SNPs do not give evidence of genetic predisposition in Caucasian pSS patients.

B cell activating factor (BAFF) plays a key role in promoting B lymphocyte activation. We investigated whether danger signals induce BAFF secretion by cultured salivary gland epithelial cells (SGEC), which are the target of primary Sjögren's syndrome, a prototypic systemic autoimmune disease. SGEC cultures were established from minor salivary glands obtained from ten patients with pSS or sicca symptoms. BAFF mRNA and protein were measured after stimulation of the different Toll-like receptors (TLR) by agonists or viruses. The expression of TLR2, -3, and -7 was detected in SGEC. Poly (I:C) (a synthetic TLR3 agonist) and reovirus-1 (a dsRNA virus) induced high expression of BAFF mRNA (multiplied by a factor of 246 +/- 39 (SEM) and 347 +/- 66, respectively) and of BAFF protein secretion (58.49 +/- 4.34 pg/mL and 69.73 +/- 5.67). Inhibition of both the endosomal (by chloroquine) and IFN (by anti-IFNAR antibody) pathways partly inhibited BAFF expression. Treatment with both dsRNA virus and poly (I:C) induced high levels of BAFF mRNA and protein expression by SGEC, through pathways dependent on and independent of TLR and dependent on and independent of IFN. BAFF induction by target organs of autoimmune diseases after viral infection may be a link between innate immunity and autoimmunity.

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 (n = 35) or without (n = 33) 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 IFNgamma-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 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.

Objectives: Patients with primary systemic (AL) amyloidosis or multiple myeloma are frequently treated with cyclic dexamethasone (DXM) courses and often require oral anticoagulants. We previously reported a strong potentiation of oral anticoagulants with intravenous methylprednisolone and observed a similar potentiation with DXM in 3 patients, which led us to prospectively investigate the interaction between DXM and oral anticoagulants., Methods: Nine patients with multiple myeloma (n=6) or AL amyloidosis (n=3), including 6 prospective patients, taking fluindione (n=8) or warfarin (n=1), were studied for a total of 10 cycles. DXM (40 mg/day for 4 days every 28 days) was administered alone (n=4) or with melphalan (n=5). One patient was studied for 2 consecutive cycles after a moderate increase in the international normalized ratio (INR) during the first course of DXM. International normalized ratio (INR) was measured serially during DXM administration. Plasma oral anticoagulant concentrations were measured for 5 cycles., Results: The mean INR increased from 2.75 (range: 1.80-3.6) at baseline to 5.22 (3.09-7.07) after DXM. Oral anticoagulants were transiently stopped during 8 cycles and 1 mg oral vitamin K was given during 2. No serious bleeding was observed. Plasma oral anticoagulant concentrations increased after DXM administration. In controls receiving DXM without oral anticoagulants, DXM alone did not increase prothrombin time., Conclusion: High dose DXM can potentiate oral anticoagulants and elevate INR substantially. INR should therefore be monitored repeatedly during concomitant administration of these 2 drugs to allow individual adaptation of oral anticoagulant doses.

Psoriatic arthritis in HIV-positive patients is not only severe, but also raises specific treatment challenges, as immunosuppressant and immunomodulating agents may adversely affect both the course of the HIV infection and the risk of opportunistic infections. TNFalpha antagonists have not been evaluated in patients with HIV infection, which is therefore considered to contraindicate their use. Two HIV-positive patients with psoriatic arthritis unresponsive to methotrexate alone were treated with infliximab (5 and 2 mg/kg, respectively), methotrexate, and antiretroviral drugs. Dramatic improvements in the skin and joint manifestations occurred in both patients. Tolerance was good, after follow-ups of 24 and 50 months, respectively. No opportunistic infections occurred. Viral load remained well controlled and CD4+T-cell counts stable, although both patients required adjustments in their antiretroviral regimens based on close monitoring of these two parameters. HIV infection classically contraindicates the use of TNFalpha antagonists to treat refractory inflammatory joint disease. However, exceptions to this rule can be made in carefully selected patients who have exhausted all other treatment options for their joint disease and who respond well to antiretroviral therapy. Potential long-term effects such as opportunistic infections, malignancies, and loss of HIV control need to be evaluated.

Background: Data on essential mixed cryoglobulinemia (MC) are scarce, and most date back to studies before 1989 (ie, before the discovery of hepatitis C virus [HCV] infection). Our objective was to describe the spectrum of MC in the era of HCV infection., Methods: Retrospective study from a single university hospital's database of 1434 patients who tested positive for MC between January 1989 and December 2003., Results: One hundred thirty-three patients (9%) with persistent MC without HCV were included in the study. Sixty-five of 133 patients who fulfilled the criteria for MC vasculitis were compared with 118 patients with HCV-related MC vasculitis. The patients without HCV had increased frequencies of renal involvement and B-cell non-Hodgkin lymphoma (NHL), lower gammaglobulin levels, and higher death rates. Twenty-three of the patients had B-cell NHL (primarily of the lymphoplasmocytic and marginal zone types), and 8 patients had Sjögren syndrome. In multivariate analysis, a cryoglobulin level higher than 0.6 g/L (odds ratio [OR], 1.44) and the presence of MC vasculitis (OR, 4.3) and hypogammaglobulinemia (OR, 6.7) were independently associated with B-cell NHL. After a mean follow-up of 49.4 months, 18 (14%) of 133 patients had died, primarily of sepsis. In multivariate analysis, age at diagnosis older than 60 years (OR, 1.06) and renal involvement (OR, 5.20) were independently associated with death., Conclusion: Patients with non-HCV-related MC vasculitis have a poor outcome and have a 4-fold increased risk of developing B-cell NHL.

Background: Patients with rheumatoid arthritis (RA) frequently display an atherogenic lipid profile which has been linked with inflammation. Tumor necrosis factor-alpha (TNF-alpha), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. We investigated whether infliximab, an anti-TNF-alpha therapy, may modify the lipid profile., Methods: 56 consecutive RA patients were treated with infliximab (3 mg/kg at weeks 0, 2, 6, 14, 22, 30). Lipid profile and CRP were assayed at baseline and before infusion at weeks 6 and 30. Baseline values were compared with those in 56 healthy volunteers., Results: At baseline, the concentrations of HDL-cholesterol were lower in RA patients than in the controls (1.3+/-0.4 vs. 1.5+/-0.2 mmol/L; p<0.01). The triglyceride concentrations (1.6+/-0.8 vs. 1.3+/-0.4 mmol/L, p<0.01), the ratio of total cholesterol/HDL-cholesterol (4.3+/-1.6 vs. 3.2+/-0.5, p<0.001) and LDL-cholesterol/HDL-cholesterol (2.6+/-1.2 vs. 1.7+/-0.5, p<0.001) were significantly higher in RA patients than in controls. After 6 weeks of infliximab therapy, the mean total cholesterol concentration increased by 25% (p<0.001), LDL-cholesterol by 24% (p<0.001) and HDL-cholesterol by 30% (p<0.001). The decrease in CRP levels to 30 week inversely correlated with the increase in HDL-cholesterol (r=-0.47, p=0.005)., Conclusions: Infliximab administration is associated with important increases in cholesterol levels in all its forms but as no significant beneficial effect on the atherogenic ratio.

B cell-activating factor (BAFF) has a key role in promoting B-lymphocyte activation and survival in primary Sjögren's syndrome (pSS). The cellular origin of BAFF overexpression in salivary glands of patients with pSS is not fully known. We investigated whether salivary gland epithelial cells (SGECs), the main targets of autoimmunity in pSS, could produce and express BAFF. We used quantitative RT-PCR, ELISA and immunocytochemistry in cultured SGECs from eight patients with pSS and eight controls on treatment with IL-10, tumor necrosis factor alpha (TNF-alpha), IFN-alpha and IFN-gamma. At baseline, BAFF expression in SGECs was low in pSS patients and in controls. Treatment with IFN-alpha, IFN-gamma and TNF-alpha + IFN-gamma increased the level of BAFF mRNA in pSS patients (the mean increases were 27-fold, 25-fold and 62-fold, respectively) and in controls (mean increases 19.1-fold, 26.7-fold and 17.7-fold, respectively), with no significant difference between patients and controls. However, in comparison with that at baseline, stimulation with IFN-alpha significantly increased the level of BAFF mRNA in SGECs of pSS patients (p = 0.03) but not in controls (p = 0.2), which suggests that SGECs of patients with pSS are particularly susceptible to expressing BAFF under IFN-alpha stimulation. Secretion of BAFF protein, undetectable at baseline, was significantly increased after IFN-alpha and IFN-gamma stimulation both in pSS patients (40.8 +/- 12.5 (+/- SEM) and 47.4 +/- 18.7 pg/ml, respectively) and controls (24.9 +/- 8.0 and 9.0 +/- 3.9 pg/ml, respectively), with no significant difference between pSS and controls. Immunocytochemistry confirmed the induction of cytoplasmic BAFF expression after stimulation with IFN-alpha and IFN-gamma. This study confirms the importance of resident cells of target organs in inducing or perpetuating autoimmunity. Demonstrating the capacity of SGECs to express and secrete BAFF after IFN stimulation adds further information to the pivotal role of these epithelial cells in the pathogenesis of pSS, possibly after stimulation by innate immunity. Our results suggest that an anti-BAFF therapeutic approach could be particularly interesting in pSS.

Polyclonal B cell activation might be related to pathogenic over-expression of B-cell-activating factor (BAFF) in primary Sjögren's syndrome (pSS) and other autoimmune diseases. We therefore investigated whether BAFF over-expression in pSS could be a primary, genetically determined event that leads to the disease. The complete BAFF gene was sequenced in Caucasian pSS patients and control individuals. The only single nucleotide polymorphism frequently observed, namely -871 T/C in the promoter region, was then genotyped in 162 French patients with pSS and 90 French control individuals. No significant differences in allele (T allele frequency: 49.7% in patients with pSS versus 50% in controls; P = 0.94) and genotype frequencies of BAFF polymorphism were detected between pSS patients and control individuals. BAFF gene polymorphism was not associated with a specific pattern of antibody secretion either. T allele carriers had significantly increased BAFF protein serum levels (mean values of 8.6 and 5.7 ng/ml in patients with TT and TC genotypes, respectively, versus 3.3 ng/ml in patients with CC genotype; P = 0.01), although no correlation was observed between BAFF polymorphism and mRNA level. In conclusion, BAFF gene polymorphism is neither involved in genetic predisposition to pSS nor associated with a specific pattern of antibody production.

We report the effect of infliximab, a monoclonal anti-TNFalpha antibody, in two patients with refractory cutaneous and articular multicentric reticulohistiocytosis (MRH). One 37-year-old woman and one 53-year-old woman with polyarthritis, facial rash and nodular lesions on the hands related to MRH were refractory to multiple agents: cariolysine, corticosteroids, hydroxychloroquine and cytotoxic agents. Infliximab at 3 mg/kg which was then increased to 5 mg/kg in combination with methotrexate or azathioprine was effective on cutaneous manifestations of the disease but not on polyarthritis. A switch to etanercept did not improve polyarthritis in the second patient. Some data suggest that TNFalpha is involved in MRH, but based on our cases anti-TNFalpha therapy needs further evaluation in patients with refractory MRH.

Objectives: Induction of antinuclear antibodies (ANA) has been reported in patients taking infliximab to treat refractory spondyloarthropathy, without concomitant methotrexate therapy. We investigated antibody induction in patients with spondyloarthropathy treated with both infliximab and methotrexate., Methods: In 33 patients meeting ESSG criteria for spondyloarthropathy, infliximab was given (infusions at weeks 0, 2, 6, 14, 22, and 30) in combination with methotrexate (10-25 mg/week). At baseline, 6 and 30 weeks after treatment initiation, the patients underwent indirect immunofluorescence testing for ANA and ELISAs for antibodies to double-stranded DNA, soluble nuclear antigens, and histones., Results: As compared to baseline, significant increases were found at week 30 in the number of patients with ANA (4% vs. 29%, P = 0.02), IgG antihistone antibodies (7% vs. 29%, P = 0.04), and IgM antihistone antibodies (29% vs. 57%, P = 0.03). No significant increases were noted for antibodies to double-stranded DNA or to soluble nuclear antigens. No cases of clinical lupus syndrome were recorded., Conclusion: Autoantibody induction was far less common in our patients than in the population studied by De Rycke et al. [Arthritis Rheum. 48 (2003) 1015], who found ANA in 88.6% and antibodies to double-stranded DNA in 17.1% of 35 patients taking infliximab without methotrexate. Methotrexate may reduce the risk of autoantibody induction and disimmunity associated with infliximab therapy.

Objectives: To investigate autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab., Methods: We included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide. We tested the sera of the patients for antinuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30. Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after three infusions., Results: At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19 vs 42%, p = 0.009). At week 30, the frequency of patients with ANA had increased from 29% to 69% (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0% to 3% for IgG (NS) and from 0% to 32% for IgM (p < 0.001); the frequency of antihistone IgG detection had increased from 22% to 32% (p = 0.04) and that of IgM detection, from 18% to 79% (p < 0.001). No lupus-like syndrome was observed. RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001). No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy., Conclusion: Infliximab therapy lead to the selective and delayed induction of autoantibodies. This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.