Predictive factors of effective tibial nerve release in tarsal tunnel syndrome.

BACKGROUND: Factors that may affect surgical decompression results in tarsal tunnel syndrome are not known. METHODS: A retrospective single-center study included patients who had undergone surgical tibial nerve release. The effectiveness of decompression was evaluated according to whether the patient would or would not be willing to undergo another surgical procedure in similar preoperative circumstances. RESULTS: The patients stated for 43 feet (51%) that they would agree to a further procedure in similar circumstances. Six feet with space-occupying lesions on imaging had improved results, but neurolysis failed in 9 feet with bone-nerve contact. Neurolysis was significantly less effective when marked hindfoot valgus (p = 0.034), varus (p = 0.014), or fasciitis (p = 0.019) were present. CONCLUSIONS: If imaging reveals a compressive space-occupying lesion, surgery has a good prognosis. In feet with static hindfoot disorders or plantar fasciitis, conservative treatment must be optimized. Bone-nerve contact should systematically be sought.

Prealbumin, platelet factor 4 and S100A12 combination at baseline predicts good response to TNF alpha inhibitors in rheumatoid arthritis.

OBJECTIVES: Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients. METHODS: Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi. RESULTS: A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually. CONCLUSION: A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment.

A bicentre retrospective study of features and outcomes of patients with reactive arthritis.

OBJECTIVE: Reactive arthritis (ReA) is a sterile arthritis following an extra-articular infection, usually of the gastrointestinal or genitourinary tract. The aim of this study was to assess the incidence and the clinical and therapeutic characteristics of ReA and to compare them with those of a historical cohort. We hypothesised that improved hygiene together with prevention and treatment of sexually transmitted infections may have decreased the incidence of ReA. METHODS: All patients with ReA diagnosed in the University Hospital Centres of Lyon Sud and Besançon from January 2002 to December 2012 were included in the study retrospectively and were compared with ReA patients diagnosed from January 1986 to December 1996 in the same two hospitals. Medical records were reviewed, clinical features, treatments and outcomes were analysed and diagnoses were compared with international diagnostic criteria. RESULTS: Twenty-seven patients were included between 2002 and 2012 compared with 31 between 1986 and 1996. The overall incidence of ReA in patients hospitalised in the rheumatology department did not change, although the current evolution is more severe with development of chronic disease in the form of more frequent spondyloarthritis. While the incidence of Chlamydiae trachomatis has decreased, new microbes are now found to be involved. CONCLUSIONS: ReA still exists and its incidence has been stable over the last 30 years. However, ReA currently more often progress to spondyloarthritis. Our study also highlights the need for diagnostic criteria that accurately detect ReA.

Variants of genes implicated in type 1 interferon pathway and B-cell activation modulate the EULAR response to rituximab at 24 weeks in rheumatoid arthritis.

BACKGROUND: The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 (IRF5 and IRF7), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4) and osteopontin (SPP1). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24). METHODS: Logistic regression analysis with a stepwise multivariate model adjusted for sex, age and DAS28-CRP (Disease Activity Score in 28 joints with C reactive protein) in 115 patients from the SMART randomised studywas used to analyse the association between the candidate variants and W24 EULAR response. Because the variant TNFSF13B rs9514828 was previously found associated with RTX response in the same population, it was included in the analysis. RESULTS: The combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate EULAR response to RTX at W24: p=9.34×10-6, OR 11.37 (95% CI 4.03 to 35.28), positive predictive value 91% and negative predictive value 54%. CONCLUSION: Our results support the contribution of the IRF5, SPP1 and TNFSF13B genotypic combination in the response to RTX for RA at W24.

Isolated positive anti-SS-B autoantibodies are not related to clinical features of systemic autoimmune diseases: Results from a routine population survey.

OBJECTIVE: To assess in clinical practice the frequency and diagnosis associated with the SS-B-positive/SS-A negative autoantibody profile. METHODS: We analyzed a one-year consecutive population of 624 patients referred by clinicians to the immunology laboratory to investigate anti-SS-A and/or anti-SS-B autoantibodies, who were detected using luminex technology. Data were analyzed for patients with isolated anti-SS-B autoantibodies. The clinical characteristics and diagnosis of connective tissue diseases (CTD) were retrieved according to the international criteria. RESULTS: Among 1173 sera positive for anti-SS-A and/or anti-SS-B autoantibodies from 624 patients, we identified 84 patients (13.5%) that had isolated anti-SS-B. Among the 75 patients positive for anti-SS-B with known clinical data, 15 were diagnosed with a CTD (20%) including 4 systemic lupus erythematosus (5%), 4 rheumatoid arthritis (5%), 2 idiopathic inflammatory myositis (3%), 1 primary Sjögren's syndrome pSS (1%), 1 systemic sclerosis (1%), 2 undefined CTD (3%), and 1 mixed CTD (1%). Among the 60 other patients, 18 had non-CTD autoimmune diseases and 42 had non-autoimmune diseases. Within the CTD population, the presence of isolated anti-SS-B was not significantly associated to characteristic indicating a specific syndrome. There was no association between diagnosis of CTD and level of anti-SS-B autoantibodies (p = 0.70). Arthralgia was the more frequent sign and encountered in 10 patients (67%), of whom 3 had arthritis. CONCLUSION: The presence of anti-SS-B, without anti-SS-A autoantibodies using luminex technology, was not associated with CTD, especially pSS, in daily clinical practice. Our data suggests that the SS-B serological profile is not contributive for the classification criteria of pSS.

Factors influencing the use of tocilizumab as monotherapy in patients with rheumatoid arthritis in a real-life setting: results at 1†year of the ACT-SOLO study.

INTRODUCTION: Using a biologic disease-modifying antirheumatic drug (bDMARD) as monotherapy in clinical practice for patients with rheumatoid arthritis (RA) is common and recognised by health authorities although current guidelines recommend to combine them with conventional synthetic (cs)DMARDs. This study mainly aimed to search for real-life factors influencing the use of tocilizumab as MONO or in combination (COMBO). METHODS: In this non-interventional, prospective, national, multicentre study, data were collected every 3 months over a 12-month period in RA patients starting tocilizumab. The proportion of monotherapy patients was described, together with significant explicative factors. RESULTS: Among the 577 analysed patients recruited from January 2012 to August 2013 (228 monotherapy patients; 40%), 79% were women, mean RA duration was 11±9 years, previous RA treatments included bDMARDs and csDMARDs in 75% of cases and mean Disease Activity Score 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) was 5.2±1.3 at inclusion. Explicative factors for monotherapy were at least 65 years (OR=1.47, p=0.0485), no methotrexate within the two last years (OR=5.96, p<0.0001), past severe infection (OR=1.99, p=0.0272) and higher baseline DAS28-ESR (OR=1.22, p=0.0086). Regarding clinical results (DAS28-ESR, Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) low disease activity and remission; ACR20/50/70 and European League Against Rheumatism (EULAR) response; Health Assessment Questionnaire Disability Index (HAQ-DI) score), no relevant differences between monotherapy and combination patients were observed at 1 year. A total of 23 tocilizumab-treated patients (4%) experienced serious infections; no new safety signals were noted with no differences between groups. CONCLUSIONS: ACT-SOLO confirms the high proportion of RA patients receiving tocilizumab as MONO in clinical practice. The study also showed that clinical results at 1 year were similar between MONO and COMBO patients in a real-life setting. TRIAL REGISTRATION NUMBER: NCT01474291.

Fibromyalgia in Spondyloarthritis: Effect on Disease Activity Assessment in Clinical Practice.

OBJECTIVE: Spondyloarthritis (SpA) is the second most frequent inflammatory rheumatic disease, characterized by spinal involvement, peripheral arthritis, or enthesitis with marked pain, stiffness, and fatigue. Fibromyalgia (FM) may be associated with SpA, and shares some common symptoms. We aimed to determine how FM influences assessment of SpA disease activity, which is mainly dependent on patient-based outcome measures such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS). METHODS: This single-center cross-sectional study included consecutive patients with SpA according to the Assessment of SpondyloArthritis International Society criteria. FM was diagnosed according to the 1990 American College of Rheumatology criteria. Patient characteristics, BASDAI, ASDAS/C-reactive protein (CRP), Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, and the Medical Outcomes Study Short Form-36 questionnaire were recorded and compared. RESULTS: The study included 103 patients with SpA; 81 with axial and 22 with peripheral forms. Eighteen patients presented with concomitant FM, of whom 12 had axial SpA and 6 peripheral SpA. Demographic characteristics did not differ except for sex, with a female predominance in the FM group that was more marked in peripheral forms. BASDAI was higher in patients with FM [median (IQR): 4.2 (4.2) vs 2.2 (3.1); p = 0.0068], whereas ASDAS-CRP was not significantly different [median (IQR): 2.7 (2) vs 2 (1.3); p = 0.1264]. Nevertheless, median ASDAS-CRP corresponded to high disease activity in patients with SpA or FM compared with moderate activity in non-FM patients. CONCLUSION: FM is a frequent comorbidity in patients with SpA, especially in peripheral forms. In patients with SpA-FM, disease activity may be overestimated when measured by BASDAI and to a lesser extent by ASDAS-CRP, and this overestimation could lead to inappropriate treatment escalation.

Variations in the metabolome in response to disease activity of rheumatoid arthritis.

BACKGROUND: Anti-Tumor Necrosis Factor (TNF) therapies are able to control rheumatoid arthritis (RA) disease activity and limit structural damage. Yet no predictive factor of response to anti-TNF has been identified. Metabolomic profile is known to vary in response to different inflammatory rheumatisms so determining it could substantially improve diagnosis and, consequently, prognosis. The aim of this study was to use mass spectrometry to determine whether there is variation in the metabolome in patients treated with anti-TNF and whether any particular metabolomic profile can serve as a predictor of therapeutic response. METHODS: Blood samples were analyzed in 140 patients with active RA before initiation of anti-TNF treatment and after 6 months of Anti-TNF treatment (100 good responders and 40 non-responders). Plasma was deproteinized, extracted and analyzed by reverse-phase chromatography-QToF mass spectrometry. Extracted and normalized ions were tested by univariate and ANOVA analysis followed by partial least-squares regression-discriminant analysis (PLS-DA). Orthogonal Signal Correction (OSC) was also used to filter data from unwanted non-related effects. Disease activity scores (DAS 28) obtained at 6 months were correlated with metabolome variation findings to identify a metabolite that is predictive of therapeutic response to anti-TNF. RESULTS: After 6 months of anti-TNF therapy, 100 patients rated as good responders and 40 patients as non-responders according to EULAR criteria. Metabolomic investigations suggested two different metabolic fingerprints splitting the good-responders group and the non-responders group, without differences in anti-TNF therapies. Univariate analysis revealed 24 significant ions in positive mode (p < 0.05) and 31 significant ions in negative mode (p < 0.05). Once intersected with PLS results, only 35 ions remained. Carbohydrate derivates emerged as strong candidate determinants of therapeutic response. CONCLUSIONS: This is the first study describing metabolic profiling in response to anti-TNF treatments using plasma samples. The study highlighted two different metabolic profiles splitting good responders from non-responders.

Atypical focal forms of Whipple's disease seen by rheumatologists.

We report two atypical cases of focal Whipple's disease with rheumatic presenting symptoms. In one of these cases, the patient presented with chronic intermittent polyarthritis, systemic inflammation, and leukocytosis. Tests were positive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. There was no structural joint damage. Combined glucocorticoid and methotrexate therapy was only partially effective. Endocarditis requiring emergency valve replacement surgery occurred 4 years later. Evaluation of this event led to the diagnosis of Tropheryma whipplei infection responsible for both the endocarditis and the joint disease. The other patient presented with subacute inflammatory low back pain. His medical history was chiefly remarkable for intermittent inflammatory involvement of the wrists and right knee replacement surgery for osteoarthritis followed by a febrile effusion of the operated knee. Radiographs showed destructive lesions of the wrists. Magnetic resonance imaging findings suggested L2-L3 diskitis. A PCR assay on biopsy specimens from the disk lesions recovered T. whipplei, thus establishing the cause of the diskitis and previous joint manifestations. Combined doxycycline and hydroxychloroquine therapy was followed by full resolution of all clinical and laboratory abnormalities in both patients.

Use of whole-blood transcriptomic profiling to highlight several pathophysiologic pathways associated with response to rituximab in patients with rheumatoid arthritis: data from a randomized, controlled, open-label trial.

OBJECTIVE: To identify a molecular signature that could be predictive of the clinical response to rituximab (RTX) and elucidate the transcriptomic changes after RTX therapy in patients with rheumatoid arthritis (RA), with the use of whole-blood transcriptomic profiling. METHODS: A microarray assay of the whole human genome was performed using RNA from peripheral blood samples obtained before the first cycle of RTX from 68 patients with RA in the SMART study. The transcriptomic profile was also assessed 24 weeks after the first administration of RTX (among 24 nonresponders and 44 responders, according to the European League Against Rheumatism response criteria at week 24). Ingenuity Interactive Pathways Analysis was used to identify molecular pathways that were modified by RTX therapy according to the clinical response. Quantitative polymerase chain reaction was performed to confirm the microarray results. RESULTS: In total, 198 genes showed significant baseline differential expression between patient groups according to their subsequent response to RTX (good or moderate responder versus nonresponder). This molecular signature could be reduced to 143 genes, which allowed for correctly classifying 89% of the patients by their EULAR response status at week 24, with 93% identification of responders and 100% identification of nonresponders. The signature for response featured up-regulation of inflammatory genes centered on NF-κB, including IL33 and STAT5A, and down-regulation of the interferon pathway. As expected, at week 24 post-RTX therapy, genes involved in the development and functions of B cells were the genes most strongly down-regulated, without any difference between the 2 groups. CONCLUSION: Whole-blood transcriptomic analyses may accurately identify patients with RA who will not respond to RTX therapy. These findings could open new perspectives on the clinical management of RA.

Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial.

BACKGROUND: The licensed dose of rituximab in rheumatoid arthritis (RA) is two doses of 1000 mg given 2 weeks apart. A lower dose has never been specifically studied in patients with an inadequate response to anti-tumour necrosis factor (TNF) agents. OBJECTIVE: To compare the efficacy and safety of rituximab repeat treatment with two doses (1000 mg×1 and 1000 mg×2) following initial treatment with 1000 mg×2. METHODS: We set up an open-label, prospective, multicentre, non-inferiority study comprising a non-controlled period (24 weeks) followed by a randomised controlled period (weeks 24-104) in patients with RA and an inadequate response to anti-TNF agents. All patients received one course of rituximab (1000 mg×2) with methotrexate. At week 24, patients achieving a EULAR response (moderate or good) were randomised to rituximab retreatment at 1000 mg×1 (Arm A) or 1000 mg×2 (Arm B). The primary objective measure was disease activity in 28 joints C-reactive protein (DAS28-CRP) area under the curve (AUC) over 104 weeks with a non-inferiority margin defined by 20% (444) of the mean DAS28-CRP AUC (mean±SD 2218±967) of the reference data. RESULTS: The intent-to-treat and per-protocol (PP) populations comprised 143 (A/B: 70/73) and 100 (A/B: 51/49) patients, respectively. The adjusted mean difference in DAS28-CRP AUC (PP) was 51.4 (95% CI -131.2 to 234), demonstrating non-inferiority between arms A and B. The overall rituximab safety profile was similar with both retreatment regimens. CONCLUSIONS: Following a clinical response to a first course of rituximab in RA at the licensed dose of 1000 mg×2, retreatment with rituximab at 1000 mg×1 results in efficacy outcomes that are non-inferior to those achieved with retreatment at 1000 mg×2. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01126541.

CCL19, a B cell chemokine, is related to the decrease of blood memory B cells and predicts the clinical response to rituximab in patients with rheumatoid arthritis.

OBJECTIVE: Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. METHODS: Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CONCLUSION: CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell-mediated RA subtype and may predict clinical response to RTX.