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Importance: There are conflicting data on the association of antidrug antibodies with response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA)., Objective: To analyze the association of antidrug antibodies with response to treatment for RA., Design, Setting, and Participants: This cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patients with RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and the UK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD. Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018, and data were analyzed in June 2022., Exposures: Patients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti-tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician., Main Outcomes and Measures: The primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay., Results: Of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%]) were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001). A similar association was found for tocilizumab alone (OR, 0.18; 95% CI, 0.04-0.83; P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factor were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody-negative vs antidrug antibody-positive status (mean difference, -9.6 [95% CI, -12.4 to -6.9] mg/L; P < 001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05)., Conclusions and Relevance: Results of this prospective cohort study suggest an association between antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrug antibodies could be considered in the treatment of these patients, particularly nonresponders to biologic RA drugs.

Objective: Osteoarthritis (OA) displays features of systemic and local inflammation, suggesting that DMARDs used in rheumatoid arthritis could potentially also be effective in OA. However, studies of the effects of DMARDs in OA have yielded conflicting data, and have been insufficiently large to draw conclusions. In this meta-analysis, we aimed to estimate the effect of DMARDs - such as methotrexate, hydroxychloroquine, TNF, and IL-1 inhibitors - on OA., Methods: We searched for relevant articles of randomized controlled trials published up to March 2022, using Pubmed, EMBASE, and the Cochrane Library. Studies were reviewed in accordance with PRISMA 2020 guidelines. The effects of DMARDs on OA outcomes (symptoms, quality of life, ESR) were expressed as the standardized mean difference., Results: We retrieved 29 references. Among these, 23 randomized controlled trials compared the effects of DMARDs versus placebo or other treatments on disease activity, including 1143 DMARD-treated OA patients and 1155 OA patients in the control group. We found statistically significant improvement of pain and stiffness with methotrexate, especially in knee OA. TNF inhibitors improved the swollen joint count in hand OA, and inflammation parameters, without change in pain, stiffness, or function. Hydroxychloroquine and IL-1 inhibitors were not effective., Conclusion: Overall, the presently available data regarding the effects of DMARDs on OA symptoms intensity are disappointing. Only methotrexate might have an analgesic effect, especially in knee OA, which warrants further investigation., (Copyright © 2022 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Mobile health applications (apps) are increasing in interest to enhance patient self-management. Few apps are actually used by patients and have been developed for patients with inflammatory arthritis (IA) treated with disease-modifying anti-rheumatic drugs which use entails risk of adverse effects such as infections., Objective: To develop Hiboot, a self-management mobile app for patients with IA, by using a user-centred step-by-step approach and assess its real-life use., Methods: The app development included first a qualitative study with semi-guided audiotaped interviews of 21 patients to identify the impact of IA on daily life and patient treatments practices and an online cross-sectional survey of 344 patients to assess their health apps use in general and potential user needs. A multidisciplinary team developed the first version of the app via five face-to-face meetings. After app launch, a second qualitative study of 21 patients and a users' test of 13 patients and 3 rheumatologists led to the app's current version. The number of app installations, current users and comments were collected from the Google Play store and the Apple store., Results: The qualitative study revealed needs for counselling, patient-health professional partnership, and skills to cope with risk situations; 86.8% participants would be ready to use an app primarily on their rheumatologist's recommendation. Six functionalities were implemented: a safety checklist before treatment administration, aids in daily life situations based on the French academic recommendations, treatment reminders, global well-being self-assessment, periodic counselling messages, and a diary. The Hiboot app was installed 20,500 times from September 2017 to October 2020, with 4300 regular current users. Scores were 4.4/5 stars at Android and iOS stores., Conclusion: Hiboot is a free self-management app for patients with IA developed by a step-by-step process including patients and health professionals. Further evaluation of the Hiboot benefit is needed., Competing Interests: CB, TP, AL, CV, GD, PB, SD, FT, DL, LG, FAL, MA, SP and JS declare no competing interests in relation is this study. SG, FM were paid by Unknowns Research department for their contribution to the study. GM, JLC, MQ, were employed by Unknowns Conseil en stratégie et innovation, Paris, France HJ and LB are owners of Unknowns Conseil en stratégie et innovation, Paris, France Disclosures of interest apart from the study Catherine Beauvais reports research grants from BMS, Fresenius Kabi, Lilly, Mylan and was an occasional speaker for BMS, Abbvie, MSD, Mylan, Pfizer, Roche, Sanofi, UCB. She participated to a medical board for Sandoz and Novartis. Thao Pham reports speaker and consulting fees from Abbvie, Amgen, Biogen, BMS, Celgene, Fresenius-Kabi, Janssen, Lilly, MSD, Nordic, Novartis, Pfizer, Sandoz, Sanofi and UCB. Florence TUBACH is head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique – Hôpitaux de Paris and the Clinical Research Unit of Pitié-Salpêtrière hospital; both of these structures have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies that have contributed indiscriminately to the salaries of its employees. Florence Tubach is not employed by these structures and did not receive any personal remuneration from these companies. Jérémie Sellam reports fees from MSD, Pfizer, Abbvie, Fresenius Kabi, BMS,Roche Chugai, Sandoz, Lilly, Gilead, Novartis, Janssen, grant research fromSchwa Medico, MSD and Roche.

Background: Spices, i.e., curcumin, ginger, saffron, and cinnamon, have a thousand-year history of medicinal use in Asia. Modern medicine has begun to explore their therapeutic properties during the last few decades. We aimed to perform a systematic literature review (SLR) of randomized controlled trials (RCTs) assessing the effect of spice supplementation on symptoms and disease activity in patients with chronic inflammatory rheumatic diseases (rheumatoid arthritis (RA), spondylarthritis, or psoriatic arthritis)., Methods: An SLR of RCTs, reviews, and meta-analyses was performed, searching for articles in MEDLINE/PubMed. Abstracts from international rheumatology and nutrition congresses (2017-2020) were also scrutinized. The risk of bias of the selected studies was evaluated using the Cochrane Collaboration's tool and the Jadad scale., Results: Altogether, six studies, assessing the use of spice supplementation only in RA patients, were included: one on garlic supplementation, two on curcumin, one on ginger, one on cinnamon, and one on saffron supplementation. Garlic, ginger, cinnamon, or saffron supplementation was associated with a decrease in RA clinical activity. However, several points limit the external validity of these studies. No conclusion on the impact of curcumin supplementation on RA activity could be drawn due to low-quality studies., Conclusions: Garlic, ginger, cinnamon, and saffron supplementation could have a beneficial effect on RA activity, but the risk of bias of these studies is difficult to assess and data are too limited to recommend them in daily practice.

Background: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients., Methods: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL., Results: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL)., Conclusions: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.

Objective: To investigate maintenance of rituximab (RTX) in RA patients re-treated with reduced doses compared with standard dose in a real life setting., Methods: The Autoimmunity and Rituximab (AIR) registry is a nationwide prospective observational cohort investigating the long-term safety and efficacy of RTX in RA. The present study included patients from the AIR registry that have been re-treated with RTX after a first course of RTX standard dose (1000 mg × 2). Two groups were defined according to dose of RTX of the first retreatment course (i.e. second course): standard dose group and reduced dose group. Five years' maintenance and rate of serious infections of the retreatment period were compared between standard dose and reduced dose groups. Analyses used the inverse probability of treatment weighting propensity score adjusted method., Results: Among the 1986 patients from the AIR registry, 1278 were included, 1093 (85.5%) treated with standard dose and 185 (14.5%) with reduced doses. Maintenance of RTX at 5 years in the standard and reduced groups was 55.5 and 53.8%, respectively, and did not significantly differ between groups in adjusted analyses (hazard ratio = 1.03; 95% CI: 0.81, 1.30), but the cumulative RTX dose received for retreatment [1.4 (0.6) vs 2.3 (1.0) g/year, P < 0.001] and the rate of serious infections were significantly lower in the reduced dose group (adjusted hazard ratio = 0.50; 95% CI: 0.27, 0.92; P = 0.02)., Conclusion: Use of reduced doses of RTX for retreatment did not alter the maintenance of RTX at 5 years in RA patients, but allowed a 39% total dose reduction and a lower rate of serious infections., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: To validate the IFN response gene (IRG) set for the prediction of non-response to rituximab in rheumatoid arthritis (RA) and assess the predictive performance upon combination of this gene set with clinical parameters., Methods: In two independent cohorts of 93 (cohort I) and 133 (cohort II) rituximab-starting RA patients, baseline peripheral blood expression of eight IRGs was determined, and averaged into an IFN score. Predictive performance of IFN score and clinical parameters was assessed by logistic regression. A multivariate prediction model was developed using a forward stepwise selection procedure. Patients with a decrease in disease activity score (ΔDAS28)≥1.8 after 6 months of therapy were considered responders., Results: The mean IFN score was higher in non-responders compared to responders in both cohorts, but this difference was most pronounced in patients who did not use prednisone, as described before. Univariate analysis in cohort I showed that baseline DAS28, IFN score, DMARD use and negativity for IgM-RF and/or ACPA were associated with rituximab non-response. The multivariate model consisted of DAS28, IFN score and DMARD use, which showed an area under the curve (AUC) of 0.82. In cohort II, this model revealed a comparable AUC in PREDN-negative patients (0.78), but AUC in PREDN-positive patients was significantly lower (0.63), which seemed due to effect modification of the IFN score by prednisone., Conclusions: Combination of predictive parameters provided a promising model for the prediction of non-response to rituximab, with possibilities for optimization via definition of the exact interfering effect of prednisone on IFN score., Trial Registration (cohort Ii, Smart Trial): NCT01126541, registered 18 May 2010., (Copyright © 2017. Published by Elsevier SAS.)

Objective: To investigate the frequency and risk factors of postoperative complications in RA patients treated with abatacept (ABA)., Methods: The Orencia RA registry recruited 1012 patients receiving ABA for RA in routine care. Data from patients treated with ABA who underwent surgery were reviewed to describe the frequency of postoperative complications. Characteristics of patients and surgeries with and without complications were compared to identify factors associated with complications., Results: We identified 205 (20.3%) patients who underwent 263 surgeries, including 176 (66.9%) orthopaedic surgeries. Nineteen (7.2%) surgeries, in 19 patients (9.3%), entailed complications, including 7 delayed wound healing (2.7% of surgeries) and 6 surgical site infections (2.3% of surgeries). The median time between the last infusion of ABA and surgery was 5.9 weeks (range: 0.3-12.0 weeks), with no significant difference between patients with and without complications. The median corticosteroids daily dosage was higher in the group with complications [10.0 (6.25-15.0) vs 6.0 (5.0-10.0) mg/day, P = 0.042]. In multivariate analysis, only the duration of ABA treatment was significantly associated with postoperative complications [adjusted odds ratio (aOR) = 0.94 (95% CI: 0.89, 0.99) for each month of treatment], as were orthopaedic surgeries compared with other kinds of surgery [aOR = 4.45 (95% CI: 1.01, 20.2)]., Conclusion: In RA patients treated with ABA, the rate of surgical complications was low: 7.2% and higher in case of orthopaedic procedure and a more recent initiation of ABA. The median time between surgery and the last infusion of ABA was short and did not influence the rate of postoperative complications., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Recent works have suggested a possible link between interleukin (IL)-33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA)., Methods: Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks., Results: At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13-9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01-5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01-5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30-674.79; p = 0.034)., Conclusion: Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level., Trial Registration: NCT01126541 ; 18 May 2010.

Background: Previous studies suggested that obesity could negatively affect the response to antitumour necrosis factor-α (TNFα) agents in rheumatoid arthritis (RA). However, data are lacking on whether obesity affects the response to abatacept (ABA). We aimed to determine whether body mass index (BMI) affects the response to ABA in RA., Materials and Methods: In this multicenter retrospective study, we included RA patients who received ABA. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, tender and swollen joint count were analysed. The primary endpoint was decrease in DAS28 ≥ 1·2. Secondary outcomes were good response and remission by EULAR criteria., Results: At baseline, among 141 RA patients included, the median [interquartile range] BMI was 26·0 [22·9-30·8] kg/m². The number of patients with normal weight, overweight and obesity was 64 (45·4%), 38 (27%) and 39 (27·6%), respectively. Baseline characteristics did not differ among the three BMI subgroups. Univariate analysis revealed no difference in BMI between responders and nonresponders: DAS28 decrease ≥ 1·2 (25·0 [23·4-31·3] vs. 26·3 [22·9-30·2], P = 0·95), EULAR good response (26·4 [23·5-30·9] vs. 26·0 [22·9-30·6], P = 0·96) and remission (26·7 [21·7-30·3] vs. 26·0 [23·0-30·1], P = 0·83)., Conclusion: In our real-life study, BMI did not affect the response to ABA in RA. If confirmed, these results suggest that obesity is not a limitation of ABA use in RA., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

The risk of infection associated with autoimmune diseases is further increased by the use of biotherapies. Recommendations to minimize this risk include administering the full complement of vaccines on the standard immunization schedule, as well as the pneumococcal and influenza vaccines. Adults with chronic inflammatory joint disease (IJD) may receive a 13-valent pneumococcal conjugate vaccine, as well as a live attenuated vaccine against recurrent herpes zoster, recently licensed by European regulatory authorities. Live attenuated vaccines can be given only after an interval without immunosuppressant and/or glucocorticoid therapy. The effectiveness of vaccines, as assessed based on titers of protective antibodies, varies across vaccine types and disease-modifying antirheumatic drugs (DMARDs). Thus, methotrexate and rituximab are usually associated with decreased vaccine responses. The risks associated with vaccines are often considerably exaggerated by the media, which serve lobbies opposed to immunizations and make some patients reluctant to accept immunizations. Increasing immunization coverage may diminish the risk of treatment-related infections. A physician visit dedicated specifically to detecting comorbidities in patients with chronic IJD may result in improved immunization coverage. In this review, we discuss immunizations for adults with chronic IJD based on the treatments used, as well as immunization coverage. Many questions remain unanswered and warrant investigation by studies coordinated by the French networks IREIVAC (Innovative clinical research network in vaccinology) and IMIDIATE (Immune-Mediated Inflammatory Disease Alliance for Translational and Clinical Research)., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations., Methods: We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded., Results: To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug-drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23-58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504-2,229 ng/ml] versus 917 ng/ml [range 208-3316 ng/ml]) (P < 0.001)., Conclusion: We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians., (© 2015, American College of Rheumatology.)

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., (Copyright © 2014 by the American College of Rheumatology.)

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., (Copyright © 2013 by the American College of Rheumatology.)

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: Rituximab improves articular symptoms in rheumatoid arthritis (RA) and it recently has been shown to be an effective induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis. We assessed the efficacy and safety of rituximab in a real-life clinical setting among patients with systemic rheumatoid vasculitis (SRV)., Methods: We analyzed data from the AutoImmunity and Rituximab registry, which includes patients with autoimmune diseases treated with rituximab., Results: Of the 1,994 patients with RA enrolled in the registry, 17 were treated with rituximab for active SRV. At baseline, the mean Birmingham Vasculitis Activity Score for RA (BVAS/RA) was 9.6, with a mean prednisone dosage of 19.2 mg/day. After 6 months of rituximab therapy, 12 patients (71%) achieved complete remission of their vasculitis, 4 had a partial response, and 1 died with uncontrolled vasculitis. Mean BVAS/RA was reduced to 0.6 and mean prednisone dosage to 9.7 mg/day. At 12 months, 14 patients (82%) were in sustained complete remission. Severe infection occurred in 3 patients, corresponding to a 6.4 per 100 patient-years rate. In the 6 patients who received further rituximab as maintenance therapy between months 6 and 12, no relapse of vasculitis was observed. However, among the 9 patients who did not, a relapse was observed in 3 patients who were treated with methotrexate alone. Remission was reestablished by reintroducing rituximab in 2 cases., Conclusion: Complete remission of SRV was achieved in nearly three-fourths of patients receiving rituximab in daily practice, with a significant decrease in daily prednisone dosage and an acceptable toxicity profile. Rituximab represents a suitable therapeutic option to induce remission in SRV, but maintenance therapy seems to be necessary., (Copyright © 2012 by the American College of Rheumatology.)

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.)

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.