Long-term mortality in treated-to-target RA and UA: results of the BeSt and IMPROVED cohort.

OBJECTIVES: To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA). METHODS: The BeSt (BehandelStrategieën) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)≤2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed. RESULTS: Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy. CONCLUSIONS: After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor.

In rheumatoid arthritis patients, total IgA1 and IgA2 levels are elevated: implications for the mucosal origin hypothesis.

OBJECTIVE: Mucosal initiated immune responses may be involved in the pathophysiology of RA. The most abundant immunoglobulin at mucosal surfaces is IgA, of which two subclasses exist: IgA1 and IgA2. IgA2 is mainly present at mucosal sites and has been ascribed pro-inflammatory properties. As IgA subclasses might provide insights into mucosal involvement and pro-inflammatory mechanisms, we investigated IgA responses in sera of RA patients. METHODS: In two cohorts of RA patients, the EAC and IMPROVED, total IgA1 and IgA2 were measured by ELISA. Furthermore, IgA subclass levels of RF and anti-citrullinated protein antibodies (anti-CCP2) were determined. The association of these IgA subclass levels with CRP and smoking was investigated. RESULTS: Total IgA1 and IgA2 were increased in RA patients compared with healthy donors in both cohorts. This increase was more pronounced in seropositive RA vs seronegative RA. For RF and anti-CCP2, both IgA1 and IgA2 could be detected. No strong associations were found between IgA subclasses (total, RF and anti-CCP2) and CRP. In smoking RA patients, a trend towards a selective increase in total IgA2 and RF IgA1 and IgA2 was observed. CONCLUSION: RA patients have raised IgA1 and IgA2 levels. No shift towards IgA2 was observed, indicating that the increase in total IgA is not due to translocation of mucosal IgA into the bloodstream. However, mucosal inflammation might play a role, given the association between smoking and total IgA2 levels. Despite its pro-inflammatory properties, IgA2 does not associate strongly with pro-inflammatory markers in RA patients.

Fostering Patient Choice Awareness and Presenting Treatment Options Neutrally: A Randomized Trial to Assess the Effect on Perceived Room for Involvement in Decision Making.

PURPOSE: Shared decision making calls for clinician communication strategies that aim to foster choice awareness and to present treatment options neutrally, such as by not showing a preference. Evidence for the effectiveness of these communication strategies to enhance patient involvement in treatment decision making is lacking. We tested the effects of 2 strategies in an online randomized video-vignettes experiment. METHODS: We developed disease-specific video vignettes for rheumatic disease, cancer, and kidney disease showcasing a physician presenting 2 treatment options. We tested the strategies in a 2 (choice awareness communication present/absent) by 2 (physician preference communication present/absent) randomized between-subjects design. We asked patients and disease-naïve participants to view 1 video vignette while imagining being the patient and to report perceived room for involvement (primary outcome), understanding of treatment information, treatment preference, satisfaction with the consultation, and trust in the physician (secondary outcomes). Differences across experimental conditions were assessed using 2-way analyses of variance. RESULTS: A total of 324 patients and 360 disease-naïve respondents participated (mean age, 52 ± 14.7 y, 54% female, 56% lower educated, mean health literacy, 12 ± 2.1 on a 3-15 scale). The results showed that choice awareness communication had a positive (Mpresent = 5.2 v. Mabsent = 5.0, P = 0.042, η2partial = 0.006) and physician preference communication had no (Mpresent = 5.0 v. Mabsent = 5.1, P = 0.144, η2partial = 0.003) significant effect on perceived room for involvement in decision making. Physician preference communication steered patients toward preferring that treatment option (Mpresent = 4.7 v. Mabsent = 5.3, P = 0.006, η2partial = 0.011). The strategies had no significant effect on understanding, satisfaction, or trust. CONCLUSIONS: This is the first experimental evidence for a small effect of fostering choice awareness and no effect of physician preference on perceived room to participate in decision making. Physician preference steered patients toward preferring that option.

Phenotype and treatment of elderly onset compared with younger onset rheumatoid arthritis patients in international daily practice.

OBJECTIVE: To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset. METHODS: Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45-65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders. RESULTS: The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02 HAQ points per month in the <45 and 45-65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant. CONCLUSION: In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.

Body mass index and treatment survival in patients with RA starting treatment with TNFα-inhibitors: long-term follow-up in the real-life METEOR registry.

OBJECTIVES: To study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a real-life longitudinal international registry. METHODS: Data from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI<18.5 kg/m2; 46% normal weight, BMI 18.5-25 kg/m2; 32% pre-obesity, BMI 25-30 kg/m2; 13% obesity class I, BMI 30-35 kg/m2; 3.4% obesity class II, BMI 35-40 kg/m2; and 1.6% obesity class III, BMI >40 kg/m2. Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan-Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days. RESULTS: Patients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found. CONCLUSION: Both underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients.

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. METHODS: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation. METHODS: The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263. FINDINGS: We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21·5 (SD 21·7) in the prednisolone group and -5·2 (24·3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16·5 (95% CI -26·1 to -6·9; p=0·0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee). INTERPRETATION: Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease. FUNDING: Dutch Arthritis Society.

Validation of a clinical pharmacogenetic model to predict methotrexate nonresponse in rheumatoid arthritis patients.

AIM: To study the performance of a clinical pharmacogenetic model for the prediction of nonresponse in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) in combination with other synthetic or biologic disease-modifying anti-rheumatic drugs . This prediction model includes gender, smoking status, rheumatoid factor positivity and four genetic variants in AMPD1 (rs17602729), ATIC (rs2372536), ITPA (rs1127354) and MTHFD1 (rs17850560). METHODS: A total of 314 RA patients from three Dutch studies were retrospectively included. Eligible patients were adults diagnosed with RA and had a treatment duration with MTX and follow-up for at least two study evaluation visits. Prediction model risk scores at the first and second evaluation were calculated and compared with the actual nonresponse (disease activity score >2.4). Regression and receiver operating characteristic curve analyses of the prediction model were performed. Also, the sensitivity, specificity and the positive and negative predictive values (PPV and NPV) were determined. RESULTS: The receiver operating characteristic area under the curve was 75% at first and 70% after second evaluation. At the second evaluation, prediction nonresponse had a sensitivity of 67% (CI: 54-78%), specificity of 69% (CI: 60-77%), PPV of 52% (CI: 45-60%) and NPV of 80% (CI: 73-85%). CONCLUSIONS: This study demonstrates that the clinical pharmacogenetic model has an inadequate performance for the prediction of nonresponse to MTX in RA patients treated with combination therapies.

SLC04A1, SLC22A2 and SLC28A2 variants not related to methotrexate efficacy or toxicity in rheumatoid arthritis patients.

AIM: A third of rheumatoid arthritis patients discontinue methotrexate treatment due to inefficacy or toxic side effects. Recently, an association between SLC04A1 rs2236553, SLC22A2 rs624249 and rs316019, and SLC28A2 rs10519020 and rs1060896 with the efficacy and toxicity of methotrexate was reported. This study aims to replicate these findings in an independent cohort (n = 324). METHODS: Regression analyses tested the associations between genotype and methotrexate response or toxicity. RESULTS: In the discovery study, there was a significant association between toxicity and rs624249, and rs1060896. These associations were not replicated in the independent cohort. Neither study observed an association between methotrexate efficacy and SLC04A1, SLC22A2 or SLC28A2 variants. CONCLUSION: Current evidence does not support associations between variants in SLC04A1, SLC22A2 and SLC28A2 with methotrexate efficacy or toxicity.

TNF inhibitor treatment is associated with a lower risk of hand osteoarthritis progression in rheumatoid arthritis patients after 10 years.

Objective: To investigate the effect of TNF inhibitors (TNFis) on incidental and progressive hand OA in recent-onset RA patients after a 10 year follow-up. Methods: Radiographs of 262 RA patients (mean age 52 years, 66% women) from the BeSt study were scored for osteophytes in DIP/PIP joints using the Osteoarthritis Research Society International atlas (0-3; summed score 0-54) and according to the Kellgren-Lawrence (KL) score (0-4; summed score 0-72) at baseline and 10 year follow-up. TNFi treatment was assessed on visits every 3 months. Associations between TNFi treatment and hand OA were analysed on the patient and joint level using generalized linear models and generalized estimating equations, respectively. Results: Fifty-eight percent of the patients were treated with TNFi, with a median duration of 42 months. A total of 143 patients (55%) had hand OA in any IP joint at baseline based on the Osteoarthritis Research Society International osteophyte score. On the patient level, TNFi treatment duration did not affect incidental hand OA. However, every month of TNFi treatment resulted in a reduced relative risk (RR) of hand OA progression in DIP joints [relative risk (RR) 0.987 (95% CI 0.978, 0.996)] but not in PIP joints. On the joint level, the effect on hand OA progression was observed in DIP joints [RR 0.996 (95% CI 0.991, 1.000)] but not in PIP joints. The results from the KL score analyses were comparable to the osteophyte score. Conclusion: TNFi treatment was associated with a reduced risk on radiographic hand OA progression in DIP joints but not in PIP joints after 10 years. Although the effect sizes are small, these results provide evidence for influence of TNF-α in hand OA pathogenesis.

Pathway analysis to identify genetic variants associated with efficacy of adalimumab in rheumatoid arthritis.

AIM: About 30% of rheumatoid arthritis patients have no clinical benefit from TNF inhibitors. Genome-wide association (GWA) and candidate gene studies tested several putative genetic variants for TNF inhibitor efficacy with inconclusive results. Therefore, this study applied a systematic pathway analysis. PATIENTS & METHODS: A total of 325 rheumatoid arthritis patients treated with adalimumab were genotyped for 223 SNPs. We tested the association between SNPs and European League Against Rheumatism response and remission at 14 weeks under the additive genetic model using logistic regression. RESULTS: A total of 3 SNPs located in CD40LG (rs1126535), TANK (rs1267067) and VEGFA (rs25648) showed association with both end points. TNFAIP3 (rs2230926) had the strongest effect related to European League Against Rheumatism response. CONCLUSION: This exploratory study suggests that TNFAIP3, CD40LG, TANK and VEGFA play a role in the response to adalimumab treatment.

Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement.

OBJECTIVES: Neuropsychiatric (NP) involvement is a poorly understood manifestation of SLE. We studied post-mortem histopathology in relation to clinical NPSLE syndromes and complement deposition in brains of NPSLE and SLE patients and controls. Furthermore, we investigated the correlation between cerebral post-mortem histopathology and ex vivo 7 T MRI findings in SLE and NPSLE. METHODS: A nationwide search for autopsy material yielded brain tissue from 16 NPSLE and 18 SLE patients. Brains obtained from 24 patients who died of acute cardiac events served as controls. Apart from a histopathological evaluation, paraffin-embedded cortical tissue was stained for components of the classical, lectin and terminal complement pathways. RESULTS: Diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE than SLE patients and were absent in controls. Focal vasculopathy was found in both SLE patients and controls. Complement deposition was strongly associated with both SLE and NPSLE, but not with controls (P < 0.001). Microthrombi were found uniquely in NPSLE and were associated with C4d and C5b-9 deposits (P < 0.05). A 7 T MRI was unable to detect most small vessel injury that was visible histopathologically. CONCLUSION: Our study demonstrates that histopathological lesions in NPSLE represent a continuum, ranging from non-specific lesions such as focal vasculopathy, to more specific lesions including C4d- and C5b-9-associated microthrombi and diffuse vasculopathy related to clinical syndromes defining NPSLE. Complement deposition may be a key factor in the interaction between circulating autoantibodies and thromboischaemic lesions observed in NPSLE. Therefore, complement inhibition may have novel therapeutic potential in NPSLE.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.

BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING: Roche Nederland BV.

Stopping Tumor Necrosis Factor Inhibitor Treatment in Patients With Established Rheumatoid Arthritis in Remission or With Stable Low Disease Activity: A Pragmatic Multicenter, Open-Label Randomized Controlled Trial.

OBJECTIVE: Tumor necrosis factor inhibitor (TNFi) biologic agents are an effective treatment for rheumatoid arthritis (RA). It is unclear whether patients whose disease is in remission or who have stable low disease activity need to continue use of TNFi or can stop this treatment. This study was undertaken to assess whether patients with established RA who are in remission or have stable low disease activity can effectively and safely stop their TNFi therapy. METHODS: The study was designed as a pragmatic multicenter, open-label randomized controlled trial. Inclusion criteria were a diagnosis of RA according to the American College of Rheumatology 1987 classification criteria, as well as use of a TNFi for at least 1 year along with a stable dose of disease-modifying antirheumatic drugs and a Disease Activity Score in 28 joints (DAS28) of <3.2 over the 6 months preceding trial inclusion. Patients were randomized in a 2:1 ratio to either stop or continue treatment with their current TNFi. Flare was defined as a DAS28 of ≥3.2 during the 12-month follow-up period and an increase in score of ≥0.6 compared to the baseline DAS28. RESULTS: In total, 531 patients were allocated to the stop group and 286 to the TNFi continuation group. At 12 months, more patients had experienced a flare in the stop group (272 [51.2%] of 531) than in the continuation group (52 [18.2%] of 286; P < 0.001). The hazard ratio for occurrence of a flare after stopping TNFi was 3.50 (95% confidence interval [95% CI] 2.60-4.72). The mean DAS28 in the stop group was significantly higher during the follow-up period compared to that in the continuation group (P < 0.001). Of the 195 patients who restarted TNFi treatment after experiencing a flare and within 26 weeks after stopping, 165 (84.6%) had regained a DAS28 of <3.2 by 6 months later, and the median time to a regained DAS28 of <3.2 was 12 weeks (95% Cl 10.7-13.3). There were more hospitalizations in the stop group than in the continuation group (6.4% versus 2.4%). CONCLUSION: Stopping TNFi treatment results in substantially more flares than does continuation of TNFi in patients with established RA in remission or with stable low disease activity.

An investigation of the added value of an ACPA multiplex assay in an early rheumatoid arthritis setting.

INTRODUCTION: Recently, arrays have become available that allow the simultaneous analysis of several anti-citrullinated protein antibody (ACPA) reactivities using distinct citrullinated peptides. Such assays are designed for exploratory studies. The interpretation of positive antibody reactivities can best be made if the diagnostic and prognostic value of a multiplex array in an early arthritis setting is known and if the multiplex-positive patients who are negative according to three commonly used commercial ACPA assays are characterized. METHODS: Using Thermo Scientific's ImmunoCap ISAC (Immuno Solid-phase Allergen Chip) system, a multiplexed array that determines reactivities to 11 citrullinated peptides, we analysed serum/plasma of 195 healthy controls and 1282 early arthritis patients from two independent cohorts: the Leiden Early Arthritis Clinic (n = 1013) and the IMPROVED (n = 269) cohort. Findings were compared with results primarily of the anti-citrullinated cyclic peptide 2 (anti-CCP-2) assay but also with anti- CCP-3 and anti-mutated citrullinated vimentin (anti-MCV) assays. The associations between ACPA reactivities and patient characteristics, risk factors (shared epitope, smoking) and disease outcomes (progression of undifferentiated arthritis to rheumatoid arthritis (RA) and severity of joint destruction) were assessed. RESULTS: Thirty-one percent of anti-CCP-2-negative RA patients displayed reactivity toward citrullinated peptides in the multiplex assay. These patients had a positive signal toward a more restricted peptide repertoire than anti-CCP-2-positive RA patients (median of 1 versus 5). Within anti-CCP-2-negative patients, ACPA reactivity as detected by multiplex array was not significantly associated with known risk factors or clinical or prognostic parameters. The frequency of sera from anti-CCP-2-negative RA patients who were positive for the multiplexed peptides was comparable to the frequency in non-RA arthritic patients (27 %). CONCLUSIONS: Additive citrulline peptide reactivities detected by the current multiplex system did not reach significant power to be RA-specific. The presence of residual citrulline reactivities detected by this multiplex system in arthritis patients who are negative in commercial ACPA assays needs to be interpreted with caution.

Rheumatoid Factor Is Associated With the Distribution of Hand Joint Destruction in Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non-fingers, with the aim of analyzing which factors are associated with destruction of the finger joints. METHODS: A total of 1,215 Japanese patients with RA were recruited from 2 different populations. The degree of joint destruction was assessed using the total modified Sharp/van der Heijde score (SHS) of radiographic joint damage. The SHS score of joint damage in the finger joints was used as the dependent variable, and the SHS score in the non-finger joints was used as a covariate. Age, sex, disease duration, smoking, C-reactive protein level, treatment for RA, and positivity for and levels of anti-citrullinated protein antibodies and rheumatoid factor (RF) were evaluated as candidate correlates. Overall effect sizes were assessed in a meta-analysis. In addition, associations observed in the Japanese patients were compared to those in a cohort of 157 Dutch RA patients in the BeSt study (a randomized, controlled trial involving 4 different strictly specified treatment strategies for early RA). RESULTS: Not surprisingly, disease duration in Japanese patients with RA was associated with the finger SHS score (P ≤ 0.00037). Both positivity for and levels of RF showed significant associations with the finger SHS score after adjustment for covariates (P = 0.0022 and P = 8.1 × 10(-7) , respectively). These associations were also true in relation to the time-averaged finger SHS score. An association between RF positivity and the finger SHS score was also observed in Dutch patients with RA in the BeSt study (P = 0.049). CONCLUSION: Positivity for and levels of RF are associated with finger joint destruction independent of non-finger joint destruction and other covariates. Our findings suggest that there are different mechanisms of joint destruction operating in the finger joints of patients with RA.

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Personalized medicine: predicting responses to therapy in patients with RA.

Personalized medicine where each patient receives the right drug and the right intensity of drug treatment for as long as needed or safe is the goal of medicine. The identification of predictors of response is the first step toward this. In rheumatoid arthritis (RA), several prediction matrices were designed to predict the risk of rapid radiological progression (RRP) in the first year of treatment, on either disease modifying anti-rheumatic drug (DMARD) monotherapy or combination therapy with prednisone or a biological agent. Both clinical markers and biomarkers of response to either anti-TNF or different mode of action biological agents, and of successful discontinuation of these agents once the treatment goal has been achieved, have been identified in different studies. Most of these markers need validation in other cohorts. Research into combining clinical markers and biomarkers of response could lead to identification of risk profiles resulting in a new step toward personalized medicine in RA.

Meta-analysis suggests that intensive non-biological combination therapy with step-down prednisolone (COBRA strategy) may also 'disconnect' disease activity and damage in rheumatoid arthritis.

BACKGROUND/OBJECTIVE: Treatment of rheumatoid arthritis (RA) with tumour necrosis factor (TNF) antagonists changes the relationship between disease activity and progression of radiological joint damage ('disconnect'): patients who have little or no response of disease activity still show reductions in damage progression. In early RA, the COBRA strategy (combination of methotrexate and sulfasalazine with step-down prednisolone) has been shown to be equivalent to high-dose methotrexate and infliximab in suppressing damage progression (BeSt trial). We investigated whether COBRA treatment can also 'disconnect' disease activity and damage. DESIGN: A meta-analysis combined data from the COBRA trial (COBRA vs sulfasalazine monotherapy) with that of two arms of the BeSt trial (COBRA vs sequential monotherapy). Linear regression related 1-year progression of damage (Sharp van der Heijde score) as a dependent variable with disease activity (time-averaged Disease Activity Score in 44 joints (DAS44) or C-reactive protein (CRP)), treatment strategy (COBRA or control) and their interaction (indicator of a disconnect) as independent variables. The main outcome was the pooled interaction term. RESULTS: Complete data from 60-100% of patients were available. Before pooling, disease activity was the only (strongly) significant independent factor related to damage progression. The pooled interaction term was (weakly) significant: time-averaged DAS44×treatment interaction, one-sided p=0.027; time-averaged CRP×treatment interaction, one-sided p=0.044. CONCLUSIONS: Changes in the relationship between disease activity and damage progression may not be limited to anti-TNF treatment, but a property of early, rapid and deep suppression of joint inflammation, also induced by conventional strategies that include glucocorticoids.