Is glucocorticoid bridging therapy associated with later use of glucocorticoids and biological DMARDs during the disease course of patients with rheumatoid arthritis in daily practice? A real-world data analysis.

OBJECTIVE: To evaluate if initially starting glucocorticoid (GC) bridging leads to a higher probability of long-term GC and biological (b)DMARD use in rheumatoid arthritis (RA)-patients. METHODS: Electronical health records data from newly diagnosed RA-patients from the Leiden University Medical Center were used. Patients who started GC as part of initial treatment (iGC group) and who did not (niGC group) were compared in terms of GC and bDMARD use later in the disease course. Multivariable adjustment was performed to account for confounding by indication. RESULTS: 465/932 newly diagnosed RA-patients (50 %) were treated with GC as initial treatment step. Patients in the iGC group were older, included fewer females, had a higher disease activity at baseline compared to the niGC group plus a more rapid decrease in DAS28 in the first 6 months. During follow-up, 42 % of the iGC group started a second course of GC and 17 % started a bDMARD, compared to 34 % and 13 % In the niGC group. The hazard to start a bDMARD later in the disease course was not significantly different between the two groups in two time periods (0.34 95 %CI(0.09;1.21) resp. 1.48 95 %CI (0.98;2.22)), but the hazard to (re)start GC later on was higher for the iGC group (aHR 1.37 95 %CI(1.09;1.73)). CONCLUSION: In this daily practice cohort of newly diagnosed RA patients, patients in the iGC group had a more rapid DAS28 decrease and an increased probability of starting GC later on compared to the niGC group. The probability of bDMARD use was not significantly increased.

Presence of SARS-CoV-2 antibodies in patients with COVID-19 like symptoms from the IENIMINI cohort.

OBJECTIVE: To evaluate the relationship between reported coronavirus disease 2019 (COVID-19)-like symptoms and the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies in patients with an immune-mediated inflammatory disorder or post-solid organ transplantation (IMIDT) with and without immunosuppressive medication (imed) and controls. METHOD: The IENIMINI cohort was a prospective cohort study set up in the Netherlands in March 2020, with 2 monthly (paper) or weekly (online) questionnaires about COVID-19-like symptoms. Participants from this cohort who reported these symptoms between March 2020 and November 2020 were approached for this substudy. SARS-CoV-2 antibodies were tested using a total antibody assay. RESULTS: Of the 1203 participants approached, 629 agreed to participate and were sent a fingerprick test; 565 participants collected a capillary blood sample, of which 562 were usable. Analysis showed that 57/202 (28.2%) of the tested IMIDT group with imed, 48/16 3(29.4%) of the IMIDT group without imed, and 69/197 (35.0%) of the control group tested positive for SARS-CoV-2 antibodies. Seroprevalences of SARS-CoV-2 antibodies between males and females, biological disease-modifying anti-rheumatic drug users and non-users, and those who had had a serious disease period (defined as an episode with dyspnoea and fever) and those who had not, were not statistically different between the three groups. CONCLUSIONS: Approximately 30% of patients who had reported COVID-19-like symptoms had SARS-CoV-2 antibodies. The seroprevalence of SARS-CoV-2 antibodies after reported COVID-19-like symptoms was similar in IMIDT patients with and without imed compared to controls.

Breakthrough infections with the SARS-CoV-2 omicron (B.1.1.529) variant in patients with immune-mediated inflammatory diseases.

OBJECTIVES: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. METHODS: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. RESULTS: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. CONCLUSIONS: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections.

No radiographic wrist damage after treatment to target in recent-onset juvenile idiopathic arthritis.

BACKGROUND: To evaluate radiographic progression of patients with new-onset juvenile idiopathic arthritis (JIA) in response to an early, tightly-controlled, treatment-to-target. METHODS: Patients with JIA participating in the BeSt-for-Kids-study, randomized to 3 treatment strategy arms, were eligible if at least 1 conventional wrist-radiograph was available. Bone damage as reflected by carpal length was assessed using the Poznanski-score. The BoneXpert-method was used to determine the Bone Age (BA, > 5 years) and bone mineral density (BMD) of the wrist. These scores were evaluated over time and compared between the treatment arms and mean JADAS10-score using linear mixed models corrected for age and symptom duration. RESULTS: In 60 patients, 252 radiographs were analysed. Baseline age and symptom duration were different between the arms. No difference in comparison to the healthy reference population was found at baseline for the Poznanski-score (IQR varying from - 0,82; 0.68), nor for BA (varying from - 0.88 to 0.74). Baseline BMD was statistically significantly lower in arm 3 (initial treatment with etanercept and methotrexate) (- 1.48; - 0.68) compared to arm 1 (- 0.84; - 0.04) and arm 2 (- 0.93; 0.15). After treatment to target inactive disease, the Poznanski-scores and the BA remained clinically unchanged, while the BMD in arm 3 improved (p < 0.05 vs arm 1). CONCLUSIONS: Recent-onset JIA patients, treated-to-target aimed at inactive disease, showed no signs of radiographic wrist damage (Poznanski-score, BA or BMD) either at baseline or at follow-up, irrespective of treatment arm. A lower BMD at baseline in arm 3, initially treated with methotrexate and etanercept, improved significantly after treatment. TRIAL REGISTRATION: NTR, NL1504 (NTR1574). Registered 01-06-2009.

Does treatment strategy influence the ability to achieve and sustain DMARD-free remission in patients with RA? Results of an observational study comparing an intensified DAS-steered treatment strategy with treat to target in routine care.

OBJECTIVES: To study the impact of treatment strategy on achieving and sustaining disease-modifying antirheumatic drug (DMARD)-free remission in patients with rheumatoid arthritis (RA). METHODS: Two hundred seventy-nine RA patients (median follow-up 7.8 years) were studied. Of these, 155 patients participated in a disease activity score (DAS) < 1.6 steered trial aimed at DMARD-free remission. Initial treatment comprised methotrexate with high-dose prednisone (60 mg/day) and a possibility to start biologicals after 4 months. In the same period and hospital, 124 patients were treated according to routine care, comprising DAS < 2.4 steered treatment. Percentages of DMARD-free remission (absence of synovitis for ≥ 1 year after DMARD cessation), late flares (recurrence of clinical synovitis ≥ 1 year after DMARD cessation), and DMARD-free sustained remission (DMARD-free remission sustained during complete follow-up) were compared between both treatment strategies. RESULTS: Patients receiving intensive treatment were younger and more often ACPA-positive. On a group level, there was no significant association between intensive treatment and DMARD-free remission (35% vs 29%, corrected hazard ratio (HR) 1.4, 95%CI 0.9-2.2), nor in ACPA-negative RA (49% versus 44%). In ACPA-positive RA intensive treatment resulted in more DMARD-free remission (25% vs 6%, corrected HR 4.9, 95%CI 1.4-17). Intensive treatment was associated with more late flares (20% versus 8%, HR 2.3, 95%CI 0.6-8.3). Subsequently, there was no difference in DMARD-free sustained remission on a group level (28% versus 27%), nor in the ACPA-negative (43% versus 42%) or ACPA-positive stratum (17% versus 6%, corrected HR 3.1, 95%CI 0.9-11). CONCLUSIONS: Intensive treatment did not result in more DMARD-free sustained remission, compared to routine up-to-date care. The data showed a tendency towards an effect of intensive treatment in ACPA-positive RA; this needs further investigation.

A comparison of three treatment strategies in recent onset non-systemic Juvenile Idiopathic Arthritis: initial 3-months results of the BeSt for Kids-study.

BACKGROUND: Combination therapy with prednisone or etanercept may induce earlier and/or more improvement in disease activity in Disease Modifying Anti Rheumatic Drug (DMARD) naïve non-systemic Juvenile Idiopathic Arthritis (JIA) patients. Here we present three months clinical outcome of initial treatments of the BeSt-for-Kids study. METHODS: Included patients were randomized to either: 1. initial DMARD-monotherapy (sulfasalazine (SSZ) or methotrexate (MTX)), 2. Initial MTX / prednisolone-bridging, 3. Initial combination MTX/etanercept. Percentage inactive disease, adjusted (a) ACR Pedi30, 50 and 70 and JADAS after 6 and 12 weeks of treatment (intention to treat analysis) and side effects are reported. RESULTS: 94 patients (67% girls, 32 (arm 1), 32 (arm 2) and 30 (arm 3) with median (InterQuartileRange) age of 9.1 (4.7-12.9) years were included. 38% were ANA positive, 10 had oligo-articular disease, 68 polyarticular JIA and 16 psoriatic arthritis. Baseline median (IQR) ACRpedi-scores: VAS physician 49 (40-58) mm, VAS patient 54 (37-70) mm, ESR 6.5 (2-14.8)mm/hr, active joint count 8 (5-12), limited joint count 3 (1-5), CHAQ score 0.88 (0.63-1.5). In arm 1, 17 started with MTX, 15 with SSZ. After 3 months, aACR Pedi 50 was reached by 10/32 (31%), 12/32(38%) and 16/30 (53%) (p = 0.19) and aACR Pedi 70 was reached by 8/32 (25%), 6/32(19%) and 14/30(47%) in arms 1-3 (p = 0.04). Toxicity was similar. Few serious adverse events were reported. CONCLUSION: After 3 months of treatment in a randomized trial, patients with recent-onset JIA achieved significantly more clinical improvement (aACRPedi70) on initial combination therapy with MTX / etanercept than on initial MTX or SSZ monotherapy. TRIAL REGISTRATION: NTR1574 . Registered 3 December 2008.

Meta-Regression of a Dose-Response Relationship of Methotrexate in Mono- and Combination Therapy in Disease-Modifying Antirheumatic Drug-Naive Early Rheumatoid Arthritis Patients.

OBJECTIVE: To investigate a possible short-term dose-response relationship of initial treatment with methotrexate (MTX) in monotherapy and combination therapy in recent-onset rheumatoid arthritis (RA) patients. METHODS: A systematic literature search was performed on trials and cohorts, including early, disease-modifying antirheumatic drug (DMARD)-naive RA patients treated with MTX, with data on clinical results within 6 months from treatment start. Cohen's effect sizes were calculated for the Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level, and/or Disease Activity Score (DAS)/in 28 joints (DAS28) in 4 treatment groups: MTX monotherapy, or MTX in combination with synthetic (cs) DMARDs, biologic (b) DMARDs, or glucocorticoids. Random-effects meta-regression analyses were performed for each outcome, with treatment group as the predictor corrected for baseline HAQ or disease activity and assessment point. RESULTS: Thirty-one studies including 5,589 patients were included. The meta-regression did not support higher effectiveness of increasing MTX dose in monotherapy. The number of treatment groups using combination therapy with csDMARDs was too small to perform meta-regression analyses. In combination therapy with glucocorticoids, a higher MTX dose was associated with higher (worse) outcome HAQ, but not with DAS/DAS28 or ESR/CRP level. In combination therapy with bDMARDs, a higher MTX dose was associated with higher outcome HAQ and DAS/DAS28, but not with ESR/CRP level. All effect sizes were small. CONCLUSION: In DMARD-naive, early RA patients who start MTX, either as monotherapy or in combination with bDMARDs or glucocorticoids, a higher initial dose of MTX was not associated with better clinical outcomes. This finding suggests that there is little short-term gain from starting with high compared to low MTX doses.

Rheumatologists' adherence to a disease activity score steered treatment protocol in early arthritis patients is less if the target is remission.

To compare rheumatologists' adherence to treatment protocols for rheumatoid arthritis (RA) targeted at Disease Activity Score (DAS) ≤2.4 or <1.6. The BeSt-study enrolled 508 early RA (1987) patients targeted at DAS ≤2.4. The IMPROVED-study included 479 early RA (2010) and 122 undifferentiated arthritis patients targeted at DAS <1.6. We evaluated rheumatologists' adherence to the protocols and assessed associated opinions and conditions during 5 years. Protocol adherence was higher in BeSt than in IMPROVED (86 and 70 %), with a greater decrease in IMPROVED (from 100 to 48 %) than in BeSt (100 to 72 %). In BeSt, 50 % of non-adherence was against treatment intensification/restart, compared to 63 % in IMPROVED and 50 vs. 37 % were against tapering/discontinuation. In both studies, non-adherence was associated with physicians' disagreement with DAS or with next treatment step and if patient's visual analogue scale (VAS) for general health was ≥20 mm higher than the physician's VAS. In IMPROVED, also discrepancies between swelling, pain, erythrocyte sedimentation rate, and VASgh were associated with non-adherence. Adherence to DAS steered treatment protocols was high but decreased over 5 years, more in a DAS <1.6 steered protocol. Non-adherence was more likely if physicians disagreed with DAS or next treatment step. In the DAS <1.6 steered protocol, non-adherence was also associated with discrepancies between subjective and (semi)objective disease outcomes, and often against required treatment intensification. These results may indicate that adherence to DAS-steered protocols appears to depend in part on the height of the target and on how physicians perceive the DAS reflects RA activity.

Age affects joint space narrowing in patients with early active rheumatoid arthritis.

BACKGROUND: Joint space narrowing (JSN) in rheumatoid arthritis (RA) may be a manifestation of (primary) osteoarthritis becoming more prominent with age. We investigated the severity and predictors of JSN progression among different age groups. METHODS: 10-year follow-up data of the BeSt study, a randomised controlled treat-to-target trial in early RA were used. Annual X-rays of hands and feet were scored using the Sharp/van der Heijde score (SHS). Subgroups were defined by age at baseline: ≥55, ≥40<55 and <40 years. JSN progression predictors were assessed by Poisson regression. RESULTS: Baseline JSN scores (median (IQR)) were higher in patients ≥55 (2.0 (0.0-6.0)) compared with the other age groups: 1.0 (0.0-3.0) ≥40<55 and 0.3 (0.0-3.0) <40, p<0.001. After 10 years, total JSN and SHS were similar in all age groups. In patients ≥55 the mean erythrocyte sedimentation rate (ESR) over time (relative risk 1.02 (95% CI 1.00 to 1.03)) and the combined presence of rheumatoid factor and anticitrullinated protein antibodies (RF+/ACPA+) (3.27 (1.25-8.53)) were significantly correlated with JSN progression. In patients <40 the baseline swollen joint count (SJC; 1.09 (1.01-1.18)) and ESR over time (1.04 (1.02-1.06)) were significantly associated. CONCLUSIONS: At baseline, patients with RA ≥55 years had more JSN than younger patients but after 10 years JSN scores were similar between age groups. Independent risk factors for JSN progression were baseline SJC and ESR over time in patients <40, RF+/ACPA+ and ESR over time in patients ≥55 years. This suggests that mechanisms leading to JSN progression are related to (residual) rheumatoid inflammation and vary between age groups. These mechanisms remain to be elucidated. TRIAL REGISTRATION NUMBERS: NTR262, NTR265.

Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial.

OBJECTIVE: To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis. METHODS: In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients. RESULTS: ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms. CONCLUSIONS: Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited. TRIAL REGISTRATION NUMBER: NTR262, NTR265.

Evaluating Adherence to a Treat-to-Target Protocol in Recent-Onset Rheumatoid Arthritis: Reasons for Compliance and Hesitation.

OBJECTIVE: To evaluate rheumatologists' adherence to a low Disease Activity Score (DAS)-steered treat-to-target (T2T) strategy in treatment of patients with rheumatoid arthritis (RA) and to assess associated conditions. METHODS: Data of the BeSt study were used, a multicenter T2T strategy trial with 10-year followup. During 3 monthly visits, the physician answered questions about satisfaction with level of RA suppression, agreement with the study protocol, and agreement with the DAS. Associations between the answers and nonadherence were evaluated. RESULTS: Protocol adherence decreased over time from 100% to 60% per visit, with an average over time of 79%. Rheumatologists mostly agreed with the DAS (80-90% of visits over time) and were satisfied with the treatment steps (75-90%) and with the level of RA suppression (85-90%). The odds for protocol violation were higher when the rheumatologist disagreed with the DAS (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 2.0-2.7 when they thought the DAS overestimated actual disease activity; OR 2.5, 95% CI 2.0-3.1 when they thought the DAS underestimated actual disease activity) or with the next required treatment step (OR 3.0, 95% CI 2.5-3.5), and when the physician was dissatisfied with disease suppression (OR 1.3, 95% CI 1.1-1.6). CONCLUSION: Rheumatologists generally agreed with and followed a 10-year followup DAS-steered T2T strategy. Disagreement with the DAS or the required treatment and dissatisfaction with the level of disease suppression were risk factors for nonadherence. These results indicate the feasibility of continued protocol-driven T2T therapy. For daily practice, adherence to T2T therapy might be improved by adopting the structure components of a clinical trial.

Can we prevent rapid radiological progression in patients with early rheumatoid arthritis?

The aim of this study is to test the performance of a matrix model to predict rapid radiological progression (RRP) in a study population of early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) patients. A matrix model using baseline CRP, erosion score, autoantibody status, and initial treatment choice to predict RRP (increase ≥5 points in Sharp-van der Heijde score (SHS) in 1 year) was derived from the BeSt study where patients with active RA (1987-criteria) were treated with initial monotherapy or combination therapy, aiming at low disease activity. In the IMPROVED study, patients with early RA (2010 criteria) and UA were initially treated with methotrexate and prednisone aiming at remission. A receiver operating characteristics (ROC) curve was used to assess the discriminative value of the model to predict damage progression in the IMPROVED population. Four hundred thirty-one out of 479 patients with RA and 106/122 with UA could be categorized as high, intermediate, low, or very low risk for RRP. One patient, with a very low risk profile, showed RRP. Thirty-two other patients (5 %) showed radiological progression ≥0.5 point SHS; none had a high risk profile and 22 had a very low risk profile. The area under the curve (AUC) of the ROC curve was 0.56 (95% CI 0.45; 0.68). A matrix model predicting RRP based on risk factors identified in recent onset active RA according to the 1987-criteria performed poorly in recent onset RA (2010 criteria) and UA. It appears that known risk factors for damage progression lose their impact with early remission steered treatment, so that RRP might be considered a phenomenon of the past.

Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1†year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study.

AIM: To assess whether in early (rheumatoid) arthritis (RA) patients, metacarpal bone mineral density (BMD) loss after 4 months predicts radiological progression after 1 year of antirheumatic treatment. METHODS: Metacarpal BMD was measured 4 monthly during the first year by digital X-ray radiogrammetry (DXR-BMD) in patients participating in the IMPROVED study, a clinical trial in 610 patients with recent onset RA (2010 criteria) or undifferentiated arthritis, treated according to a remission (disease activity score<1.6) steered strategy. With Sharp/van der Heijde progression ≥0.5 points after 1 year (yes/no) as dependent variable, univariate and multivariate logistic regression analyses were performed. RESULTS: Of 428 patients with DXR-BMD results and progression scores available, 28 (7%) had radiological progression after 1 year. Independent predictors for radiological progression were presence of baseline erosions (OR (95% CI) 6.5 (1.7 to 25)) and early DXR-BMD loss (OR (95% CI) 1.5 (1.1 to 2.0)). In 366 (86%) patients without baseline erosions, early DXR-BMD loss was the only independent predictor of progression (OR (95% CI) 2.0 (1.4 to 2.9)). CONCLUSIONS: In early RA patients, metacarpal BMD loss after 4 months of treatment is an independent predictor of radiological progression after 1 year. In patients without baseline erosions, early metacarpal BMD loss is the main predictor of radiological progression.

Comparison of characteristics of international and national databases for rheumatoid arthritis: a systematic literature review.

OBJECTIVES: To evaluate current (inter)national registers and observational cohorts in Europe, and to compare inclusion criteria, aims, collected data, and participation in the European League Against Rheumatism (EULAR) repository. METHOD: We performed a systematic search strategy in six literature databases for rheumatoid arthritis (RA). Publications reporting European (inter)national prospective registers/cohorts including > 200 RA patients with at least half a year of follow-up were selected. RESULTS: In total, 417 articles and abstracts were included from four international databases and 39 national databases/cohorts. International databases were of similar design, frequency of data collection and selection criteria and are mostly initiated to monitor and compare clinical patient care among countries. National databases/cohorts vary in aims and inclusion criteria. Half of the national registers are connected to the EULAR repository of databases. CONCLUSIONS: Our findings indicate that, among researchers, there is little awareness of guidelines to set up registers or cohorts and of the existence of the database collaboration network of EULAR.

Drug-free holiday in patients with rheumatoid arthritis: a qualitative study to explore patients' opinion.

Clinical trials have shown that in patients with long-standing low disease activity, tapering and/or stopping antirheumatic medication is a realistic option. The objective of this study is to explore patients' opinion about tapering and discontinuing antirheumatic drugs. This qualitative study is based on interviews with 20 patients with rheumatoid arthritis (RA) about RA treatment and treatment discontinuation through structured interviewing. Interviews were tape-recorded, transcribed verbatim, and screened by three assessors independently for meaning units. Not only positive emotions about drug discontinuation such as hope, happiness, and relief, but also fear and disappointment were mentioned. Some patients expect that drug discontinuation will be possible in other patients and/or themselves, while others do not expect this. The concept of increase in disease activity after discontinuing medication was mentioned, and while patients expect that disease activity will decrease again after restarting medication, they expect that this will take (too much) time. Positive emotions about the option to taper and discontinue antirheumatic medication, with negative expectations is a common combination in these RA patients. In particular, patients expect that disease activity will flare and that improvement upon restarting medication will take time. Patients' expectations and feelings should be addressed before drug tapering is attempted in a clear strategy of continued monitoring of disease activity.

A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study.

OBJECTIVES: To assess which treatment strategy is most effective in inducing remission in early (rheumatoid) arthritis. METHODS: 610 patients with early rheumatoid arthritis (RA 2010 criteria) or undifferentiated arthritis (UA) started treatment with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (Disease Activity Score <1.6 after 4 months) tapered prednisone to zero and those with persistent remission after 8 months, tapered and stopped MTX. Patients not in early remission were randomised to receive either MTX plus hydroxychloroquine plus sulfasalazine plus low-dose prednisone (arm 1) or to MTX plus adalimumab (ADA) (arm 2). If remission was present after 8 months both arms tapered to MTX monotherapy; if not, arm 1 changed to MTX plus ADA and arm 2 increased the dose of ADA. Remission rates and functional and radiological outcomes were compared between arms and between patients with RA and those with UA. RESULTS: 375/610 (61%) patients achieved early remission. After 1 year 68% of those were in remission and 32% in drug-free remission. Of the randomised patients, 25% in arm 1 and 41% in arm 2 achieved remission at year 1 (p<0.01). Outcomes were comparable between patients with RA and those with UA. CONCLUSIONS: Initial MTX and prednisone resulted in early remission in 61% of patients with early (rheumatoid) arthritis. Of those, 68% were in remission and 32% were in drug-free remission after 1 year. In patients not in early remission, earlier introduction of ADA resulted in more remission at year 1 than first treating with disease-modifying antirheumatic drug combination therapy plus prednisone.

The BeSt way of withdrawing biologic agents.

OBJECTIVES: Treat-to-target strategies in the management of patients with rheumatoid arthritis (RA) involve intensifying medication as long as low disease activity or remission is not achieved. Our aim was to discuss reasons and opportunities for tapering and discontinuing medication when the target is achieved, in particular of biological agents. METHODS: Data from the Behandel Strategieën (BeSt) study are presented, a multicentre randomised clinical trial comparing 4 treatment strategies in patients with recent onset active RA (1987 criteria): 1. Sequential monotherapy, 2. Step up to combination therapy (both starting with methotrexate (MTX) monotherapy), 3. Initial combination therapy with MTX, sulfasalazine and prednisone and 4. Initial combination therapy with MTX and infliximab. Treatment adjustments involving dose increases, drug changes or expansion to combination therapy occurred based on three-monthly calculations of the Disease Activity Score (DAS), with a target of ≤2.4. If this was achieved for 2 consecutive evaluations, treatment was tapered (combinations to monotherapy, monotherapy to maintenance dose). Prednisone and infliximab (either as part of initial treatment or as delayed treatment after failure on earlier therapies in arms 1, 2 and -for infliximab- 3) were always tapered and discontinued before other drugs. The outcomes of discontinuation of infliximab are presented. RESULTS: 77/120 (64%) of patients who started initial infliximab were able to discontinue infliximab, whereas 27/109 (25%) of patients who started delayed infliximab in arms 1-3 could discontinue infliximab. Discontinuation was independent of previous dose increases in order to achieve low DAS. After discontinuation of infliximab, 16 of 27 patients (59%) in arms 1-3 and 34 of 77 patients (44%) in arm 4 suffered a DAS flare >2.4 and had to restart treatment. Median time without infliximab treatment was 17 (IQR 3-47) months, and 29 of the 61 patients (58%) who needed to restart had been at least 1 year without infliximab. Restarting infliximab resulted in DAS ≤2.4 in all patients, and there was no progression of radiological damage. Presence of shared epitope, smoking, and a long treatment with infliximab were independent predictors of infliximab restart. CONCLUSIONS: Data on infliximab discontinuation in the BeSt study suggest that this possible in 1 in 4 patients, or more if infliximab was the initial treatment, who have had at least 6 consecutive months of low disease activity. While MTX is continued, about 50% of patients can permanently stop infliximab without radiological damage progression, the others regain low disease activity after restarting infliximab. Treat to target strategies using biologic agents should include strategies for discontinuation.

The relationship between disease activity and depressive symptoms severity and optimism--results from the IMPROVED study.

To assess depressive symptoms severity and dispositional optimism in patients with recent onset arthritis both before and after 4 months treatment. Two hundred twenty-two patients with recent onset RA and undifferentiated arthritis in the IMPROVED study filled out the Beck Depression Inventory (BDI-II) to assess depressive symptoms severity and the Life Orientation Test Revised (LOT-R) to measure optimism before and after 4 months of treatment. All patients were treated with methotrexate 25 mg/week and prednisone 60 mg/day (tapered to 7.5 mg/day in 7 weeks). Linear regression analysis was used to assess the association between the disease activity score (DAS) and its components (tender joint count, general well-being measured with a visual analogue scale (VAS), swollen joint count, and erythrocyte sedimentation rate) with the BDI-II an LOT-R scores. In general, depressive symptoms were mild. The DAS was an independent predictor of depressive symptoms scores both at baseline and after 4 months follow-up, in particular tender joint count and VAS global health. Disease activity was not associated with the level of optimism. Nevertheless, patients who achieved clinical remission improved significantly more in both depression score and optimism score than patients who did not. Patients with early arthritis report improvement in depressive symptoms and optimism with improvement in disease activity and achieving clinical remission. Depression scores are associated with pain and unwell being but not with swollen joint counts and inflammatory parameters.

Drug therapy in undifferentiated arthritis: a systematic literature review.

Undifferentiated arthritis (UA) is defined as an inflammatory oligoarthritis or polyarthritis in which no definitive diagnosis can be made. We performed a literature review to assess the efficacy of various drug therapies in patients with UA. The literature search was conducted using electronic databases Pubmed, EMBASE and MEDLINE in adults with UA or early arthritis (not fulfilling the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis). Drug therapy consisted of disease modifying antirheumatic drugs (DMARDs), biological agents and oral, intramuscular or intra-articular corticosteroids. Nine publications on eight randomised controlled trials (RCTs), two publications on two uncontrolled open-label trials and seven publications on three cohort studies were included. Temporary treatment with methotrexate (MTX), abatacept and intramuscular corticosteroids were demonstrated in RCTs with 12 months to 5 years follow-up to be more effective than placebo in suppressing disease activity or radiological progression. One study suggests that DMARD combination therapy is, at least after 4 months, superior to MTX monotherapy in patients with UA at high risk of developing persistent arthritis. The open-label uncontrolled trials and cohort studies also suggested that early treatment may provide immediate suppression of inflammation. The long-term benefit of early treatment in UA remains unclear. In conclusion, patients with UA benefit from early treatment with MTX. Combining multiple DMARDs or DMARDs with corticosteroids and biological agents may be even more beneficial. However, which treatment may provide the best results or may alter the disease course has still to be determined. More RCTs with longer follow-up time are needed.