B. Grillet

Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis

Objectives: To compare the occurrence of drug-free remission, functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis (RA). Methods: Patients with recent-onset, active RA (n  =  508) were randomly assigned to four different treatment strategies: (1) sequential monotherapy; (2) step-up combination therapy; (3) initial combination therapy with prednisone and (4) initial combination therapy with infliximab. Treatment was adjusted based on 3-monthly disease activity score (DAS) assessments, aiming at a DAS ⩽2.4. From the third year, patients with a sustained DAS <1.6 discontinued treatment. Results: In total, 43% of patients were in remission (DAS <1.6) at 4 years and 13% were in drug-free remission: 14%, 12%, 8% and 18% of patients in groups 1–4, respectively. The absence of anti-cyclic citrullinated peptide antibodies, male gender and short symptom duration were independently associated with drug-free remission. Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment, without significant differences between the groups. Significant progression of joint damage was observed in 38% and 31% of patients in groups 3 and 4 versus 51% and 54% of patients in groups 1 and 2 (p<0.05, group 4 versus groups 1 and 2, group 3 versus group 2). Conclusions: In patients with recent-onset active RA, drug-free remission was achieved in up to 18% of patients. DAS-driven treatment maintained clinical and functional improvement, independent of the treatment strategy. Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy.

Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial

Objective To determine the most effective induction disease-modifying antirheumatic drug (DMARD) strategy in early rheumatoid arthritis (RA), second to compare one single dose of intramuscular glucocorticoids (GCs) with daily oral GCs during the induction phase. Methods The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis (tREACH) were used. Patients were included who had a high probability (>70%) of progressing to persistent arthritis, based on the prediction model of Visser. Patients were randomised into three induction therapy strategies: (A) combination therapy (methotrexate (MTX) + sulfasalazine + hydroxychloroquine) with GCs intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. A total of 281 patients were randomly assigned to strategy (A) (n=91), (B) (n=93) or (C) (n=97). Results The Disease Activity Score (DAS) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67 to 0.11, 95% CI)). DAS did not differ between the different GC bridging treatments. After 3 months 50% fewer biological agents were prescribed in the combination therapy groups. Although the proportion of patients with medication adjustments differed significantly between the treatment arms, no differences were seen in these adjustments due to adverse events after stratification for drug. Conclusion Triple DMARD induction therapy is better than MTX monotherapy in early RA. Furthermore, no differences were seen in medication adjustments due to adverse events after stratification for drug. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used.

Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study)

Aim Classifying more patients as rheumatoid arthritis (RA) (2010 American College of Rheumatology/European League Against Rheumatism criteria for RA) may improve treatment outcomes but may cause overtreatment in daily practice. The authors determined the efficacy of initial methotrexate (MTX) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis (UA). Method 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks. Percentage remissions after 4 months were compared between RA (1987 or 2010 criteria) and UA. Predictors for remission were identified. Results With the 2010 criteria, 19% more patients were classified as RA than with the 1987 criteria, but similar remission rates were achieved: 291/479 (61%) 2010 classified RA and 211/264 (58%) 1987 classified RA patients (p=0.52), and 79/122 (65%) UA patients (p=0.46). Anticitrullinated protein antibodies (ACPA) positive RA patients achieved more remission (66%) than ACPA negative RA patients (51%, p=0.001), but also had a lower mean baseline Disease Activity Score (DAS) (3.2 vs 3.6, p<0.001). Independent predictors for remission were male sex, low joint counts, DAS and Health Assessment Questionnaire, low body mass index and ACPA positivity. Conclusion Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months (about 60%) in RA patients, regardless of fulfilling the 1987 or 2010 criteria, and in UA patients. Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission.

Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (BeSt trial)

Objective: To determine treatment preferences among patients with recent onset rheumatoid arthritis participating in a randomised controlled trial comparing four therapeutic strategies. Methods: A questionnaire was sent to all 508 participants of the BeSt trial, treated for an average of 2.2 years with either sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Treatment adjustments were made every 3 months to achieve low disease activity (DAS ⩽2.4). The questionnaire explored patients’ preferences or dislikes for the initial therapy. Results: In total, 440 patients (87%) completed the questionnaire. Despite virtually equal study outcomes at 2 years, more patients in group 4 reported much or very much improvement of general health: 50%, 56%, 46% and 74% in groups 1–4, respectively (overall, P<0.001). Almost half of the patients expressed no preference or aversion for a particular treatment group, 33% had hoped for assignment to group 4 and 38% had hoped against assignment to group 3. This negative perception was much less prominent in patients actually in group 3. Nevertheless, 50% of patients in group 3 disliked having to take prednisone, while only 8% in group 4 disliked going to the hospital for intravenous treatment. Conclusions: Within the limitations of our retrospective study, patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone. After actual exposure, this preference remained, but the perception of prednisone improved. Patient perceptions need to be addressed when administering treatment.

Large-joint damage in patients with early rheumatoid arthritis and its association with treatment strategy and damage of the small joints

OBJECTIVE To determine the prevalence of large-joint damage and the association with small-joint damage in patients with RA after 8 years of low DAS (≤2.4)-targeted treatment with different treatment strategies. METHODS Radiological data of 290 patients participating in the BeSt study, a randomized trial comparing initial monotherapy and initial combination therapy strategies, were used. Radiographs of large joints were scored using the Larsen score and of the small joints using the Sharp-van der Heijde score. With multivariate logistic regression analysis, an association between total damage of the small joints and of the large joints was investigated. RESULTS After 8 years of treatment, damage was observed in 12% of shoulders, 10% of elbows, 26% of wrists, 13% of hips, 18% of knees and 7% of the ankles. Damage in one or more large joints was found in 64% of patients, with a median score of 1. No difference was found between initial monotherapy or combination therapy strategies. There was a significant association between damage progression in small joints and damage to one or more large joints (OR 1.02; 95% CI 1.00-1.04). CONCLUSION After 8 years of DAS-targeted treatment in early RA patients, large-joint damage was found in 64% of patients and was associated with small-joint damage. Continued DAS-targeted treatment is probably more important in damage suppression than initial treatment strategy. Patients with more damage to hands and feet also have more damage to the large joints.

Tapering conventional synthetic DMARDs in patients with early arthritis in sustained remission: 2-year follow-up of the tREACH trial

Objectives With early and intensive treatment many patients with early RA attain remission. Aims were to investigate (1) the frequency and time to sustained remission and subsequent tapering in patients initially treated with conventional synthetic disease modifying anti-rheumatic drug ((cs)DMARD) strategies and (2) the frequency and time to flare and regained remission in patients tapering csDMARDs and biological (b)DMARDs during 2 years of follow-up. Methods Two-year follow-up data from the treatment in the Rotterdam Early Arthritis Cohort (tREACH) cohort were used. Patients were randomised to initial treatment with triple DMARD therapy (iTDT) with glucocorticoid (GC) bridging or methotrexate monotherapy (iMM) with GC bridging. Patients were evaluated every 3 months. In case Disease Activity Score (DAS) was >2.4 treatment was switched to a TNF-blocker. In case DAS<1.6 at 2 consecutive time points, tapering was initiated according to protocol. Outcomes were rates of sustained remission (DAS<1.6 at 2 consecutive time points), flare (medication increase after tapering) and remission after flare (DAS<1.6). Data were analysed using Kaplan-Meier analyses. Results During 2 years of follow-up, sustained remission was achieved at least once by 159 (57%) of patients, of whom 118 and 23 patients initiated tapering of csDMARDs and bDMARDs, respectively. Thirty-four patients achieved drug-free remission. Flare rates were 41% and 37% and within 1 year, respectively. After flare, 65% of patients tapering csDMARDs re-achieved remission within 6 months after treatment intensification. Conclusions Regardless of initial treatment strategy, 57% of patients achieved sustained remission during 2 years of follow-up. Flare rates were 41% and 37% within 12 months in patients tapering csDMARDs and bDMARDs, respectively. Trial registration number ISRCTN26791028; Post-results.

SAT0111 Induction therapy with a combination of dmards is superior to methotrexate mono-therapy, unbiased for corticosteroids

Background The recently published EULAR treatment guideline recommended treatment for DMARD naïve patients is Methotrexate (MTX) with(out) glucocorticoids (GCs). Combination therapy with classical DMARDs however is not recommended, because well proven evidence of superior efficacy is suggested to be lacking. Furthermore possible drug toxicities might influence the physician’s choice of induction therapy. Objectives To compare the 3 month clinical efficacy of: (1) combination DMARD vs. MTX mono-therapy and (2) oral GCs bridging therapy vs. 1 dose of intramuscular (im) GCs in patients with early RA. Methods For this study data are used of a currently ongoing single-blinded randomized clinical trial in patients ≥18 years with recent-onset arthritis (tREACH). We included patients who had a high probability (>70%) according to their likelihood of progressing to persistent arthritis based of the prediction model of Visser. The Visser algorithm and 2010 criteria for RA have similar discriminative abilities to identify patients at risk of persistent arthritis at 1 year. Patients were randomized into 3 induction therapy strategies: (A) Combination therapy (MTX 25 mg/wk + SASP 2 gr./day + HCQ 400 mg/day) with GCs im (Depomedrol 120mg), (B) Combination therapy with an oral GCs tapering scheme (starting dose 15 mg) and (C) MTX with oral GCs similar to B. In case of “treatment failure”, defined as DAS>2.4, medication is intensified to MTX with a biological. Disease activity, functional ability, and adverse events were assessed. Results A total of 281 patients were randomly assigned to [A] (n=91), [B] (n=93) or [C] (n=97). Disease activity, after 3 months, was 0.39 (0.67–0.11, 95% CI) lower in patients with initial combination therapy compared to MTX mono-therapy. Difference in disease activity between the different GCs bridging therapies was 0.03 (–0.24–0.31, 95% CI). After three months 50% less biologicals were prescribed in the combination therapy groups. Functional ability (respectively 0.53 (0.40–0.66) [A] vs 0.53 (0.40–0.65) [B] vs 0.69 (0.55–0.84) [C]) and medication adjustments due to adverse events (resp. 22% [A] vs 20% [B] vs 16% [C]) did not differ between groups. Conclusions In patients with >70% chance of developing a RA a combination of DMARDs is superior to MTX mono-therapy in achieving low disease activity after three months, unbiased for GCs. Consequently 50% less biologicals were prescribed in the combination therapy groups. Furthermore intramuscular and oral GCs are equally effective as bridging therapy and can both be used. Funding Unrestricted grant from Pfizer bv. [0881-102217] Disclosure of Interest None Declared

OP0176 Five Year Outcomes of Remission Steered Treatment Including Drug Tapering Strategies in Early Arthritis Patients

Background The window of opportunity hypothesis suggests that early initiation of treatment targeted at remission in early arthritis patients may avoid chronicity of inflammation and may result in early drug-free remission (DFR). Objectives To assess clinical outcomes of induction therapy followed by 5 years DAS-remission targeted therapy including rapid drug tapering strategies in early arthritis patients. Methods The IMPROVED study included 610 early rheumatoid arthritis (RA, 2010 criteria) or undifferentiated arthritis (UA) patients starting with methotrexate (MTX) and tapered high dose of prednisone. Patients in early DAS-remission (ER) (disease activity score (DAS)<1.6 after 4 months) stopped prednisone and if remission persisted at t=8 months also MTX. Patients not in ER (DAS≥1.6) were randomized to MTX+sulfasalazine+hydroxychloroquine+low dose prednisone (arm 1) or MTX+adalimumab (arm 2), 50 patients were not randomized and were treated “outside of protocol” (OP). Four monthly treatment adjustments aimed at DAS<1.6; if DAS<1.6 taper/stop medication and if DAS≥1.6 restart/intensify medication. Percentages of patients in (drug free) DAS-remission after 5 years were compared between RA and UA patients and the different treatment strategies. Logistic regression analysis was used to identify predictive factors of DAS-remission and DFR after 5 years. Results After 5 years mean±SD DAS decreased and functional ability improved in all treatment groups without differences between arm 1 and 2. 295/610 (48%) patients were in DAS-remission: 220/387 (57%) in the ER group, 31/83 (37%) in arm 1, 29/78 (37%) in arm 2 (p=0.768 arm 1 vs arm 2) and 15/50 (30%) in OP. 134/610 (22%) patients were in DFR: 105/387 (27%) in the ER group, 9/83 (11%) in arm 1, 12/78 (15%) in arm 2 (p=0.374 arm 1 vs arm 2) and 8/50 (16%) in OP. DAS-remission was achieved in similar percentages in RA and UA patients and autoantibody positive (+) vs negative (−) patients. More UA than RA patients were in DFR at year 5 (33% vs 19%, p<0.001), and the same was true for anti-citrullinated protein antibodies (ACPA)− vs ACPA+ patients (31% vs 15%, p<0.001) and rheumatoid factor (RF)− vs RF+ positive patients (28% vs 17%, p<0.001). Between anti-carbamylated antibodies (anti-CarP)+ and − patients there was no difference in DFR rates. Predictors of DAS-remission were age (OR 0.97 (95% CI 0.96–0.99)), symptom duration (0.99 (0.98–0.99)), baseline tender joint count (0.95 (0.90–1.00)) and achieving ER (1.95 (1.23–3.10)) (figure). Predictors of DFR were symptom duration (0.99 (0.97–1.00) and ER (2.67 (1.48–4.84)). ACPA+ was mostly associated with less DFR. Conclusions After 5 years of DAS-remission steered treatment, 48% of early RA and UA patients were in DAS-remission and 22% in DFR. Remission results were better for patients who achieved ER and who had a shorter symptom duration. Remission results were similar for RA and UA patients, randomization arms and autoantibody status, but more UA than RA patients and more autoantibody? than + patients were in DFR. Disclosure of Interest G. Akdemir: None declared, L. Heimans: None declared, R. J. Goekoop: None declared, M. van Oosterhout: None declared, J. B. Harbers: None declared, C. Bijkerk: None declared, G. M. Steup-Beekman: None declared, L. Lard: None declared, P. B. J. de Sonnaville: None declared, B. A. M. Grillet: None declared, T. W. J. Huizinga: None declared, C. F. Allaart Grant/research support from: Year 1 of the IMPROVED study was sponsored by Abbott.

FRI0076 Low Disease Activity or DAS-Remission as Treatment Target in Early Rheumatoid Arthritis Patients

Background It is unknown what the optimum treatment target for early rheumatoid arthritis (RA) patients is. Objectives To assess which treatment target, low disease activity or disease activity score (DAS)-remission is more effective in early RA patients. Methods The BeSt study included early (≤2 years symptom duration) active (≥6 of 66 swollen joints, ≥6 of 68 tender joints, and either erythrocyte sedimentation rate ≥28 mm/hour or a visual analogue scale global health score ≥20mm) RA (1987 criteria) patients to compare 4 treatment strategies, targeted at DAS≤2.4. In arm 3 treatment started with a combination of methotrexate (MTX), sulfasalazine and a tapered high dose of prednisone. In the IMPROVED study, early arthritis patients started with MTX and a tapered high dose of prednisone, with subsequent treatment options aiming at DAS-remission (<1.6). We compared clinical outcomes during 5 years in 133 BeSt patients randomized to arm 3 with 175 IMPROVED patients who fulfilled the inclusion criteria of the BeSt study. Predictive factors for DAS<1.6 at year 1 and drug-free remission (DFR) at year 5 were assessed by logistic regression analysis. Results At baseline IMPROVED patients had a significantly lower mean±SD DAS compared to BeSt patients (4.1±0.7 vs 4.4±0.9, p=0.012) and a shorter median (IQR) symptom duration (17 (8–28) vs 23 (15–53) weeks, p<0.001) (figure). At 3 months in the BeSt study, DAS decreased by 2 to 2.4±1.0, functional ability improved from 1.4±0.7 to 0.6±0.6, 56% of patients achieved DAS≤2.4 and 20% were in DAS-remission. At 4 months in IMPROVED patients, DAS decreased >2 to 1.8±1.0, functional ability improved from 1.5±0.6 to 0.5±0.6, 72% of patients achieved DAS≤2.4 and 53% were in DAS-remission. At year 1, DAS was decreased by 2.5 in IMPROVED and 2.4 in BeSt compared to baseline, to 1.6±1.0 and 2.0±0.9, p=0.004, and more IMPROVED patients than BeSt patients had achieved DAS<1.6 (51% vs 30%, p<0.001). Similar percentages in both studies achieved DAS≤2.4 (73% in IMPROVED vs 67% in BeSt, p=0.333). By protocol, BeSt patients could not achieve DFR at year 1. DFR was achieved in 15% of IMPROVED patients. At year 5, DAS was decreased by 2.7 in IMPROVED and 2.6 in BeSt compared to baseline, to 1.5±0.8 and 1.7±0.8, respectively (p=0.014). DAS≤2.4 was achieved in 61% of IMPROVED patients and in 61% of BeSt patients (p=0.092), DAS<1.6 was achieved in 43% vs 32%, p=0.003, and DFR was achieved in 18% vs 8%, p=0.003. Predictive factors for DAS<1.6 at year 1 were type of treatment study (OR for IMPROVED (95% CI) 2.16 (1.27–3.68)), male gender (2.31 (1.34–3.98)) and baseline tender joint count (0.94 (0.90–0.99)). IMPROVED study (3.33 (1.44–7.66)) and absence of RF (rheumatoid factor) and ACPA (anti-citrullinated protein antibodies) 4.24 (1.71–10.51) were predictive factors for DFR at year 5. Conclusions Although the treatment target was less often achieved for DAS<1.6 compared to DAS≤2.4, irrespective of baseline disease activity, patients with early active RA had better outcomes after DAS<1.6 than DAS≤2.4 targeted therapy. Male gender, low baseline tender joint count and absence of RF and ACPA were also associated with more favourable treatment outcomes. Disclosure of Interest G. Akdemir: None declared, I. M. Markusse: None declared, A. A. Schouffoer: None declared, P. B. de Sonnaville: None declared, B. A. Grillet: None declared, P. J. Kerstens: None declared, W. F. Lems: None declared, T. W. Huizinga: None declared, C. F. Allaart Grant/research support from: Year 1 of the IMPROVED study was sponsored by Abbott. The BeSt study was designed by the investigators and supported by a government grant from the Dutch Insurance Companies, with additional funding from Schering-Plough B.V. and Janssen B.V. Data collection, trial management, data analysis and preparation of the manuscript were performed by the authors.

FRI0087 Predictors for Attaining Remission at Two Consecutive Visits in Newly Diagnosed Early RA Patients

Background Early and intensive treatment with DMARDs are essential for remission induction in newly diagnosed RA patients. However, demographic, psychosocial and disease related factors may play a role as well. Objectives To investigate which demographic, psychosocial and disease related factors are associated with attaining remission at two consecutive visits in early RA patients treated in a treat-to-target manner Methods We used 12 months follow-up data from patients participating in the tREACH trial1,2 in which induction therapy strategies were compared: (A) combination high dose conventional therapy ((MTX + sulfasalazine + hydroxychloroquine or (B) MTX. Both groups had glucocorticoid (GCs) bridging. Disease activity (DAS) was assessed every 3 months. Remission was defined as DAS<1.6 at 2 consecutive visits (3 months). Univariate and multivariate logistic and Cox regression analyses were performed including demographic, disease related and psychosocial factors evaluated at baseline as predictors for attaining remission during 12 months of follow-up. Results 281 patients (68% female; mean DAS 3.4, median HAQ 1.00) were included. During 1 year of follow-up, 129 of 281 (46%) patients (group A: 90 (49%), group B: 39 (40%)) attained remission at 2 consecutive visits. 76/281 (27)% achieved remission within 6 months. Univariate analyses revealed that female sex was associated with a lower chance of attaining remission (demographic factors). Similar relations were observed for higher DAS, HAQ and worse physical functioning (disease factors) and higher levels of anxiety, depression, fatigue and passive coping with pain and lower levels of mental functioning and internal locus of control (psychosocial factors). In multivariate analyses, female sex, treatment and higher levels of fatigue were associated with a lower chance to attain remission within 6 months, whereas older age, female sex and higher levels of depression were associated with increased time to remission within 12 months. Conclusions In the tREACH trial, 46% of early RA patients attained remission within 1 year of follow-up. Female sex, higher baseline DAS, HAQ, and several psychosocial factors were predictors for attaining remission, but in the final models age, sex, baseline DAS, fatigue and depression remained. Results suggest that high levels of fatigue and depressive symptoms may prevent patients from attaining remission despite treatment according to a tight control and treat-to-target strategy. References Claessen et al. BMC Musculoskelet Disord 2009:71. De Jong et al. Ann Rheum Dis. 2013 Jan;72. Disclosure of Interest None declared