L. Heimans

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.

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.

Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)

Objective To assess long-term disease outcome of undifferentiated arthritis (UA) after initial treatment with methotrexate (MTX) or placebo. Methods 110 patients with UA were randomised to receive MTX (n=55) or placebo (n=55) for 1 year. After 5 years the outcomes for diagnosis (rheumatoid arthritis, 1987 criteria (RA (1987)), UA or UA in remission) and radiographic progression were compared between treatment arms and anti-citrullinated protein antibody (ACPA)-positive and -negative patients. Outcomes were recalculated for patients who, with hindsight, might have been classified at baseline as having RA according to the 2010 criteria (RA (2010)). Results 25 patients in the MTX group and 29 in the placebo group progressed to RA (1987) (p=0.45). MTX delayed progression from UA to RA (1987) but only in ACPA-positive patients. Drug-free remission was achieved in 35 patients, 20 of whom were initially treated with MTX, and 32 were ACPA-negative. ACPA-positive patients had more radiographic progression, regardless of treatment. Forty-three patients (39%) could be reclassified as having had RA (2010) at baseline, 6/24 (25%) of whom achieved remission after placebo treatment. Conclusions After 5 years there is no lasting benefit of a 1 year initial course of MTX for patients with undifferentiated arthritis, compared with initial placebo. Progression to classifiable RA was not suppressed, drug-free remission not induced and the progression of radiological damage was similar in both groups. Reclassification at baseline with the 2010 criteria showed that 25% of patients with RA (2010) achieved spontaneous drug-free remission.

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study.

IntroductionThe aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.MethodsIn this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.ResultsDuring year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.ConclusionsIn early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.Trial registrationsISRCTN11916566 and EudraCT2006-006186-16

Predictive factors of radiological progression after 2 years of remission-steered treatment in early arthritis patients: a post hoc analysis of the IMPROVED study

Objectives To identify predictive factors of radiological progression in early arthritis patients treated by remission-steered treatment. Methods In the IMPROVED study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (disease activity score (DAS) <1.6 after 4 months) tapered prednisone to zero. Patients not in early remission were randomised to arm 1: MTX plus hydroxychloroquine, sulfasalazine and prednisone, or to arm 2: MTX plus adalimumab. Predictors of radiological progression (≥0.5 Sharp/van der Heijde score; SHS) after 2 years were assessed using logistic regression analysis. Results Median (IQR) SHS progression in 488 patients was 0 (0–0) point, without differences between RA or UA patients or between treatment arms. In only 50/488 patients, the SHS progression was ≥0.5: 33 (66%) were in the early DAS remission group, 9 (18%) in arm 1, 5 (10%) in arm 2, 3 (6%) in the outside of protocol group. Age (OR (95% CI): 1.03 (1.00 to 1.06)) and the combined presence of anticarbamylated protein antibodies (anti-CarP) and anticitrullinated protein antibodies (ACPA) (2.54 (1.16 to 5.58)) were independent predictors for SHS progression. Symptom duration <12 weeks showed a trend. Conclusions After 2 years of remission steered treatment in early arthritis patients, there was limited SHS progression in only a small group of patients. Numerically, patients who had achieved early DAS remission had more SHS progression than other patients. Positivity for both anti-CarP and ACPA and age were independently associated with SHS progression. Trial registration numbers ISRCTN Register number 11916566 and EudraCT number 2006 06186-16.

OP0182 Drug Free Remission After One Year of Treatment in Patients with Early Rheumatoid Arthritis: Also Possible for ACPA Positive Patients?

Background In rheumatoid arthritis (RA) remission is a realistic treatment goal. Is tapering medication to drug free remission (DFR) possible for all patients? Objectives To assess which patients with early (rheumatoid) arthritis achieve DFR after one year (DFR1year) of early remission induction therapy. Methods By protocol of the IMPROVED study, patients who achieved remission (DAS<1.6) after 4 months (early remission, n=375) of combination therapy with methotrexate 25 mg/wk and a tapered high dose of prednisone (60 mg/day tapered in 7 weeks to 7.5 mg/day, continued up to 4 months) had to taper stepwise and finally discontinue these drugs as long as remission was maintained. Characteristics of patients achieving and not achieving DFR1year were compared and predictors of DFR were identified using logistic regression. Follow up data of 16 months were included to investigate in how many patients DFR1year was sustained for 4 more months. Results 119 patients (32%) achieved DFR1year, while 245 (65%) flared and restarted medication over time. Eleven patients had insufficient data. Of patients in DFR1year, 51 (28%) at baseline fulfilled the 1987 and 2010 classification criteria for RA, 34 (35%) only fulfilled the 2010 criteria and 20 (35%) patients had UA and fulfilled neither criteria (p=0.4). In 77 (65%) DFR1year was sustained up to 16 months. Patients in DFR1year were more often rheumatoid factor (RF) negative than patients not achieving DFR1year, (50% versus 62%, p=0.04). There were no differences in baseline DAS (2.9 (0.9) versus 3.1 (0.8), p=0.12), symptom duration (16 (8-29) versus 17 (9-32), p=0.52) or ACPA positivity (56% versus 61% respectively, p=0.27). Univariable predictors were positive RF (OR 95%CI 0.6 (0.4-0.99)) and high baseline tender joint count (TJC) (OR 95%CI 0.9 (0.9-1.0). Baseline DAS, positive ACPA, age, male sex, being classified as RA according to the 2010 ACR/EULAR criteria or short symptom duration were not predictive for DFR1year. The only independent predictor was RF negativity (OR 95%CI 0.6 (0.4-0.97, adjusted for baseline TJC). Conclusions Of 375 early (rheumatoid) arthritis patients who achieved remission after 4 months of initial combination therapy with methotrexate and prednisone, 32% maintained in remission despite having tapered and discontinued all drugs at 1 year. DFR was sustained up to 16 months in 65% of these. With this treatment strategy, presence of ACPA appears not to preclude drug discontinuation, but patients with positive RF achieved DFR after 1 year somewhat less often than RF negative patients. Disclosure of Interest None Declared

Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study

Objectives To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis. Methods In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years. Results After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR. Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0–2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years. Conclusions Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.

FRI0517 Early metacarpal bone mineral density loss is predictive for radiologic joint damage progression after 1 year in patients with early arthritis

Background In patients with established RA, radiological progression is preceded by metacarpal bone mineral density (mBMD) loss. Objectives To assess whether in early (rheumatoid) arthritis patients, mBMD loss after 4 months is an independent predictor for radiological progression after 1 year of antirheumatic treatment. Methods mBMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry (DXR) in patients participating in the IMPROVED study, a single blind multicenter study in 479(79%) RA (2010 ACR/EULAR criteria, symptom duration < 2 years) and 122(20%) UA (arthritis >1 joint, at risk for developing RA by rheumatologists estimation but not fulfilling the 2010 criteria) patients. All patients started treatment with 4 months of methotrexate (MTX) and a tapered high dose of prednisone, followed by tapering or adjusting treatment aiming at DAS <1.6. We performed univariable logistic regression with radiologic progression (increase in total Sharp-van der Heijde Score (tSHS) ≥0.5 after 1 year) as dependent variable and mBMD loss after 4 months and other known predictors as covariates. For power reasons, we selected those two univariable predictive variables (p-value ≤0.10) with the lowest p-value for multivariate regression. Results Of 237 patients (43(18%) UA, 192(81%) RA, 2 missing classification) mBMD measurements at baseline and 4 months and radiological progression data after 1 year were available. Median mBMD loss after 4 months (4mo-mBMD loss, mg/cm2 unless indicated otherwise) was 2.3(-1.7 to 6.8) (corresponding to 0.6(-0.4 to 1.7) mg/cm2/month). Seventeen (7%) patients had radiological progression after 1 year and 220(93%) had not. Patients with radiological progression had a median (IQR) 4mo-mBMD loss of 5.5(2.7 to 13.6) compared to 2.0(-2.0 to 6.6) in patients without progression (corresponding to 1.4(0.7 to 3.4) and 0.5(-0.5 to 1.6) mg/cm2/month), (p=0.002). Univariable predictors for progression (OR (95%CI) were age (1.0(1.0-1.1)), fulfilling the 2010 criteria for RA (6.4(0.9-48)), postmenopausal status (6.2(1.4-27)), ESR (1.0(0.999-1.0)), tSHS (1.1(0.996-1.1)), presence of erosions (4.4(2.0-10.0)) and presence of ACPA (3.5(1.3-9.4)), all at baseline, and 4mo-mBMD loss (mg/cm2/months) (1.5(1.2-1.9)). Female gender, RF positivity, symptom duration, baseline swollen and tender joint counts were not predictive. Independent predictors for progression after 1 year were presence of baseline erosions (5.2(1.7-16)) and 4mo-mBMD loss (mg/cm2/month) (1.5(1.1-2.0)). In 203(86%) patients who had no erosions at baseline, 4mo-mBMD loss (mg/cm2/month) was the only independent predictor for progression after 1 year (1.8(1.3-2.7), adjusted for age). Conclusions In early (rheumatoid) arthritis patients, mBMD loss after 4 months of MTX and prednisone is an independent predictor for radiological joint damage progression, despite the fact that radiological progression was only present in 7% of patients after 1 year of a remission steered treatment strategy. In particular in patients who are non-erosive at baseline, mBMD loss after 4 months may help to steer treatment decisions as predictor of damage progression. Disclosure of Interest None Declared

FRI0061 Remission after one year follow up of the improved-study, a randomized clinical trial aiming at remission in patients with early rheumatoid and undifferentiated arthritis

Objectives To evaluate the 1 year clinical outcomes of remission steered therapy in early arthritis, initially with methotrexate (MTX) and a tapered high dose of prednisone, in case of remission followed by tapering medication to zero, in case of no remission followed by randomization to two combination therapy strategies. Methods IMPROVED is a multicenter clinical trial in 479 patients with early (symptoms <2 years) rheumatoid arthritis (RA 2010 criteria) and 131 patients with undifferentiated arthritis (UA) with a baseline Disease Activity Score (DAS) ≥1.6. All patients started with MTX 25mg/wk and prednisone 60mg/day tapered in 7 weeks to 7.5 mg/day. Patients in early remission (DAS <1.6 at t=4 months) tapered prednisone to zero and when still in remission at t=8 months, also tapered MTX to zero. Patients not in early remission were randomized either to a combination of MTX 25 mg/wk, hydroxychloroquine (HCQ) 400mg/day, sulphasalazine 2000mg/day (SSZ) and prednisone 7.5 mg/day (arm 1) or to adalimumab (ADA) 40mg/2weeks with MTX 25mg/wk (arm 2). If not in remission at t=8 months, patients in arm 1 switched to ADA+MTX and patients in arm 2 increased ADA to 40mg/week. Proportions of remission after one year follow up were compared between the different treatment strategies and between RA and UA patients. Results After 4 months 375/610 (61%) patients achieved early remission (mean DAS (SD) 0.94 (0.36)) and 221/610 (36%) did not (mean DAS (SD) 2.45 (0.65), p<0.001). 161/610 patients (26%) were randomized, 83 to arm 1 and 78 to arm 2. In 66/610 (11%) patients the appropriate treatment step was not taken for various reasons. 12 patients were lost to follow up at t=4 months and 34 at t=1 year. At t=4 months, 361/375 (96%) patients in early remission started tapering prednisone. At t=8 months 257/375 (68%) were still in remission on MTX monotherapy and 200/375 (53%) tapered MTX to zero. At t=1 year, 255/375 (68%) were in remission, 135/375 (36%) were in drug free remission. At t=8 months 50/83 (60%) patients in arm 1 did not achieve remission and 31/83 (37%) switched to ADA+MTX. 47/78 (60%) patients in arm 2 did not achieve remission and 27/78 (35%) increased ADA. At t=1 year 21/83 (25%) patients in arm 1 and 32/78 (41%) in arm 2 were in remission (p<0.001). At t=1 year, 326/610 (53%) of the total study population were in remission: 252/479 (53%) RA patients and 70/131 (53%) UA patients. Conclusions In patients with early RA or UA, early remission was achieved in 61% after initial treatment with MTX and a tapered high dose of prednisone. After one year of tapering treatment, 68% of those were still in remission and 36% in drug free remission. For those not in early remission, treatment with adalimumab resulted in more remission than a combination of DMARDs with low dose prednisone. Of the total study population 53% were in remission after one year, without a significant difference between early RA and UA patients. Disclosure of Interest L. Heimans: None Declared, K. Wevers-de Boer Grant/Research support from: Abbott, K. Visser: None Declared, H. Ronday: None Declared, M. Oosterhout: None Declared, J. Harbers: None Declared, A. Peeters: None Declared, M. Westedt: None Declared, P. de Buck: None Declared, P. de Sonnaville: None Declared, B. Grillet: None Declared, T. Huizinga: None Declared, C. Allaart: None Declared

FRI0155 Patient reported outcomes in early arthritis patients

Background Besides suppression of inflammation and prevention of radiographic damage, improvement of functional ability and Health Related Quality Of Life (HRQOL) is one of the main goals of treatment in patients with RA. Objectives To investigate patient reported outcomes (PROs) of functioning and HRQOL after 1 year remission-steered treatment. Methods 610 patients with early RA or undifferentiated arthritis (UA) were included in the IMPROVED-study. All started with methotrexate (MTX) and tapered high dose prednisone. Patients in early remission (Disease Activity Score (DAS)<1.6 after 4 months) tapered prednisone to 0 and when in remission after 8 months, also tapered MTX. Patients not in early remission were randomized to MTX plus hydroxychloroquine, sulphasalazine and prednisone (arm 1) or to MTX+adalimumab (arm 2). Every 4 months, patients filled out the McMaster-Toronto Arthritis Patients Preference Questionnaire (MACTAR) and the Health Assessment Questionnaire (HAQ) to measure functional ability, the Short Form 36 (SF-36) for mental en physical HRQOL and visual analogue scales (VAS). Scores were analyzed separately for all treatment arms and compared between arm 1 and 2. Predictors of HRQOL were identified using linear mixed models. Results 387 patients achieved early remission and 221 patients did not; 83 patients were randomized to arm 1 and 78 to arm 2, 50 did not follow the protocol. After 1 year, remission was most often achieved by patients who were in early remission. Patients in arm 2 more often achieved remission (40%) than patients in arm 1 (25%). Except mental HRQOL, which was stable over 1 year and close to the population mean of 50 in all patients, all PROs and VAS results improved over 1 year, the most during the first 4 months (table). Only VAS disease activity improved significantly more in arm 2 (mean difference 13, 95%CI 2;23), other VAS scores were similar in both arms. The strongest independent predictor for HRQOL was baseline HAQ (beta for mental HRQOL:-1.8, 95%CI -2.8;-0.8, for physical HRQOL:-9.1, 95%CI -9.8;-8.4). Conclusions In early arthritis patients functional ability and HRQOL improve after 1 year of remission targeted treatment, with the largest change in the first 4 months. Patients who achieve early remission improve the most, achieving functional ability and HRQOL in the normal range. In patients who did not achieve early remission, there was no difference in improvement after treatment with DMARD+prednisone or adalimumab+MTX although more patients achieved remission after 1 year in the latter group. Disclosure of Interest None Declared