Gülşah Akdemir

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.

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.

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.

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.

Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: a European retrospective multicohort analysis

OBJECTIVES To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.

Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis

Objectives To compare outcomes of targeted treatment aimed at either low disease activity or remission in patients with early active rheumatoid arthritis (RA). Methods Five-year outcomes were compared in 133 patients with early active RA (1987), starting with methotrexate, sulfasalazine and tapered high dose of prednisone (arm 3 of the BehandelStrategieën (Treatment Strategies for Rheumatoid Arthritis) (BeSt) study), targeted at Disease Activity Score (DAS) ≤2.4 (low disease activity), and 175 patients with early RA, starting methotrexate and tapered high dose of prednisone, targeted at DAS <1.6 (selected from IMPROVED study who would have fulfilled inclusion criteria of the BeSt study). Association of treatment target with outcomes DAS <1.6, Boolean remission at year 1 and drug-free DAS remission (DFR) at year 5 were analysed by logistic regression analysis. Results At baseline, DAS <1.6 steered patients had a milder disease than DAS ≤2.4 steered patients (mean DAS 4.1±SD 0.7vs4.4±0.9, p=0.012) and less radiological damage. DAS decrease, functional ability and radiological damage progression over time were similar in both patient groups. DAS ≤2.4 was achieved in similar percentages in both patient groups, but more DAS <1.6 steered patients achieved DAS <1.6 and DFR. DAS <1.6 steered treatment was associated with achieving DAS <1.6 (OR 3.04 (95% CI 1.64 to 5.62)) and Boolean remission (3.03 (1.45 to 6.33)) at year 1 and DFR at year 5 (3.77 (1.51 to 9.43)). Conclusions In patients with early active RA who start with comparable disease-modifying antirheumatic drug+prednisone combination therapy, subsequent DAS <1.6 steered treatment is associated with similar clinical and radiological outcomes over time as DAS ≤2.4 steered treatment; however, in the DAS <1.6 steered group, more patients achieved remission and drug-free remission.

SAT0067 Further treatment intensifications in undifferentiated and rheumatoid arthritis patients already in low disease activity have limited benefit towards physical functioning

Background It is recommended to optimize treatment as long as a predefined treatment target is not met, but should we aim at remission if patients are in low disease activity (LDA)? Objectives To assess if RA or undifferentiated arthritis (UA) patients who achieved LDA benefit with better functional ability from treatment intensification aimed at DAS remission. Methods In the IMPROVED study 610 patients with early RA (ACR 2010) or UA were “treated to target” aimed at DAS remission, assessed 4-monthly. Initial treatment was methotrexate (MTX) + tapered high dose prednisone. Patients with DAS≤1.6 tapered treatment. Patients with DAS>1.6 were randomized to MTX + hydroxychloroquine + sulphasalazine + prednisone or to MTX + adalimumab. Over 5 years, patients with DAS>1.6 were required to increase, change or restart medication. HAQ was measured 4-monthly. A linear mixed model analysis with random intercept was performed to test the relationship between changes in therapy and HAQ over time. Patients in LDA with DAS>1.6 with and without (i.e. protocol violation) treatment change were compared. ΔHAQ and ΔDAS at each visit compared to the previous visit were calculated. We tested the interaction effect between change in treatment and follow-up time adjusted for possible confounders. Results Overall, over 5 years DAS (baseline mean (SD) 3.2 (1.7)) and HAQ (1.2 (0.7)) showed a statistically significant and clinically relevant decrease (ΔHAQ -0.59, 95% CI -0.61, -0.57; ΔDAS -1.77, 95% CI -1.79; -1.75). The number of patients in LDA per visit ranged from 88 to 146, of which 26% to 73% (increasing over time) had no treatment change due to protocol violations. We found a statistically significant but not clinically relevant effect of treatment change on ΔHAQ, corrected for baseline HAQ, age, gender and treatment arm (model 1, β -0.085, 95% CI -0.13, -0.044). When ΔDAS was added (model 2), the effect of treatment change was partly explained by ΔDAS and no longer statistically significant (β -0.022, 95% CI -0.060; 0.015). The effect of treatment intensification on HAQ improvement became less over time, as demonstrated by a statistically significant interaction between change in HAQ and time in follow-up in model 3 (β 0.0098, 95% CI 0.0010; 0.019) (table 1). Conclusions Treatment intensification in early RA or UA patients who have already achieved low disease activity is associated with a statistically significant decrease in HAQ, but not with a clinically meaningful improvement in functional ability. The effect on ΔHAQ decreased with increasing follow-up time. Therefore not remission or low disease activity, but good functional ability may be the optimal treatment target at which to steer treatment adjustments. These results suggest that, whereas remission may be the optimal goal, when patients in low disease activity have acceptably low HAQ, further treatment intensification may only have downsides such as side effects and costs. Disclosure of Interest None declared

SAT0610 Magnetic Resonance Imaging Outcomes in Patients with Chronic or Recurrent Gonarthritis Treated with Intra-Articular Infliximab or Corticosteroid Injections

Background Intra-articular corticosteroid injection can be used to treat arthritis. It is unknown whether and which signs of joint inflammation on magnetic resonance imaging (MRI) change after such treatment. Objectives To evaluate changes in signs of synovial inflammation by MRI. Methods In the RIA study (Remicade Intra Articularly), a prospective, randomized, double-blind trial to compare the efficacy of intra-articular (ia) injection with infliximab (IFX) or methylprednisolone (MP), 23 patients with active inflammatory recurrent gonarthritis despite ≥1 previous ia corticosteroid injection underwent T1 contrast enhanced MRI of the affected knee before and 4 weeks after the study medication. MRIs were scored using the MRI Osteoarthritis Knee Score (MOAKS), scoring Hoffa synovitis 0-3, and the Knee Osteoarthritis Scoring System (KOSS), scoring joint effusion 0-3. Outcomes of two consecutive MRIs were compared between the randomization groups. Results Two consecutive MRIs were available for 20 knees of 18 patients, which were treated with ia IFX (14 interventions) or with MP (12 interventions). There were no differences in age, number of disease modifying antirheumatic drugs (DMARDs) and number of previous ia corticosteroid injections between the IFX and MP treated patients. Median (IQR) Hoffa synovitis scores and effusion scores were similar prior to IFX injections or MP injections. Four weeks after an injection the Hoffa synovitis scores and effusion scores had decreased significantly in IFX injected knees (from 2.5 (1.8-3.0) to 2.0 (1.0-2.3), p=0.021 and from 2.5 (2.0-3.0) to 1.0 (1.0-3.0), p=0.007, respectively) but not significantly in MP injected knees (from 2.0 (2.0-2.0) to 1.5 (1.0-2.0), p=0.157 and from 3.0 (2.0-3.0) to 2.0 (1.0-3.0), p=0.102, respectively). Clinical evaluation 6 months after the injections showed recurrence of clinical arthritis in all IFX injected knees, and in 50% of MP injected knees. Median (IQR) Hoffa synovitis scores and effusion scores before injection were similar in MP injected patients who did or did not had recurrence of clinical arthritis 2.0 (2.0-3.0) and 2.0 (1.0-2.0) p=0.080 in patients with recurrence, respectively, and 3.0 (3.0-3.0) and 2.5 (1.8-3.0) p=0.617 in patients with no recurrence, respectively. MP injected patients who did or did not have a recurrence of clinical arthritis also showed no difference in improvement in Hoffa synovitis scores and effusion scores after injection (delta Hoffa synovitis score 0.0 (-1.5-0.5) p=0.414 and 0 (-1-0) p=0.157, respectively, delta effusion score 0.0 (-1.0-0.0), p=0.157 and 0.0 (-0.5-0.0) p=0.317, respectively. Conclusions In patients with chronic or recurrent gonarthritis treated with ia IFX or MP, there is a statistically significant improvement in MRI Hoffa synovitis and effusion scores after ia IFX injections but not after ia MP injections. This may represent short term efficacy which could be greater for IFX than for MP. However, improvement in MRI scores was not associated with long term clinical efficacy: after 6 months all IFX injected knees and 50% of MP injected knees showed clinical recurrence of arthritis. Disclosure of Interest G. Akdemir: None declared, A. van der Bijl: None declared, B. de Lange-Brokaar: None declared, T. Huizinga: None declared, C. Allaart Grant/research support from: The study was sponsored by Schering-Plough BV and Centocor, Inc., M. Kloppenburg: None declared