Sytske Anne Bergstra

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

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.

Erosions in the foot at baseline are predictive of orthopaedic shoe use after 10 years of treat to target therapy in patients with recent onset rheumatoid arthritis

The objective of this study is to investigate if foot joint damage due to rheumatoid arthritis (RA) can predict whether patients will start wearing orthopaedic shoes (OS) within 10xa0years after treatment start. Data from recent onset RA patients with 10xa0years follow-up from the BeSt (Dutch acronym for treatment strategies) study were used. Treatment was tightly controlled, targeted at disease activity score (DAS) ≤2.4, according to 1 of 4 pre-specified treatment strategies. After 10xa0years of follow-up, orthopaedic shoe use was recorded in 285/508 patients (responders to questionnaires at 10xa0years). Between-group differences for orthopaedic shoe users and non-users were calculated at baseline, after 10xa0years, and change scores over the 10-year period were calculated. Predictors for orthopaedic shoe use were identified by univariable and multivariable logistic regression analyses. Orthopaedic shoe use was reported by 57/285 patients after 10xa0years. Orthopaedic shoe users had more joint damage, joint swelling and pain in the feet already at baseline and after 10xa0years. At both time points, DAS of orthopaedic shoe users and non-users was similar. Multivariable logistic regression showed that dichotomized foot erosions score (cut-off ≥1 erosion) (OR 2.42), anti-citrullinated protein antibodies (ACPA) (OR 4.64) and DAS (OR 1.77) were independent predictors of orthopaedic shoe use. Despite intensive targeted treatment, 57/285 recent onset RA patients started using orthopaedic shoes over 10xa0year of follow-up. Presence of foot erosions at treatment start predicts orthopaedic shoe use after 10xa0years. The risk of orthopedic shoe use increased for ACPA-positive patients and for those with higher baseline disease activity.

Meta-regression of a dose-response relationship of methotrexate in mono- and combination therapy in DMARD naive early rheumatoid arthritis patients.

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.

Sex-associated Treatment Differences and Their Outcomes in Rheumatoid Arthritis: Results from the METEOR Register

Objective. To assess differences in initial treatment and treatment response in male and female patients with rheumatoid arthritis (RA) in daily clinical practice. Methods. The proportion of patients with RA starting different antirheumatic treatments (disease-modifying antirheumatic drugs; DMARD) and the response to treatment were compared in the international, observational METEOR register. All visits from start of the first DMARD until the first DMARD switch or the end of followup were selected. The effect of sex on time to switch from first to second treatment was calculated using Cox regression. Linear mixed model analyses were performed to assess whether men and women responded differently to treatments, as measured by Disease Activity Score (DAS) or Health Assessment Questionnaire. Results. Women (n = 4393) more often started treatment with hydroxychloroquine, as monotherapy or in combination with methotrexate (MTX) or a glucocorticoid, and men (n = 1142) more often started treatment with MTX and/or sulfasalazine. Time to switch DMARD was shorter for women than for men. Women had a statistically significantly higher DAS over time than men (DAS improvement per year β −0.69, 95% CI −0.75 to −0.62 for men and −0.58, 95% CI −0.62 to −0.55 for women). Subanalyses per DMARD group showed for the conventional synthetic DMARD combination therapy a slightly greater decrease in DAS over time in men (−0.89, 95% CI −1.07 to −0.71) compared to women (−0.59, 95% CI −0.67 to −0.51), but these difference between the sexes were clinically negligible. Conclusion. This worldwide observational study suggests that in daily practice, men and women with RA are prescribed different initial treatments, but there were no differences in response to treatment between the sexes.

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) 25u2009mg/week and prednisone (60u2009mg/day tapered to 7.5u2009mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400u2009mg/day and sulfasalazine 2000u2009mg/day, or arm 2, switching to MTX plus adalimumab 40u2009mg/2u2009weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5u2009years. Results After 4u2009months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5u2009years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1u2009year) (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

OBJECTIVESnTo evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients.nnnMETHODSnThe study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (nu202f=u202f240) or infliximab (nu202f=u202f126), 92.4% of them anti-TNF naive (nu202f=u202f328/355) and 96.6% of them co-treated with methotrexate (nu202f=u202f341/353) 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.nnnRESULTSnADAs were detected within 18 months in 19.2% (nu202f=u202f46) of the adalimumab-treated patients and 29.4% (nu202f=u202f37) 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 (1-3u202fvs.u202f<u202f1 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 3.2-5.1u202fvs.u202f<u202f3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3).nnnCONCLUSIONSnThe 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.

Autoantibody status is not associated with early treatment response to first-line methotrexate in patients with early rheumatoid arthritis

ObjectivesnIn RA, the relationship between autoantibody status and treatment response to MTX remains unclear. We investigated the association between autoantibody status and early remission in newly diagnosed RA patients treated with MTX using real-world data.nnnMethodsnRA-patients initially treated with MTX were selected from an international observational database (METEOR). Patients were stratified into autoantibody-positive (RF- and/or ACPA-positive) or autoantibody negative (RF- and ACPA-negative). The effect of autoantibody status on the chance of achieving remission within 3 to 6 months was analysed using Cox-proportional hazards regression.nnnResultsnData from 1826 RA patients were available for analysis. DAS remission was achieved in 17% (318/1826). This was similar in autoantibody-positive [17% (282/1629)] and -negative patients [18% (36/197)]. Hence, autoantibody positivity was not associated with remission [hazard ratio (HR) 0.89, 95% CI 0.57, 1.38]. Similar findings were found when stratified for MTX monotherapy (HR 0.75, 95% CI 0.41, 1.37) or combination treatment (HR 0.76, 95% CI 0.37, 1.54). Good physical function (HAQ < 0.5) was achieved in 33% (530/1590) of all patients. Autoantibody-positivity was also not associated with HAQ < 0.5 (HR 1.05, 95% CI 0.71, 1.57).nnnConclusionnAutoantibody status is not associated with early remission in newly diagnosed RA-patients receiving MTX. This indicates that MTX is effective as an initial treatment strategy regardless of autoantibody status.

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 <1.6u2009and 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+prednisoneu2009combination 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.

How to treat patients with rheumatoid arthritis when methotrexate has failed? The use of a multiple propensity score to adjust for confounding by indication in observational studies

Objectives To compare consecutive disease modifying antirheumatic drug (DMARD)-treatment regimes in daily practice in patients with rheumatoid arthritis (RA) who failed on initial methotrexate, while using a multiple propensity score (PS) method to control for the spurious effects of confounding by indication. Methods Patients with newly diagnosed RA who had failed initial treatment with methotrexate were selected from METEOR, an international, observational registry. Subsequent DMARD-treatment regimens were categorised as: (1) conventional synthetic DMARD(s) (csDMARD(s)) only (143 patients), (2) csDMARD(s)+glucocorticoid (278 patients) and (3) biological DMARD (bDMARD)±csDMARD(s) (89 patients). Multiple PS that reflect the likelihood of treatment with each treatment-regime were estimated per patient using multinomial regression. Linear mixed model analyses were performed to analyse treatment responses per category (Disease Activity Score (DAS)) after a maximum follow-up duration of 6 and 12 months, and results were presented with adjustment for the multiple PS. Results After 6 months, follow-up PS-adjusted treatment responses yielded a change in DAS per year (95% u2009CI) of −2.00 (−2.65 to −1.36) if patients received a bDMARD; of −0.96 (−1.33 to −0.59) if patients received csDMARD(s)+glucocorticoids and of −0.73 (−1.21 to −0.25) if patients received csDMARDs only. These changes were −0.91 (−1.23 to −0.60); −0.43 (−0.62 to −0.23) and −0.39 (−0.66 to −0.13), respectively after 1 u2009year of follow-up. Conclusions In this analysis of worldwide common practice data with adjustment for multiple PS, patients with RA who had failed initial treatment with methotrexate monotherapy had a better DAS-response after a subsequent switch to a bDMARD-containing treatment regimen than to a regimen with csDMARD(s) only, with or without glucocorticoids.

Inequity in access to bDMARD care and how it influences disease outcomes across countries worldwide: results from the METEOR-registry

Objective To establish in a global setting the relationships between countries’ socioeconomic status (SES), measured biological disease modifying antirheumatic drug (bDMARD)-usage and disease outcomes. To assess if prescription and reimbursement rules and generic access to medication relates to a countries’ bDMARD-usage. Methods Data on disease activity and drug use from countries that had contributed at least 100 patients were extracted from the METEOR database. Mean disease outcomes of all available patients at the final visit were calculated on a per-country basis. A questionnaire was sent to at least two rheumatologists per country inquiring about DMARD-prices, access to treatment and valid regulations for prescription and reimbursement. Results Data from 20 379 patients living in 12 different countries showed that countries’ SES was positively associated with measured disease activity (meanDAS28), but not always with physical functioning (HAQ-score). A lower country’s SES, stricter rules for prescription and reimbursement of bDMARDs as well as worse affordability of bDMARDs were associated with lower bDMARD-usage. bDMARD-usage was negatively associated with disease activity (although not with physical functioning), but the association was moderate at best. Conclusions Disease activity in patients with rheumatoid arthritis as well as bDMARD-usage varies across countries worldwide. The (negative) relationship between countries’ bDMARD-usage and level of disease activity is complex and under the influence of many factors, including—but not limited to—countries’ SES, affordability of bDMARDs and valid prescription and reimbursement rules for bDMARDs.