Iris M. Markusse

Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BeSt study

IntroductionFlares in patients with rheumatoid arthritis are suggested to sometimes spontaneously resolve. Targeted therapy could then entail possible overtreatment. We aimed to determine the flare prevalence in patients who are treated-to-target and to evaluate associations between flares and patient-reported outcomes and radiographic progression.MethodsIn the BeSt study, 508 patients were treated-to-target for 10 years. After initial treatment adjustments to achieve disease activity score ≤2.4, a flare was defined from the second year of follow-up onwards, according to three definitions. The first definition is a disease activity score >2.4 with an increase of ≥0.6 regardless of the previous disease activity score. The other definitions will be described in the manuscript.ResultsThe flare prevalence was 4–11 % per visit; 67 % of the patients experienced ≥1 flare during 9 years of treatment (median 0 per patient per year). During a flare, functional ability decreased with a mean difference of 0.25 in health assessment questionnaire (p < 0.001), and the odds ratios (95 % confidence intervals) for an increase in patients’ assessment of disease activity, pain and morning stiffness of ≥20 mm on a visual analogue scale were 8.5 (7.3–9.8), 8.4 (7.2–9.7) and 5.6 (4.8–6.6), respectively, compared to the absence of a flare. The odds ratio for radiographic progression was 1.7 (1.1–2.8) in a year with a flare compared to a year without a flare. The more flares a patient experienced, the higher the health assessment questionnaire at year 10 (p < 0.001) and the more radiographic progression from baseline to year 10 (p = 0.005).ConclusionFlares were associated with concurrent increase in patient’s assessment of disease activity, pain and morning stiffness, functional deterioration and development of radiographic progression with a dose–response-effect, both during the flare and long term. This suggests that intensifying treatment during a flare outweighs the risk of possible overtreatment.Trial registrationDutch trial registry NTR262 (7 September 2005) and NTR265 (8 September 2005).

Rheumatoid Factor Is Associated With the Distribution of Hand Joint Destruction in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non‐fingers, with the aim of analyzing which factors are associated with destruction of the finger joints.

Predicting cardiopulmonary involvement in patients with systemic sclerosis: complementary value of nailfold videocapillaroscopy patterns and disease-specific autoantibodies.

Objective To evaluate the prevalence of anti-extractable nuclear antigen (anti-ENA) antibodies in Dutch SSc patients and the predictive power of the combination of specific anti-ENA antibodies and nailfold videocapillaroscopy (NVC) patterns to improve identification of patients with high risk for cardiopulmonary involvement. Methods A total of 287 patients (79%) from the Leiden SSc-Cohort had data available on NVC-pattern (no SSc-specific, early, active, late) and anti-ENA antibodies. Associations between anti-ENA/NVC combinations with cardiopulmonary parameters were explored using logistic regression. Results Prevalence of ACA was 37%, anti-Scl-70 24%, anti-RNP 9%, anti-RNAPIII 5%, anti-fibrillarin 4%, anti-Pm/Scl 3%, anti-Th/To 0.3% and anti-Ku 1.4%. NVC showed a SSc-specific pattern in 88%: 10% early, 42% active and 36% late. The prevalence of different NVC patterns was equally distributed among specific anti-ENA antibodies, except for the absence of early pattern in anti-RNP positive patients. Fifty-one percent had interstitial lung disease (ILD), 59% had decreased diffusion capacity for carbon monoxide and 16% systolic pulmonary artery pressure >35 mmHg (sPAP↑). Regardless of ENA-subtype, NVC-pattern showed a stable association with presence of ILD or sPAP↑. For ILD, the odds ratios (ORs) were 1.3-1.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). For diffusion capacity for carbon monoxide, the OR was 1.5 ( P < 0.05 for analyses with ACA, anti-Scl-70, anti-RNAPIII, anti-RNP). For sPAP↑, the ORs were 2.2-2.4 ( P < 0.05 for analyses with anti-RNAPIII, anti-RNP). Conclusion In Dutch SSc patients, all SSc-specific auto-antibodies were found, with ACA and anti-Scl-70 being the most prevalent. Strikingly, the association between NVC-pattern and heart/lung involvement was independent of specific anti-ENA antibodies, which might indicate microangiopathy is an important cause of organ involvement.

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

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.

Continued Participation in a Ten-Year Tight Control Treat-to-Target Study in Rheumatoid Arthritis: Why Keep Patients Doing their Best?

To identify risk factors for early study termination and motivators for adherence to a long‐term followup trial and to improve completeness of long‐term studies.

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.

Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis.

IntroductionPersonalized medicine is the holy grail of medicine. The EULAR recommendations for the management of rheumatoid arthritis (RA) support differential treatment between patients with baseline characteristics suggestive of a non-poor prognosis (non-PP) or poor prognosis (PP) (presence of autoantibodies, a high inflammatory activity and damage on radiographs). We aimed to determine which prognostic risk groups benefit more from initial monotherapy or initial combination therapy.Methods508 patients were randomized to initial monotherapy (iMono) or initial combination therapy (iCombo). Disease outcomes of iMono and iCombo were compared within non-PP or PP groups as determined on baseline characteristicsResultsPP patients treated with iCombo after three months more often achieved ACR20 (70% vs 38%, P <0.001), ACR50 (48% vs 13%, P <0.001) and ACR70 response (24% vs 4%, P <0.001) than those treated with iMono, and had more improvement in HAQ (median decrease 0.75 vs 0.38, P <0.001). After 1 year, differences in ACR20 response and DAS-remission remained; PP patients treated with iCombo (vs iMono) had less radiographic progression (median 0.0 vs 1.5, P =0.001).Non-PP patients treated with iCombo after three months more often achieved an ACR response (ACR20: 71% versus 44%, P <0.001; ACR50: 49% vs 13%, P <0.001; ACR70: 17% vs 3%, P =0.001) than with iMono, and functional ability showed greater improvement (median decrease in HAQ 0.63 vs 0.38, P <0.001). After 1 year, differences in ACR20 and ACR50 response remained; radiographic progression was comparable between the groups.Non-PP and PP patients responded equally well to iCombo in terms of improvement of functional ability, with similar toxicity.ConclusionsSince PP and non-PP patients benefit equally from iCombo through earlier clinical response and functional improvement than with iMono, we conclude that personalized medicine as suggested in the guidelines is not yet feasible. The choice of treatment strategy should depend more on rapid relief of symptoms than on prognostic factors.Trial registrationNetherlands Trial Register NTR262 (registered 7 September 2005) and NTR265 (8 September 2005).

Linear extrapolation of missing radiographic change scores in clinical trials does not spuriously overestimate group radiographic changes in rheumatoid arthritis

OBJECTIVE To assess linear extrapolation (LE) and last observation carried forward (LOCF) as imputation methods for radiographic change in patients with RA. METHODS The OSKIRA-1 trial enrolled 918 patients with active RA for studying the efficacy of fostamatinib. Radiographs were scheduled for all patients at baseline and week 12, regardless of early escape, and at weeks 24 and 52 for patients who remained in the study. Complete radiographic data for the 24-week follow-up were available for 623 patients and were assessed according to the Sharp/van der Heijde score. From this complete set of data, a random selection of 10% missingness was generated. This was done 1000 times, and for each replicate the missing radiographic change at week 24 was imputed, first by LE, then by LOCF. The mean of the mean and mean of the s.d. across the 1000 replications was calculated. A similar approach was iterated for different proportions of missingness. RESULTS The mean (s.d.) observed Sharp/van der Heijde score change from baseline to week 24 was 0.36 (2.39). With LE, the mean (s.d.) change was estimated as 0.36 (2.65), 0.35 (2.88), 0.35 (3.17), 0.34 (3.57) and 0.32 (4.45) with 10/20/30/50/90% missingness, respectively. With LOCF, the mean (s.d.) change was estimated as 0.34 (2.39), 0.32 (2.38), 0.30 (2.37), 0.26 (2.36) and 0.18 (2.34) with 10/20/30/50/90% missingness, respectively. CONCLUSION LE led to stable estimates of progression at the group level, but increasing variability with increasing proportions of missingness. In contrast, LOCF imputation systemically underestimated mean progression with increasing proportions of missingness, with artificially reduced variability estimates.

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.