Background: We have previously reported a 37% remission rate in patients with early rheumatoid arthritis (RA) treated with a combination therapy with 3 DMARDs and prednisolone (the FIN-RACo treatment strategy). Here we set out to study the contribution of infliximab (INFL) added as an induction therapy during the first 6 months in patients with early RA treated with FIN-RACo strategy by using full doses of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ) and prednisolone (PRED) (= COMBI) compared with COMBI+ placebo (PLA). Here we report the 2- year clinical and radiological outcome. Methods: In this multicenter (15 centres), randomized, double-blind, parallel-group trial, we enrolled 100 patients aged <65 y with early RA (symptoms ≤ 12 mo), active (≥ 6 swollen and ≥ 6 tender joints, early morning stiffness ≥ 45 min and/or ESR ≥ 30 mm/h and/or CRP520 mg/l). COMBI was started in all patients targeted to remission. The patients were randomized in a double-blind way to receive INFL (3 mg/kg) or PLA at weeks 4 6, 10, 18 and 26. Doses of MTX (max 25 mg) and SSZ (max 2 g) were individually tailored to reach remission. Doses of HCQ (35 mg/ kg/week) and PRED (7.5 mg/day) were constant. Remission was assessed by the strict ACR criteria (no swollen or tender joints), and by DAS28. In cases of inefficacy/intolerability, the DMARDs were substituted, but it was obligatory to use 3 DMARDs and PRED. Local glucocorticoid injections were allowed. Primary outcomes were proportion of patients in remission and radiology. Results: At entry, the mean age (SD) of the patients was 46 y (10), median duration (IQR) of symptoms 4 mo (2, 6), 68% were RF+, and 67% female. Mean number (SD) of swollen joints was 15 (6), tender joints 20 (10), ESR 33 (22) mm/h and HAQ 1.0 (0.7). At 24 months, 62% of the patients were in ACR remission (COMBI+PLA 53%, COMBI+INFL 70%). Remission rate over time was higher in the COMBI+INFL group [OR=1.97 (95% CI: 1.03 to 3.74), p=0.04]. By DAS28 criteria, 85% of the patients were in remission (COMBI+PLA 82%, COMBI+INFL 88%, n.s., over 3-24 months more often in COMBI+INFL (p=0.047). The median total Sharp score (TSS) was 0 in both groups at baseline. At 24 months, 41% of patients in COMBI+PLA and 54% in COMBI+INFL had 0 score. A mean (95% CI) change of TSS from baseline to 24 months was 1.4 (0.8 to 2.2) in COMBI+PLA and -0.2 (-1.1 to 0.4) in COMBI+INFL (p=0.005). Conclusions: Intensified use of the FIN-RACo combination strategy in patients with early active RA induced strict remission by ACR criteria in 62% and by DAS28criteria in 82% of the patients. Radiological changes were rare during the study. Adding INFL during the first 6 months reflected in higher frequency of remissions and prevention of radiological progression during 2 years.
OBJETIVO: El tratamiento precoz de los pacientes con artritis reumatoide (AR) con tratamiento de combinación de comenzar con metotrexato, sulfasalazina, hidroxicloroquina y prednisolona (estrategia FIN-raco) es superior a la monoterapia. Se realizó un estudio para determinar si el infliximab (INFL) añadido al tratamiento intensificado FIN-raco de los 6 meses iniciales mejora el resultado de 2 años.
MÉTODOS: 99 pacientes con AR activa sin tratamiento temprano se inscribieron en una, aleatorizado, doble ciego, multicéntrico, ensayo de grupos paralelos iniciada por el investigador. Los resultados primarios fueron la remisión y cambios radiológicos a los 2 años. Todos los pacientes comenzaron con FIN-raco. Además, se asignaron al azar para recibir INFL o placebo (Pla) de las semanas 4 a 26.
RESULTADOS: A los 24 meses, 66% y 53%, respectivamente, de los pacientes de los grupos de FIN-raco + INFL y FIN-raco + Pla se encontraban en remisión según el Colegio Americano modificado de Reumatología (ACR) criterios (p = 0,19 ), el 26% y el 10% estaban en remisión sostenida ACR modificado (p = 0,042) y el 82% en ambos grupos estaban en remisión por 28 articulaciones actividad de la enfermedad (no significativo). Cambios medios en la puntuación total de Sharp-van der Heijde fueron 0,2 y 1,4, respectivamente (p = 0,0058).
CONCLUSIONES: La mayoría de los pacientes con AR temprana activa lograr la remisión clínica y desarrollan daño articular insignificante con el régimen de FIN-raco intensificado. Adición INFL para los primeros 6 meses retrasa la progresión radiológica.
OBJECTIVE: To study whether adding initial infliximab to remission-targeted initial combination-DMARD treatment improves the long-term outcomes in patients with early rheumatoid arthritis (RA).
METHODS: Ninety-nine patients with early, DMARD-naïve RA were treated with a triple combination of DMARDs, starting with methotrexate (max 25 mg/week), sulfasalazine (max 2 g/day), hydroxychloroquine (35 mg/kg/week), and with prednisolone (7.5 mg/day), and randomised to double blindly receive either infliximab (3 mg/kg; FIN-RACo+INFL) or placebo (FIN-RACo+PLA) infusions during the first 6 months. After 2 years the treatment strategies became unrestricted, but the treatment goal was strict ACR remission. At 5 years the clinical and radiographic outcomes were assessed.
RESULTS: Ninety-one patients (92%) were followed up to 5 years, 45 in the FIN-RACo+INFL and 46 in the FIN-RACo+PLA groups. At 5 years, the respective proportions of patients in strict ACR and in disease activity score 28 remissions in the FIN-RACo+INFL and FIN-RACo+PLA groups were 60% (95% CI 44% to 74%) and 61% (95% CI 45% to 75%) (p=0.87), and 84% (95% CI 71% to 94%) and 89% (95% CI 76% to 96%) (p=0.51). The corresponding mean (SD) total Sharp/van der Heijde scores at 5 years were 4.3 (7.6), and 5.3 (7.3), while the respective mean Sharp/van der Heijde scores changes from baseline to 5 years were 1.6 (95% CI 0.0 to 3.4) and 3.7 (95% CI 2.2 to 5.8) (p=0.13).
CONCLUSIONS: In early RA, targeted treatment with a combination of traditional DMARDs and prednisolone induces remission and minimises radiographic progression in most patients up to 5 years; adding initial infliximab for 6 months does not improve these outcomes.
OBJECTIVES: It is well recognized that medication adherence of rheumatoid arthritis (RA) patients is often poor. As less attention has been paid to physicians' adherence to targeted treatment, we aimed to investigate how it affects outcomes in aggressively treated early RA patients.
METHOD: In the new Finnish RA Combination Therapy (NEO-RACo) trial, 99 patients with early active RA were treated, targeting remission, with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and low-dose prednisolone for 2 years, and randomized to receive infliximab or placebo for the initial 6 months. After 2 years, therapy was unrestricted while remission was still targeted. Patients were divided into tertiles by physicians' adherence to treat-to-target, which was evaluated with a scoring system during the initial 2 years. After 5 years of follow-up, the between-tertile differences in remission rates, 28-joint Disease Activity Score (DAS28) levels, radiological changes, cumulative days off work, and the use of anti-rheumatic medication were assessed.
RESULTS: Follow-up data were available for 93 patients. Physicians' good adherence was associated with improved remission rates at 2-4 years and lower DAS28 levels throughout the follow-up. In a multivariable model, physicians' adherence was the most important predictor of remission at 3 months and 2 years (p < 0.001 for both). Between 2 and 5 years, biologics were used more often in the tertile of low adherence compared with the other two groups (p = 0.024). No significant differences were observed in radiological progression and cumulative days off work.
CONCLUSIONS: Physicians' good adherence is associated with improved remission rates and lesser use of biologics in early RA.
OBJECTIVES: To study the effects of neglecting intra-articular glucocorticoid injections (IAGCIs) into swollen joints in early rheumatoid arthritis (RA).
METHODS: Ninety-nine patients with early, DMARD naive RA were treated, aiming at remission, with methotrexate, sulfasalazine, hydroxychloroquine, low-dose oral prednisolone and, when needed, IAGCIs for 2 years, and randomised to receive infliximab or placebo from weeks 4 to 26. During each of the 15 study visits, patients were scored retrospectively 0.2-0.4 points (depending on the number of non-injected joints) if IAGCIs to all swollen joints were not given. Patients were divided into tertiles by their cumulative scores for neglected injections (CSNI) over 24 months. 28-joint disease activity score (DAS28) area under the curve (AUC) between 0-24 months, remission rates, changes in quality of life, and radiological changes during the follow-up were assessed. Trends across tertiles of CSNI were tested with generalised linear models.
RESULTS: Higher CSNI was associated with lower strict remission rates (p=0.005), and lower quality of life (p=0.004) at 24 months, and higher DAS28 AUC (p<0.001) during the follow-up. At 24 months, DAS28 remission rates were 90%, 93% and 76% (p=0.081), and strict remission rates were 74%, 77% and 39% by tertiles of CSNI. No significant differences were observed in radiological progression (p=0.089). IAGCIs were well tolerated.
CONCLUSIONS: Neglecting IAGCIs into swollen joints is associated with lower remission rates, higher disease activity, and lower quality of life. Hence, IAGCIs should be used as an integral part of the targeted treatment of early RA.
OBJECTIVE: YKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission.
METHODS: Ninety-nine patients with early DMARD-naïve RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay.
RESULTS: At the baseline, plasma YKL-40 concentration was 57 ± 37 (mean ± SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor-α antagonist infliximab was added on the combination treatment.
CONCLUSIONS: High YKL-40 levels were found to be associated with disease activity in early DMARD-naïve RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission.
Identifying prognostic factors for remission in early rheumatoid arthritis (ERA) patients is of key clinical importance. We studied patient-reported outcomes (PROs) as predictors of remission in a clinical trial. We randomized 99 untreated ERA patients to receive remission-targeted treatment with three disease-modifying antirheumatic drugs and prednisolone for 24 months, and infliximab or placebo for the initial 6 months. At baseline, we measured following PROs: eight Short Form 36 questionnaire (SF-36) dimensions, patient's global assessment [PGA, visual analogue scale (VAS)], Health Assessment Questionnaire (HAQ), and pain VAS. We used multivariable-adjusted regression models to identify PROs that independently predicted modified American College of Rheumatology remission at 2 years. Follow-up data at 2 years were available for 93 patients (92%), and 58 patients (62%) were in remission. At baseline, patients who achieved remission had higher radiological score (p = 0.04), lower tender joint count (p = 0.001), lower PGA (p = 0.005) and physician's global assessment (p = 0.019), lower HAQ (p = 0.016), less morning stiffness (p = 0.009), and significantly higher scores in seven out of eight SF-36 dimensions compared with patients who did not. In multivariable models that included all PROs, remission was associated with SF-36 dimensions higher vitality (odds ratio 2.01; 95% confidence interval 1.19-3.39) and better emotional role functioning (odds ratio 1.64; 95% confidence interval 1.01-2.68). PGA, pain VAS, HAQ, and other SF-36 dimensions were not associated with remission. We conclude that self-reported vitality and better emotional role functioning are among the most important PROs for the prediction of remission in ERA.
Adverse events (AEs) are common during disease-modifying antirheumatic drug (DMARD) treatment, but their influence on treatment results is unclear. We studied AEs in relation to disease activity in early rheumatoid arthritis (RA). Ninety-nine patients started intensive treatment with three conventional synthetic DMARDs (csDMARDs) and oral prednisolone, and were randomized to a 6-month induction treatment with infliximab or placebo. All AEs during the first 12 months of treatment were recorded. We scored each AE based on severity (scale 1-4) and defined the burden of AEs as the sum of these scores. Patients were divided into tertiles according to the burden of AEs. As outcomes, we assessed 28-joint disease activity score (DAS28) levels and remission rates at 12 and 24 months. Three hundred thirty-one AEs in 99 patients were reported, and 27 (8%) were categorized as severe or serious. Mean burden of AEs per patient was 5.4 ± 4.3. Seventy-nine AEs (24%) led to temporary (n = 52) or permanent (n = 27) csDMARD discontinuation. Of discontinuations, 1, 21, and 57 were detected in the first, second, and third tertiles, respectively. DAS28 remission rates decreased across tertiles at 12 months (94, 94, and 76%; p for linearity 0.029) and at 24 months (90, 86, and 70%; p for linearity 0.021). Mean DAS28 levels increased across tertiles at 12 months (1.5 ± 1.0, 1.7 ± 0.9, and 1.9 ± 1.2; p for linearity 0.021) and at 24 months (1.4 ± 0.8, 1.6 ± 1.0, and 1.9 ± 1.1; p for linearity 0.007). High burden of AEs is associated with higher disease activity and lower likelihood of remission in early RA.
OBJECTIVE: The short-term outcomes of remission-targeted treatments of rheumatoid arthritis (RA) are well-established, but the long-term success of such strategies is speculative, as is the role of early add-on biologics. We assessed the 10-year outcomes of patients with early RA treated with initial remission-targeted triple combination of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 7.5-mg prednisolone, and additional infliximab (IFX) or placebo infusions.
METHODS: Ninety-nine patients with early, DMARD-naive RA were treated with a triple combination of csDMARDs and prednisolone and randomized to double-blind receipt of infusions of either IFX (the Finnish Rheumatoid Arthritis Combination Therapy Trial [FIN-RACo] + IFX) or placebo (FIN-RACo + placebo) during the first 6 months. After 2 years, the treatment strategies became unrestricted, but the treatment goal was strict remission in the TNF-Blocking Therapy in Combination With Disease-Modifying Antirheumatic Drugs in Early Rheumatoid Arthritis (NEO-RACo) study. At 10 years, the clinical and radiographic outcomes and the drug treatments used between 5 and 10 years were assessed.
RESULTS: Ninety patients (91%) were followed after 2 years, 43 in the FIN-RACo + IFX and 47 in the FIN-RACo + placebo group. At 10 years, the respective proportions of patients in strict NEO-RACo remission and in Disease Activity Score using 28 joints remission in the FIN-RACo + IFX and FIN-RACo + placebo groups were 46% and 38% (P = 0.46) and 82% and 72% (P = 0.29), respectively. The mean total Sharp/van der Heijde score was 9.8 in the FIN-RACo + IFX and 7.3 in the FIN-RACo + placebo group (P = 0.34). During the 10-year follow-up, 26% of the FIN-RACo + IFX group and 30% of the FIN-RACo + placebo group had received biologics (P = 0.74).
CONCLUSION: In early RA, excellent results can be maintained up until 10 years in most patients treated with initial combination csDMARDs and remission-targeted strategy, regardless of initial IFX/placebo infusions.
OBJECTIVE: To evaluate the development of radiological changes of the cervical spine in patients with rheumatoid arthritis (RA) in the NEO-RACo trial treated with an intensive, remission-targeted combination of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and additional infliximab (IFX) or placebo (PLA) for the first 6 months.
METHODS: Ninety-nine patients with early, DMARD-naive RA were treated with a triple combination of csDMARD and prednisolone, and randomized to double-blindly receive either IFX (FIN-RACo+IFX) or PLA (FIN-RACo+PLA) infusions during the first 6 months. After 2 years the treatment strategies became unrestricted, but the treatment goal was strict NEO-RACo remission. At the 10-year visit, radiographs of the cervical spine were taken of 85 patients (38 in the FIN-RACo+IFX group and 47 in the FIN-RACo+PLA group). The study was registered at ClinicalTrials.gov (NCT00908089).
RESULTS: There were 4/85 patients (4.7%) with cervical spine involvement (CSI) by 10 years. Atlantoaxial subluxation was found in 2/85 patients (2.4%), both in the FIN-RACo+IFX group, and none in the FIN-RACo+PLA group. Atlantoaxial impaction was found in 1/85 patients (1.2%) in the FIN-RACo+IFX group. Subaxial subluxation was found in 1/85 patients (1.2%).
CONCLUSION: Early and intensive remission-targeted treatment has reduced the incidence of CSI and our results show that intensive treatment also prevents its development in the long run.
Background: We have previously reported a 37% remission rate in patients with early rheumatoid arthritis (RA) treated with a combination therapy with 3 DMARDs and prednisolone (the FIN-RACo treatment strategy). Here we set out to study the contribution of infliximab (INFL) added as an induction therapy during the first 6 months in patients with early RA treated with FIN-RACo strategy by using full doses of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ) and prednisolone (PRED) (= COMBI) compared with COMBI+ placebo (PLA). Here we report the 2- year clinical and radiological outcome. Methods: In this multicenter (15 centres), randomized, double-blind, parallel-group trial, we enrolled 100 patients aged <65 y with early RA (symptoms ≤ 12 mo), active (≥ 6 swollen and ≥ 6 tender joints, early morning stiffness ≥ 45 min and/or ESR ≥ 30 mm/h and/or CRP520 mg/l). COMBI was started in all patients targeted to remission. The patients were randomized in a double-blind way to receive INFL (3 mg/kg) or PLA at weeks 4 6, 10, 18 and 26. Doses of MTX (max 25 mg) and SSZ (max 2 g) were individually tailored to reach remission. Doses of HCQ (35 mg/ kg/week) and PRED (7.5 mg/day) were constant. Remission was assessed by the strict ACR criteria (no swollen or tender joints), and by DAS28. In cases of inefficacy/intolerability, the DMARDs were substituted, but it was obligatory to use 3 DMARDs and PRED. Local glucocorticoid injections were allowed. Primary outcomes were proportion of patients in remission and radiology. Results: At entry, the mean age (SD) of the patients was 46 y (10), median duration (IQR) of symptoms 4 mo (2, 6), 68% were RF+, and 67% female. Mean number (SD) of swollen joints was 15 (6), tender joints 20 (10), ESR 33 (22) mm/h and HAQ 1.0 (0.7). At 24 months, 62% of the patients were in ACR remission (COMBI+PLA 53%, COMBI+INFL 70%). Remission rate over time was higher in the COMBI+INFL group [OR=1.97 (95% CI.: 1.03 to 3.74), p=0.04]. By DAS28 criteria, 85% of the patients were in remission (COMBI+PLA 82%, COMBI+INFL 88%, n.s., over 3-24 months more often in COMBI+INFL (p=0.047). The median total Sharp score (TSS) was 0 in both groups at baseline. At 24 months, 41% of patients in COMBI+PLA and 54% in COMBI+INFL had 0 score. A mean (95% CI) change of TSS from baseline to 24 months was 1.4 (0.8 to 2.2) in COMBI+PLA and -0.2 (-1.1 to 0.4) in COMBI+INFL (p=0.005). Conclusions: Intensified use of the FIN-RACo combination strategy in patients with early active RA induced strict remission by ACR criteria in 62% and by DAS28criteria in 82% of the patients. Radiological changes were rare during the study. Adding INFL during the first 6 months reflected in higher frequency of remissions and prevention of radiological progression during 2 years.
