Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial.

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.

Early treatment intensification induces favourable radiographic outcomes according to predicted versus observed radiographic progression in early rheumatoid arthritis: a subanalysis of the randomised FIN-RACo and NEO-RACo trials.

OBJECTIVES: Predicted versus observed radiographic progression in early rheumatoid arthritis (POPeRA) was applied to demonstrate how various treatment modalities affect and potentially minimise radiographic progression over time. METHODS: The POPeRA method utilises the baseline radiographic score and patient-reported symptom duration to predict radiographic outcomes. It was applied at baseline, 2, and 5 years to patients with eRA from the randomised Finnish RA Combination trial (FIN-RACo) (n=144) and New Finnish RA Combination Therapy (NEO-RACo) (n=90) trials. For FIN-RACo, patients were randomised either to a single DMARD (sulfasalazine, with or without prednisolone) or to combination therapy (methotrexate+sulfasalazine+hydroxychloroquine, i.e. triple therapy, with prednisolone). In NEO-RACo, all patients were assigned intensified combination therapy (including 7.5 mg prednisolone/day) plus a randomised 6-month induction of either placebo or anti-TNF treatment (infliximab). RESULTS: In FIN-RACo, combination versus monotherapy resulted in superior outcomes in the change from predicted progression over 2 and 5 years (mean 35.7% reduction vs. -32.9%, a worsening from predicted, p=0.001; 34.2% vs. -17.8%, p=0.003, respectively). In NEO-RACo, combination+anti-TNF induction led to significantly greater reductions from predicted progression than combination+placebo, both at 2 and 5 years of follow-up (98.5% vs. 83.4%, p=0.005; 92.4% vs. 82.5%, p=0.027, respectively). Importantly, anti-TNF add-on led to superior reductions from predicted among RF-positive patients (2 years: 97.4% vs. 80.4%, p=0.009; 5 years: 90.2% vs. 80.1%, p=0.030), but not among RF-negative patients. CONCLUSIONS: These results confirm that conventional combination therapy in eRA has a long-term radiographic benefit versus monotherapy. Through POPeRA, it was made evident that anti-TNF induction therapy for 6 months further increases the long-term radiographic benefit of combination therapy in RF-positive patients.

Intra-articular glucocorticoid injections should not be neglected in the remission targeted treatment of early rheumatoid arthritis: a post hoc analysis from the NEO-RACo trial.

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.

Cost-effectiveness of biologic compared with conventional synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: a Register study.

OBJECTIVE: The aim of this study was to explore the cost-effectiveness of biological DMARDs (bDMARDs) compared with conventional synthetic DMARDs (csDMARDs) for RA using real-world data from Finnish registers. METHODS: RA patients starting their first bDMARD and comparator patients using csDMARDs during 2007-11 were obtained from the National register of biologic treatments in Finland and the Jyväskylä Central Hospital patient records. Propensity score matching was applied to adjust for differences between bDMARD and csDMARD users. Effectiveness was measured in quality-adjusted life years (QALY) and based on the register of biologic treatments in Finland and Jyväskylä Central Hospital patient records, whereas the direct costs were obtained from relevant Finnish national registers. Patients were followed up for 2 years, and both costs and effectiveness for the second year were discounted at 3%. The incremental cost-effectiveness ratio (ICER) with 95% CI was calculated based on bootstrapped mean costs and effectiveness. RESULTS: Of 1581 RA patients meeting study inclusion criteria, 552 bDMARD and 220 csDMARD users were included in analyses after matching. Mean costs for bDMARDs and csDMARDs were €55 371 and €24 879, while mean effectiveness was 1.23 and 1.20 QALYs, respectively. Consequent ICER was €902 210/QALY. Results were confirmed in sensitivity analyses. CONCLUSION: The high incremental cost and the small, non-significant difference in effectiveness resulted in high ICER, suggesting that bDMARDs are not cost-effective. Regardless of matching, latent confounders may introduce bias to the results.

Epstein-Barr virus in peripheral blood is associated with response to rituximab therapy in rheumatoid arthritis patients.

Autoreactive B cells infected by Epstein-Barr virus (EBV) are suspected to be involved in the etiology of various human chronic autoimmune diseases. This motivated us to study the relationship between peripheral blood EBV load at baseline and treatment response to B cell-depleting therapy in rheumatoid arthritis (RA) patients. Thirty-five RA patients who started treatment with rituximab (RTX) in a routine clinical setting were assessed for baseline disease activity using disease activity score using 28 joint counts (DAS28) (erythrocyte sedimentation rate [ESR]). Treatment response was evaluated 3-7 months after RTX. EBV load in baseline whole blood (WB) samples was determined using quantitative PCR. EBV DNA was detected in 16/35 (46 %) of the WB samples. In these 16 EBV-positive patients, the median viral load was 3.15 (2.68-4.00) log copies/ml. Good/moderate European League Against Rheumatism (EULAR) response was observed in 16/16 of the EBV DNA-positive vs 13/19 EBV DNA-negative patients, p = 0.022. Significant response (DAS28 change >1.2) was observed in 14/16 of the EBV DNA-positive vs 10/19 EBV DNA-negative patients, p = 0.035. The decline in DAS28 after RTX was 2.10 (1.03-4. 78) in the EBV DNA-positive vs 1.47 (-0.7-4.70) in the EBV DNA-negative patients, p = 0.13. EBV load at baseline significantly correlated with change in DAS28 after RTX (τB = -0.261, p = 0.042). Our results suggest that the presence of EBV genome in WB could serve as a predictive marker to RTX therapy in RA.

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels.

OBJECTIVE: Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines. METHODS: The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-γ, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis. RESULTS: STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation. CONCLUSION: The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.

Long-term real-life experience with rituximab in adult Finnish patients with rheumatoid arthritis refractory or with contraindication to anti-tumor necrosis factor drugs.

OBJECTIVE: The objective of this study was to evaluate the long-term safety and efficacy of repeated rituximab (RTX) infusions in the treatment of rheumatoid arthritis in daily clinical practice in Finland. METHODS: Data were collected from the medical records of a total of 151 patients with rheumatoid arthritis treated with RTX and followed up for at least 12 months after the treatment onset. Change in the 28-joint Disease Activity Score (DAS28), European League Against Rheumatism response criteria and proportions of patients reaching disease remission (DAS28 < 2.6) or low disease activity (DAS28 < 3.2) were used to assess the clinical response. RESULTS: Of the 151 patients 128 received 2 courses, 76 received 3 courses, and 42 received 4 courses of RTX. The mean time to retreatment for the first 4 courses varied between 11 and 13 months. Median DAS28 decreased from 5.4 (0.5-8.6) to 3.3 (0.6-6.6) after the first course. After the second treatment course, the DAS28 was 3.1 (range, 0.1-6.5). The median precourse baseline DAS28 before the second and third courses were 4.6 (range, 1.7-7.8) and 4.24 (range, 1.7-7.2), respectively. The number of previously failed tumor necrosis factor inhibitors did not predict response to RTX in this patient cohort with extensive use of previous disease-modifying antirheumatic drugs (median = 6). CONCLUSIONS: The treatment as-needed regimen used in this study cohort led to delayed RTX retreatment and disease flare in a significant proportion of patients. A regular retreatment every 6 months, at least, after the first 2 treatment courses in patients who are not in remission could allow better control of disease activity.

Failure in longterm treatment is rare in actively treated patients with rheumatoid arthritis, but may be predicted by high health assessment score at baseline and by residual disease activity at 3 and 6 months: the 5-year followup results of the randomized clinical NEO-RACo trial.

OBJECTIVE: With modern initial aggressive combination treatments with synthetic disease-modifying antirheumatic drugs (sDMARD), most patients with rheumatoid arthritis (RA) achieve remission, have marginal radiographic progression, and sustain normal function. Here we aim to identify the patients failing these targets even after aggressive treatment. METHODS: Ninety-nine patients with early, active RA were treated with a combination of 3 sDMARD and prednisolone (PRD), and either infliximab or placebo infusions during the first 6 months, aiming at strict remission. After 24 months, the treatments became unrestricted. At 60 months, 4 evident clinical features of treatment failure were defined: area under curve (AUC) between 6-60 months for disease activity score assessing 28 joints > 2.6; AUC 6-60 for health assessment questionnaire > 0.5; progression in total Sharp/van der Heijde score 0-60 months > 3 units; and need of PRD or biologic DMARD treatment at 60 months. RESULTS: A total of 93 patients were followed up for 60 months. Of them, 45 had no features of treatment failure, 30 had 1, 10 had 2, 7 had 3, and 1 patient had all 4 features. Having 2-4 features of treatment failure at 5 years was predicted by the health assessment score at baseline, and by even low residual disease activity at 3 and 6 months. CONCLUSIONS: Only 20% of the patients with RA treated early with combination sDMARD and PRD have more than 1 clinical feature of treatment failure at 60 months. Residual clinical disease activity at 3-6 months was the most important predictor for identifying these patients. The study was registered at www.clintrials.gov (NCT00908089).

The duration of gastrointestinal and joint symptoms after a large waterborne outbreak of gastroenteritis in Finland in 2007--a questionnaire-based 15-month follow-up study.

An extensive drinking water-associated gastroenteritis outbreak took place in the town of Nokia in Southern Finland in 2007. 53% of the exposed came down with gastroenteritis and 7% had arthritis-like symptoms (joint swelling, redness, warmth or pain in movement) according to a population-based questionnaire study at 8 weeks after the incident. Campylobacter and norovirus were the main pathogens. A follow-up questionnaire study was carried out 15 months after the outbreak to evaluate the duration of gastrointestinal and joint symptoms. 323 residents of the original contaminated area were included. The response rate was 53%. Participants were inquired about having gastroenteritis during the outbreak and the duration of symptoms. Of those with gastroenteritis, 43% reported loose stools and abdominal pain or distension after the acute disease. The prevalence of symptoms declined promptly during the first 3 months but at 15 months, 11% reported continuing symptoms. 32% of the respondents with gastroenteritis reported subsequent arthritis-like symptoms. The disappearance of arthritis-like symptoms was more gradual and they levelled off only after 5 months. 19% showed symptoms at 15 months. Prolonged gastrointestinal symptoms correlated to prolonged arthritis-like symptoms. High proportion of respondents continued to have arthritis-like symptoms at 15 months after the epidemic. The gastrointestinal symptoms, instead, had declined to a low level.

ESSPRI and other patient-reported indices in patients with primary Sjogren's syndrome during 100 consecutive outpatient visits at one rheumatological clinic.

OBJECTIVE: A European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and a patient-reported index (ESSPRI) have recently been developed and validated. In our previous study the ESSDAI correlated significantly with serum ß2 microglobulin concentration. We now aim to establish whether the ESSPRI is also associated with serum ß2 microglobulin or with other patient-reported indices. METHODS: The data on 100 consecutive visits of patients with primary SS (pSS) were reviewed from the patient charts. Patients who had filled out the ESSPRI questionnaire and fulfilled at least four of the revised American-European consensus group criteria for pSS were included. Data were gathered on the ESSPRI (0-10 cm) and on the patient's global health assessment [visual analogue scale (VAS) 0-10 cm] (PGH-VAS), pain-VAS (0-10 cm) and HAQ (range 0-3). RESULTS: The ESSPRI correlated significantly with the PGH-VAS (r = 0.753, P < 0.0001), pain-VAS (r = 0.656, P < 0.0001) and HAQ (r = 0.542, P < 0.0001) (Spearman's correlation). It also correlated weakly with serum ß2 microglobulin (r = 0.214, P = 0.043) and ESR levels (r = 0.235, P = 0.019). CONCLUSION: The ESSPRI correlated significantly with other patient-reported indices, serum ß2 microglobulin and ESR in patients with pSS. Our results support the view that the ESSPRI is a useful tool in the follow-up of patients with pSS.

Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial.

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.

Disease activity of idiopathic juvenile arthritis continues through adolescence despite the use of biologic therapies.

OBJECTIVES: To investigate the use of DMARDs and biologic treatments and disease activity in patients with JIA referred to the adult rheumatology clinic and to provide further information regarding the need for long-term rheumatologic care. METHODS: We studied the data of 154 patients retrospectively from hospital records if they met the following criteria: diagnosis of JIA and at least one visit to the adult rheumatologic unit. Previous and current antirheumatic treatment, duration of biologic therapy and disease activity were recorded. RESULTS: At the end of patient follow-up, the median age of the eligible patients was 19 years (range 16-24 years) and the disease duration was 8 years (range 0-20 years). Twenty-nine per cent of the patients were still on biologic therapies. The total median duration of treatment with at least one biologic agent was 4.2 years, and 44% of treatment durations lasted >5 years. Some disease activity was present in the last year in 58% of patients. Activity in the temporomandibular joint was detected in 14% and uveitis in 8%. Thirteen per cent did not need further specialist care and in 14% all antirheumatic medication could be tapered off. CONCLUSION: Almost one-third of adolescents and young adults with JIA who needed specialist care were on biologics. The need for treatment in many cases is long term (>5 years). Most patients (58%) still showed evidence of mild disease activity. Adolescents and young adults with JIA are a distinct patient group in adult health care and a specialized multidisciplinary approach to treatment is needed.

Outcome of reactive arthritis after an extensive Finnish waterborne gastroenteritis outbreak: a 1-year prospective follow-up study.

The purpose of the study was to assess the 1-year outcome of definitive reactive arthritis (ReA) after a waterborne outbreak. A cohort of 21 patients (15 females and 6 males, median age 54 years) with ReA related to an extensive waterborne outbreak in Finland was clinically followed-up by rheumatologists with visits at baseline, at 1 month and 3, 6 and 12 months. Although the outcome was in general favourable, 1/3 of the patients had chronic course; 7 (33 %) of the 21 patients needed disease-modifying anti-rheumatic drugs (DMARDs) and even 8 (38 %) of them used glucocorticoids at 12 months. Four (19 %) were using non-steroidal anti-inflammatory drugs and nine (43 %) other analgesics. Many patients had articular pain and impaired physical function still at 12 months, even though inflammatory parameters and the number of swollen joints were low. Only one patient (5 %) was human leucocyte antigen-B27-positive. She had the most severe ReA and also additional infectious arthritis caused by Salmonella serotype enteritidis leading to osteonecrosis of her hip joint with subsequent need for arthroplasty. ReA as observed in our study was overall fairly mild, but in many individuals, postinfectious arthralgia and DMARD use continued at least up to 1 year.

Decline in work disability caused by early rheumatoid arthritis: results from a nationwide Finnish register, 2000-8.

OBJECTIVES: To study whether the work disability (WD) rates in early rheumatoid arthritis (RA) have changed in Finland, where the treatment of RA has long been active but has intensified further since 2000. METHODS: All incident non-retired patients with RA of working age (18-64 years) in a nationwide register maintained by the Finnish Social Insurance Institution from 1 January 2000 to 31 December 2007 were identified. Patient cohorts were analysed in 2-year time periods (2000-1, 2002-3, 2004-5, 2006-7) and initial disease-modifying antirheumatic drugs (DMARDs) were elucidated from the drug purchase register. The incidence of continuous WD in the RA cohorts as well as in the entire Finnish population up to 31 December 2008 was analysed. RESULTS: A total of 7831 patients were identified (71% women, 61% rheumatoid factor-positive). Throughout the follow-up period the use of methotrexate and combination DMARDs as the initial treatment of early RA increased. During the first 2 years the incidence of RA-related continuous WD was 8.9%, 9.4%, 7.2% and 4.8% in the year cohorts, respectively (p<0.001 for linearity). Compared with the entire Finnish population, the age- and sex-stratified standardised incidence ratio of a WD pension due to any cause was 3.69, 3.34, 2.77 and 2.80 in the year cohorts, respectively (p<0.001 for linearity). CONCLUSIONS: Since 2000 the frequency of continuous WD in early RA has declined in Finland. The present data allow no explanatory analysis but, at the same time, increasingly active treatment strategies have been introduced.

Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study).

OBJECTIVE: Early treatment of patients with rheumatoid arthritis (RA) with combination treatment starting with methotrexate, sulfasalazine, hydroxychloroquine and prednisolone (FIN-RACo strategy) is superior to monotherapy. A study was undertaken to determine whether infliximab (INFL) added to intensified FIN-RACo treatment for the initial 6 months improves the 2-year outcome. METHODS: 99 patients with early untreated active RA were enrolled in an investigator-initiated, randomised, double-blind, multicentre, parallel-group trial. Primary outcomes were remission and radiological changes at 2 years. All patients started with FIN-RACo. In addition, they were randomised to receive INFL or placebo (Pla) from weeks 4 to 26. RESULTS: At 24 months, 66% and 53%, respectively, of the patients in the FIN-RACo+INFL and FIN-RACo+Pla groups were in remission according to the modified American College of Rheumatology (ACR) criteria (p=0.19), 26% and 10% were in sustained modified ACR remission (p=0.042) and 82% in both groups were in remission by 28-joint disease activity score (not significant). Mean changes in the total Sharp-van der Heijde score were 0.2 and 1.4, respectively (p=0.0058). CONCLUSIONS: Most patients with early active RA achieve clinical remission and develop negligible joint damage with the intensified FIN-RACo regimen. Adding INFL for the first 6 months delays radiological progression.