Real-world data on seropositive rheumatoid arthritis, then and now: ten-year outcomes of 1151 patients diagnosed between 1997 and 2011.

OBJECTIVES: To study 10-year outcomes in patients with early seropositive rheumatoid arthritis (RA) whether the outcomes improve over time. METHODS: Data of 1754 patients with early RA, diagnosed in 1997-2011 were explored; 66% (n=1151) were seropositive and included in the analyses. Patients were divided into five groups by diagnosis year: 1997-1999, 2000-2002, 2003-2005, 2006-2008 and 2009-2011. Clinical parameters including disease activity and function were compared between the groups. RESULTS: A total of 832 (72%) patients attended the 10-year visit, while 319 did not (e.g. 196 had died and 49 moved). The median (IQR) DAS28 decreased from 2.9 (2.2, 3.7) to 2.3 (1.4, 3.0) (p<0.001) between groups 1997-1999 and 2009-2011. The proportion of patients with 2 or more swollen joints on 46 joint count decreased from 33% to 13%, respectively. Median (IQR) pain decreased from 30 (15, 52) to 25 (6, 51) (p=0.03) and fatigue from 31 (12, 52) to 15 (2, 50) (p=0.012). Median (IQR) dr.global decreased from 20 (5, 40) to 0 (0, 5) p<0.001. The proportion of patients with a HAQ-score of ≤0.5 increased from 39% to 49% (p=0.002). The proportion of patients that had used methotrexate by the 10-year visit increased from 79% to 96% (p<0.001) and the proportion of patients who had used bDMARDs increased from 11% to 28% (p=0.001), respectively. CONCLUSIONS: Several clinical outcomes were better in patients who were diagnosed more recently. More intensive use of medications over time might have contributed to these improvements.

Is seronegative rheumatoid arthritis true rheumatoid arthritis? A nationwide cohort study.

OBJECTIVES: The classification of seronegative arthritides can be challenging. Our aim was to examine the incidence of SpA diagnosis among patients initially diagnosed as seronegative RA. METHODS: Using nationwide Finnish registers from social insurance institutions, we identified all adult patients who were diagnosed with incident seronegative RA [International Classification of Diseases (ICD)-10 code M06] from 1 January 2000 to 31 December 2014. The patients whose diagnoses subsequently changed to the ICD-10 codes of SpA (M07, M45, M46, K50 and K51) were identified in the national care register, until 31 December 2016. RESULTS: A total of 9784 adult seronegative RA patients were identified. Of these, 564 patients had their diagnosis subsequently changed to SpA: 275 (48.7%) patients with PsA, 245 (43.4%) patients with axial SpA and 44 (7.8%) patients with diagnoses related to IBD. The cumulative incidence of SpA diagnoses in 15 years was 10.4% (95% CI 8.9, 12.1) and 8.1% (95% CI 7.1, 9.3) in men and women, respectively. CONCLUSION: This study calls for vigilance in seronegative RA patients, especially those with more atypical presentations, since the diagnosis could change. The possibility of SpA diagnosis should be considered and specifically looked for, as this could impact on management and response to treatment.

Prevalence of calcium pyrophosphate deposition disease in a cohort of patients diagnosed with seronegative rheumatoid arthritis.

OBJECTIVES: We aimed to characterise the clinical and radiographical phenotype of calcium pyrophosphate dihydrate deposition (CPPD) disease in patients initially diagnosed with seronegative RA, and to increase the awareness that CPPD disease can be falsely diagnosed as seronegative rheumatoid arthritis (RA). METHODS: Altogether 435 early seronegative RA patients were clinically diagnosed in a single rheumatology centre and scheduled for a 10-year follow-up. All clinical data were collected and reviewed. CPPD-related arthritis was suspected if a patient had typical radiographical findings and suitable clinical pattern of CPPD or calcium pyrophosphate crystals were found in the synovial fluid. These patients are the subjects of this study. RESULTS: Among 435 seronegative RA patients, 17 patients (3.9%) (baseline mean age 71.2 years, 82% women) with CPPD disease were identified. CPPD resembling clinical patterns in these patients were: chronic CPP crystal inflammatory arthritis (9 patients), acute CPP crystal arthritis (6 patients) and OA with CPPD (2 patients). All had typical radiographical findings of CPPD: Chondrocalcinosis (CC) of triangular fibrocartilage (17 patients [100%]), CC of knee (9 patients [53%]), CC or narrowing of metacarpophalangeal joints (7 patients [41.2%]), CC of metatarsophalangeal joints (4 patients [23.5%]), CC of symphysis pubis (1 patient [5.8%]), CC of glenohumeral joint (1 patient [5.8%]) and scapholunate advanced collapse (5 patients [29.4%]). None of these patients developed typical RA-like erosions. CONCLUSIONS: CPPD disease can mimic seronegative RA at baseline and is important in the differential diagnosis of seronegative arthritis at baseline and during follow-up. The prevalence of CPPD patients in our early seronegative RA patients was 3.9%, the percentage was 7.0% among patients ≥60 years at baseline.

Cervical Spine Involvement among Patients with Rheumatoid Arthritis Treated Actively with Treat-to-target Strategy: 10-year Results of the NEO-RACo Study.

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.

Does early seronegative arthritis develop into rheumatoid arthritis? A 10-year observational study.

OBJECTIVES: To investigate the 10-year clinical course of patients with seronegative arthritis with the emphasis of reclassification of diagnoses when applicable. METHODS: A total of 1030 patients including 435 seronegative cases were classified as early RA in 1997-2005 at Jyväskylä Rheumatology Centre and prospectively scheduled for a ten-year follow-up. Clinical data from the follow-up visits and the case-reports until and including the 10-year visit or death, whichever happened earlier, were retrospectively collected and reviewed with re-classification of the cases when applicable. Descriptive statistics were used. RESULTS: Among the 435 seronegative cases (69 % women, baseline mean age was 59 years), 13 (13/435 [3%]) could be reclassified as seropositive or erosive RA: 4 turned seropositive (2 for ACPA and 2 for RF [> 2x reference level]) and 9 developed erosions typical for RA. Reclassification revealed 68 (16%) cases of polymyalgia rheumatica, 46 (11%) psoriatic arthritis, 45 (10%) osteoarthritis, 38 (8.7%) spondyloarthritis, 15 (3.4%) plausible reactive arthritis, 10 (2.3%) gout, 17 (3.9%) pseudogout, 6 (1.4%) paraneoplastic arthritis, 6 (1.4%) juvenile arthritis, 2 (0.5%) haemochromatosis, 3 (0.7%) ankylosing spondylitis, 2 (0.5%) giant cell arteritis, and 8 miscellaneous diagnoses. The other 140 patients (32%) could not be reclassified in any clear-cut diagnosis and had features of transient arthritis (n=41), seronegative spondyloarthritis (n=47), while 49 remained unspecified. CONCLUSIONS: Over a 10-year follow-up period, reclassification revealed significant heterogeneity in the diagnosis of seronegative RA. Therefore, seronegative arthritis should not be studied as a homogenous entity.

Survival and safety of infliximab bio-original and infliximab biosimilar (CT-P13) in usual rheumatology care.

OBJECTIVES: Reports to-date indicate similarity between infliximab biosimilar (IB) and infliximab bio-original (IO) in clinical efficacy and safety. This study examines the survival of IB and IO using routinely collected data over a 2-year period. METHODS: Routinely collected clinical data inputted directly in an electronic database at a large rheumatology centre were analysed. Adult patients taking IO or IB for any rheumatological diagnosis were included. Kaplan-Meier survival analyses were used to examine IB and IO survival, with a sub-group analysis among those starting infliximab from 2008 onwards. RESULTS: Out of 395 patients analysed, 53% (n=209) were female; the majority had rheumatoid arthritis (31%) followed by spondyloarthritis (28%). Ninety-nine patients had IB as the first infliximab drug. Patients who started on IB vs. IO as their first infliximab product, had better survival over the first 2 years (log rank=0.001). Discontinuation due to inefficacy was much commoner in IO versus IB users (18 vs. 5%). In patients switching from IO to IB, drug survival was better versus those receiving IB as the first infliximab drug (log rank=0.073). CONCLUSIONS: IB was well-tolerated and comparable to IO, with no additional safety signals identified. The results suggest superior survival of IB over IO over the first 2 years.

Early Targeted Combination Treatment With Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Long-Term Outcomes in Rheumatoid Arthritis: Ten-Year Follow-Up Results of a Randomized Clinical Trial.

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.

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.

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.

Delivering a one-stop, integrated, and patient-centered service for patients with rheumatic diseases.

OBJECTIVE: To describe a one-stop, integrated rheumatology service and assess patient satisfaction. METHODS: A descriptive report and patient satisfaction survey of a rheumatology clinic model first developed in 1996 to enhance the patient "journey" through rheumatology services. A patient-satisfaction survey over a 3-week period assessed several aspects of care including quality of services, consultations, and patient education. RESULTS: All referrals are screened by a rheumatologist to pre-schedule laboratory/radiology/other tests for the visit. Upon arrival to the clinic, patients check-in at an electronic desk, and then complete the electronic GoTreatIT monitoring system which assesses patient-reported outcomes. The patient is reviewed by a doctor in a 30- to 60-min consultation, and then by a nurse (for diagnosis/treatment education, vaccinations). An ultrasound machine and capillaroscopy are available for use in the clinic. Patients can be scheduled on the same day to see a nutritionist, physiotherapist, or other heath professionals as necessary. An "early-rheumatoid arthritis treatment path" is available to ensure early, intensive treatment. A patient satisfaction survey revealed high rating of the overall service (90.6/100). None of the patients felt that they lacked education on their disease or medication. Only 6% of the respondents gave negative feedback, reasons including feeling overwhelmed with information or not being given a cause for their symptoms. The multi-disciplinary approach was highly valued and only 3% would rather see a doctor and nurse on separate days. CONCLUSION: The specific clinic model provides an ideal setting for a one-stop service, avoiding unnecessary visits, collecting patient data, and enhancing the patient experience and journey through the system. Where possible, the specific clinic model could be used or adapted to build similar models in other rheumatology departments. The clinic model could also form the basis for services in other specialties dealing with chronic conditions.

Long-term outcomes of destructive seronegative (rheumatoid) arthritis - description of four clinical cases.

BACKGROUND: Seronegative rheumatoid arthritis is associated with a milder course of progression compared to seropositive disease. However, long-term follow-up data of the clinical course of seronegative rheumatoid arthritis are sparse. Here we describe four cases with a rare disease entity of aggressive destructive seronegative (rheumatoid) arthritis with 20-35 years of follow-up. CASE PRESENTATION: The four cases are women with an initial presentation of seronegative rheumatoid arthritis in 1980-1996 and have received disease-modifying anti-rheumatic drugs since the diagnosis. In all cases, the condition has been refractory to treatments and evolved into a severe disease with destructions of the wrists, sub-talar and ankle joints, as well as large joints but not small joints of fingers and toes. All cases are negative with regard to rheumatoid factor, anti-cyclic citrullinated peptide antibodies and antibodies against carbamylated proteins. CONCLUSIONS: This report adds to the existing literature, making the reader aware of this sub-type of inflammatory arthritis which despite being seronegative, can have devastating disease consequences. The report highlights the need for further research into this field in order to better understand this disease sub-type, the pathogenesis, disease course and outcomes.

Is long-term radiographic joint damage different between men and women? Prospective longitudinal data analysis of four early RA cohorts with greater than 15 years follow-up.

OBJECTIVES: To examine gender-related differences in radiographic joint damage in rheumatoid arthritis (RA) using four prospective early RA cohorts. METHODS: Radiographs of patients from four early prospective RA cohorts were examined. The extent of joint damage in hands and feet was assessed by three evaluators according to the Larsen score (0-100). Descriptive statistics and two-way bootstrap ANOVA with time as a covariate were employed. RESULTS: A total of 312 patients were included who had at least 15 years of follow up: 68 from the Rheumatism Foundation Hospital in Heinola in the 1970s (Heinola1970), 117 patients from Lund University Hospital in the 1980s, (Lund1980), and 81 and 46 patients from Jyväskylä Central Hospital in the 1980s (JYV1980) and the 1990s (JYV1990), respectively. Median Larsen scores in seropositive women vs. men were 43 vs. 48 (p=0.57), 37 vs. 34 (p=0.25), 31 vs. 9.5 (p=0.008), and 3.0 vs. 4.0 (p=0.34) in the Heinola1970, Lund1980, JYV1980, and JYV1990 cohorts, respectively. The corresponding figures in seronegative women vs. men were 12 vs. 23 (p=0.59), 2.0 vs. 8.0 (p=0.36), and 1.0 vs. 1.5 (p=0.63), in the Lund1980, JYV1980 and JYV1990 cohorts. All Heinola patients were seropositive. CONCLUSIONS: After a 15-20 year follow-up period, RA joint damage appears comparable in women and men. The results suggest that management should not differ at least based on gender.

[What have biological drugs changed in inflammatory rheumatic, skin and bowel diseases?]. / Mitä biologiset lääkkeet ovat muuttaneet tulehduksellisten reuma-, iho- ja suolistosairauksien hoidossa?

Biological drugs are the most rapidly growing group of medicinal agents. In addition to hormone and vaccine products, the significance of drugs produced using genetic engineering has increased in numerous indications, especially in oncology. Furthermore, they have significantly contributed to the treatment of inflammatory musculoskeletal as well as cutaneous and intestinal diseases. Their use is limited by parenteral administration, immunogenicity, uncertainty about possible severe adverse effects and especially the high price of the drugs. The cessation of patent protection of the original brand pharmaceuticals, and marketing of biosimilar drugs are expected to lower the prices of the original biological, as well.

Early Remission Is a Realistic Target in a Majority of Patients with DMARD-naive Rheumatoid Arthritis.

OBJECTIVE: We analyzed remission rates at 3 and 12 months in patients with rheumatoid arthritis (RA) who were naive for disease-modifying antirheumatic drugs (DMARD) and who were treated in a Finnish rheumatology clinic from 2008 to 2011. We compared remission rates and drug treatments between patients with RA and patients with undifferentiated arthritis (UA). METHODS: Data from all DMARD-naive RA and UA patients from the healthcare district were collected using software that includes demographic and clinical characteristics, disease activity, medications, and patient-reported outcomes. Our rheumatology clinic applies the treat-to-target principle, electronic monitoring of patients, and multidisciplinary care. RESULTS: Out of 409 patients, 406 had data for classification by the 2010 RA criteria of the American College of Rheumatology/European League Against Rheumatism. A total of 68% were female, and mean age (SD) was 58 (16) years. Respectively, 56%, 60%, and 68% were positive for anticyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF), and RF/anti-CCP, and 19% had erosive disease. The median (interquartile range) duration of symptoms was 6 (4-12) months. A total of 310 were classified as RA and 96 as UA. The patients with UA were younger, had better functional status and lower disease activity, and were more often seronegative than the patients with RA. The 28-joint Disease Activity Score (3 variables) remission rates of RA and UA patients at 3 months were 67% and 58% (p = 0.13), and at 12 months, 71% and 79%, respectively (p = 0.16). Sustained remission was observed in 57%/56% of RA/UA patients. Patients with RA used more conventional synthetic DMARD combinations than did patients with UA. None used biological DMARD at 3 months, and only 2.7%/1.1% of the patients (RA/UA) used them at 12 months (p = 0.36). CONCLUSION: Remarkably high remission rates are achievable in real-world DMARD-naive patients with RA or UA.

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force.

BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Clinical effectiveness of CT-P13 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data.

OBJECTIVE: To gain clinical experience on the effectiveness and safety of switching from infliximab-Remicade(INX) to infliximab-biosimilar-CT-P13(INB) in patients with established rheumatic disease. METHODS: Patients receiving INX treatment at a rheumatology clinic consented to switching from INX to INB. Patient reported outcomes (PROs), disease-activity, and inflammatory markers were recorded at every visit. Generalized estimating equation models and time-dependent area under the curve (AUC) before/during INX and INB treatments were employed. RESULTS: Thirty-nine consecutive patients [mean (SD) age 53 (11), 17 F] with various rheumatic diseases were switched to INB after a mean (SD) of 4.1 (2.3) years on INX. Thirty-one patients were on concomitant methotrexate. At a median (range) of 11 (7.5-13) months following the first administration of INB, AUCs for disease activity and PROs were similar for INX and INB. They were better compared to those prior to INX. Eleven patients (28.2%) discontinued INB, due to INX antidrug antibodies detected prior to INB infusion (n = 3); latent tuberculosis (n = 1); new-onset neurofibromatosis (n = 1); subjective reasons with no objective deterioration of disease (n = 6). CONCLUSION: The clinical effectiveness of INB in both PROs and disease-activity measures was comparable to INX during the first year of switching, with no immediate safety signals. Subjective reasons (negative expectations) may play a role among discontinuations of biosimilars. Larger patient numbers and longer follow-up are necessary for confirming this clinical experience.

Separate and overlapping specificities in rheumatoid arthritis antibodies binding to citrulline- and homocitrulline-containing peptides related to type I and II collagen telopeptides.

INTRODUCTION: Our objective was to find out if there are antibodies binding to homocitrulline-containing type I and II collagen carboxyterminal telopeptides in sera of patients with rheumatoid arthritis (RA), and if these antibodies cross-react with citrulline and homocitrulline in the same peptide sequence. METHODS: A total of 72 RA and 72 control sera were analyzed for binding using enzyme-linked immunosorbent assay to citrulline- or homocitrulline-containing type I and II collagen carboxyterminal telopeptides, as well as to cyclic citrullinated peptide (CCP) and to mutated citrullinated vimentin (MCV). Specificities of the antibodies were tested using inhibition-ELISA. RESULTS: Of the RA sera, 39 (54%) and 41 (57%) were positive for binding to CCP and MCV, respectively. Further, 34 (47%) and 30 (42%) of the patients had specific antibodies binding to and being inhibited by citrulline-containing type I collagen telopeptides and by citrulline-containing type II collagen carboxyterminal telopeptides, respectively. The corresponding figures regarding homocitrulline-containing type I and homocitrulline-containing type II collagen telopeptides were 16 (22%) and 14 (19%). Most of the patients, who were seropositive for citrullinated peptides, showed binding in multiple assays. A total of 10 (14%) RA patients were positive for all the tested peptide pairs, while 28 (39%) of them had antibodies that contained overlapping specifities between citrulline and homocitrulline in the same peptide sequence. CONCLUSIONS: Antibodies to both citrulline and homocitrulline containing type I and II collagen telopeptides can be found in sera of RA patients. These antibodies are not constant from one RA patient to another, but contain separate or overlapping specificities within the same peptide sequence varying between individuals. Our results suggest some relationship between citrulline and homocitrulline-recognizing antibodies, since homocitrulline antibodies exist mainly in individuals seropositive to anti-CCP and anti-MCV.

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).