Short interruptions of TNF-inhibitor treatment can be associated with treatment failure in patients with immune-mediated diseases.

INTRODUCTION: The prevalence of immune-mediated diseases has increased in the past decades and despite the use of biological treatments all patients do not achieve remission. The aim of this study was to characterise the reasons for short interruptions during treatment with two commonly used TNF-inhibitors infliximab and adalimumab and to analyse the possible effects of the interruptions on immunisation and switching the treatment. MATERIAL AND METHODS: This case-control study was based on retrospective analyses of patient records and a questionnaire survey to clinicians. A total of 370 patients (194 immunised cases and 172 non-immunised controls, 4 excluded) were enrolled from eight hospitals around Finland. Eleven different diagnoses were represented, and the largest patient groups were those with inflammatory bowel or rheumatic diseases. RESULTS: Treatment interruptions were associated with immunisation in patients using infliximab (p < .001) or adalimumab (p < .000001). Patients with treatment interruptions were more likely to have been treated with more than one biological agent compared to those without treatment interruptions. This was particularly prominent among patients with a rheumatic disease (p < .00001). The most frequent reason for a treatment interruption among the cases was an infection, whereas among the control patients it was remission. The median length of one interruption was one month (interquartile range 1-3 months). CONCLUSION: Our results suggest that the interruptions of the treatment with TNF-inhibitors expose patients to immunisation and increase the need for drug switching. These findings stress the importance of careful judgement of the need for a short interruption in the biological treatment in clinical work, especially during non-severe infections.

Clinical trials of new drugs for the treatment of rheumatoid arthritis: focus on early disease.

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases convened a task force of experts in rheumatoid arthritis (RA) and clinical trial methodology to comment on the new draft 'Guideline on clinical investigation of medicinal products for the treatment of RA' released by the European Medicines Agency (EMA). Special emphasis was placed by the group on the development of new drugs for the treatment of early RA. In the absence of a clear definition of early RA, it was suggested that clinical investigations in this condition were conducted in disease-modifying antirheumatic drugs naïve patients with no more than 1 year disease duration. The expert group recommended using an appropriate improvement in disease activity (American College of Rheumatology (ACR) or Simplified/Clinical Disease Activity Index (SDAI/CDAI) response criteria) or low disease activity (by any score) as primary endpoints, with ACR/European League Against Rheumatism remission as a secondary endpoint. Finally, as compelling evidence showed that the Disease Acrivity Score using 28-joint counts (DAS28) might not provide a reliable definition of remission, or sometimes even low disease activity, the group suggested replacing DAS28 as a measurement instrument to evaluate disease activity in RA clinical trials. Proposed alternatives included SDAI, CDAI and Boolean criteria.

Do the 2010 ACR/EULAR or ACR 1987 classification criteria predict erosive disease in early arthritis?

BACKGROUND: The new 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) aim at earlier diagnosis of RA compared to the 1987 ACR criteria. OBJECTIVE: To evaluate the ability of the 2010 ACR/EULAR and the 1987 ACR classification criteria to predict radiographic progression after 10 years of follow-up. METHODS: All early arthritis patients referred to Central Hospital in Jyväskylä from 1997 to 1999 (cases with peripheral joint synovitis, other specific diseases excluded) were included in this 10-year follow-up study. Radiographs of hands and feet were analysed according to Larsen on a scale of 0-100. RESULTS: At 10 years, 58% of the patients had an erosive disease (defined as Larsen ≥2 in at least one joint). The discriminative power of the 2010 ACR/EULAR and the 1987 ACR criteria (erosive disease at 10 years) were comparable, with area under the curve 0.72 (95% CI 0.65 to 0.79) (2010 ACR/EULAR criteria) and 0.65 (95% CI 0.58 to 0.72) (1987 ACR criteria). The respective sensitivities and specificities were 0.87 and 0.70, and 0.44 and 0.47. At 10 years, median (IQR) Larsen score was 6 (0, 15) among patients who had fulfilled both sets of criteria, 2 (0, 8) in those who met the 2010 ACR/EULAR and did not meet the ACR 1987 criteria, 0 (0, 5) in those who met ACR 1987 criteria but did not meet 2010 ACR/EULAR criteria, and 0 (0, 2) among patients who did not fulfil either of the criteria. The percentage of patients with erosions was 69%, 64%, 32% and 26%, respectively. CONCLUSIONS: The ability of the 2010 ACR/EULAR and 1987 ACR classification criteria to identify erosive disease in early arthritis is low. The discriminative power of the 2010 ACR/EULAR criteria of erosiveness in 10 years is slightly better than that of the 1987 ACR criteria.

Remission makes its way to rheumatology.

Remission was a rare event, even in the most advanced rheumatology clinics, until recent times. However, in the early 1990s, it was chosen as the treatment goal and the primary outcome measure for the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, which can be considered the beginning of remission's way to rheumatology. In addition to remission in patients with rheumatoid arthritis, remission in patients with psoriatic arthritis is now being studied, although remission criteria for psoriatic arthritis have yet to be defined. Better treatment results with more active treatment strategies and availability of biologic agents motivate rheumatologists to monitor their patients as part of usual rheumatology care.

[The goal for the treatment of rheumatoid arthritis should be remission]. / Nivelreuman varhainen diagnoosi ja hoito--tavoitteena remissio.

Early diagnosis is the cornerstone for a successful treatment of rheumatoid arthritis. The Finnish way is to start early using the combination of three disease modifying drugs (methotrexate, sulphasalazine, hydroxychloroquine) and a low dose of glucocorticoid (FIN-RACo strategy) aiming at remission. A tight control of disease activity and flexible adjustment of drug therapy are needed using local joint injections, as well. In severe disease with insufficient treatment response, the new biologicals are indicated before marked joint damages occur.

Drug management of early rheumatoid arthritis - 2008.

Modern therapy of rheumatoid arthritis (RA) is based on recognition of the severity of the natural history of disease, with early and aggressive treatment strategies. Methotrexate is the anchor drug, with addition of other disease-modifying anti-rheumatic drugs (DMARDs) in combinations, and biological targeted therapies. The approach emphasizes 'tight control', aiming for remission and low disease activity according to quantitative monitoring. In this chapter, we review selected randomized controlled studies for data concerning early versus delayed therapies. We present a historical perspective for the treatment of early RA using early RA cohorts from Finland as an example. Finally, we discuss principles of contemporary treatment of early RA in 2008.

Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study.

INTRODUCTION: Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). METHODS: The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. RESULTS: Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. CONCLUSIONS: In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Remission and rheumatoid arthritis: data on patients receiving usual care in twenty-four countries.

OBJECTIVE: To compare the performance of different definitions of remission in a large multinational cross-sectional cohort of patients with rheumatoid arthritis (RA). METHODS: The Questionnaires in Standard Monitoring of Patients with RA (QUEST-RA) database, which (as of January 2008) included 5,848 patients receiving usual care at 67 sites in 24 countries, was used for this study. Patients were clinically assessed by rheumatologists and completed a 4-page self-report questionnaire. The database was analyzed according to the following definitions of remission: American College of Rheumatology (ACR) definition, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), clinical remission assessed using 42 and 28 joints (Clin42 and Clin28), patient self-report Routine Assessment of Patient Index Data 3 (RAPID3), and physician report of no disease activity (MD remission). RESULTS: The overall remission rate was lowest using the ACR definition of remission (8.6%), followed by the Clin42 (10.6%), Clin28 (12.6%), CDAI (13.8%), MD remission (14.2%), and RAPID3 (14.3%); the rate of remission was highest when remission was defined using the DAS28 (19.6%). The difference between the highest and lowest remission rates was >or=15% in 10 countries, 5-14% in 7 countries, and <5% in 7 countries (the latter of which had generally low remission rates [<5.5%]). Regardless of the definition of remission, male sex, higher education, shorter disease duration, smaller number of comorbidities, and regular exercise were statistically significantly associated with remission. CONCLUSION: The use of different definitions of RA remission leads to different results with regard to remission rates, with considerable variation among countries and between sexes. Reported remission rates in clinical trials and clinical studies have to be interpreted in light of the definition of remission that has been used.

A new disease activity index for rheumatoid arthritis: Mean Overall Index for Rheumatoid Arthritis (MOI-RA).

OBJECTIVE: To develop a continuous composite index of disease activity for rheumatoid arthritis (RA) based on the 7 American College of Rheumatology (ACR) core data set of disease activity measures: Mean Overall Index for Rheumatoid Arthritis (MOI-RA). METHODS: The MOI-RA is the mean of standardized values of tender and swollen joint counts (28, 42, or 66/68 joint counts), physical function (Health Assessment Questionnaire 0-3), patient's and physician's assessments of global health and patient's assessment of pain (visual analog scale 0-100 mm) and erythrocyte sedimentation rate (1-100). All the 7 components were standardized (0-100), and the mean of standardized values was calculated. The range of MOI-RA is 0-100; higher values indicate poorer outcomes. The validity and measurement properties of MOI-RA were analyzed in 169 patients in the Finnish RA Combination therapy trial. RESULTS: The mean MOI-RA28 decreased from 38.5 to 13.3 [standardized response mean (SRM) = 1.8, effect size (ES) = 1.9] from baseline to 6 months, compared to Disease Activity Score (DAS) 28, which decreased from 5.55 to 2.77 (SRM = 2.0, ES = 2.8). Correlation between MOI-RA28 and DAS28 was 0.90. When compared to the ACR response categories (20/50/ACR remission), changes in MOI-RA versions (using 28/42/66 joints) were similar. The reproducibility of MOI-RA with different joint counts was 0.97. A simulation in which 15% of the component values of MOI-RA were randomly omitted indicated an intraclass correlation coefficient of 0.98 between incomplete and complete data. CONCLUSION: MOI-RA is a simple and feasible index based on the ACR core data set of disease activity measures for assessment of disease activity and treatment response in RA trials and clinical settings.

Disease activity score 28 as an instrument to measure disease activity in patients with early rheumatoid arthritis.

OBJECTIVE: To examine the influence of components of the Disease Activity Score 28 (DAS28) [tender joint count (TJC), swollen joint count (SJC), patient's general health (GH), and erythrocyte sedimentation rate (ESR)] on the total DAS28 score, and overlapping of the 4 individual components in rheumatoid arthritis (RA) patients with low, moderate, or high disease activity. METHODS: The effect of each component was studied in the FIN-RACo trial patients at 6 months and in a "theoretical model," where each component of the DAS28 ranged as follows: TJC and SJC from 0 to 28, GH from 0 to 100, and ESR from 1 to 100, while the other 3 components were 0 (ESR1). Overlapping of the components was studied in the FIN-RACo trial patients at 6 months with low (DAS28 < or = 3.2), moderate (DAS28 > 3.2 and < or = 5.1), and high (DAS28 > 5.1) disease activity. The higher limit for overlapping was defined as the highest SJC in the low disease activity group, and the lower limit as the lowest SJC in the high disease activity group; the percentage of patients who fall between these limits represent overlapping in SJC. Overlapping was calculated similarly concerning TJC, ESR, and GH. RESULTS: ESR had the greatest effect on DAS28, followed by TJC, GH, and SJC, while in the "theoretical model" TJC had the greatest effect on the DAS28, followed by ESR, SJC, and GH. At 6 months, overlapping was present in 54%, 45%, 49%, and 31% of patients in SJC, TJC, GH, and ESR, respectively. CONCLUSION: In real-life patients, ESR had the greatest effect of the 4 components of DAS28 on the total DAS28 score. The values of the individual components of DAS28 overlap considerably among the 3 disease activity groups.

QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries.

OBJECTIVE: To conduct a cross-sectional review of non-selected consecutive outpatients with rheumatoid arthritis (RA) as part of standard clinical care in 15 countries for an overview of the characteristics of patients with RA. METHODS: The review included current disease activity using data from clinical assessment and a patient self-report questionnaire, which was translated into each language. Data on demographic, disease and treatment-related variables were collected and analysed using descriptive statistics. Variation in disease activity on DAS28 (disease activity score on 28-joint count) within and between countries was graphically analysed. A median regression model was applied to analyse differences in disease activity between countries. RESULTS: Between January 2005 and October 2006, the QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) project included 4363 patients from 48 sites in 15 countries; 78% were female, >90% Caucasian, mean age was 57 years and mean disease duration was 11.5 years. More than 80% of patients had been treated with methotrexate in all but three countries. Overall, patients had an active disease with a median DAS28 of 4.0, with a significant variation between countries (p<0.001). Among 42 sites with >50 patients included, low disease activity of DAS28 50% of patients had high disease activity of DAS28 >5.1. CONCLUSIONS: This international multicentre cross-sectional database provides an overview of clinical status and treatments of patients with RA in standard clinical care in 2005-6 including countries that are infrequently involved in clinical research projects.

Sustained remission and reduced radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis.

OBJECTIVE: To study sustainability of remission and good treatment response, and the association of both with radiographic progression, in early rheumatoid arthritis (RA) in the Finnish Rheumatoid Arthritis Combination Therapy trial (FIN-RACo). METHODS: Patients were randomized to receive either a combination of disease modifying antirheumatic drugs (DMARD; COMBI, n = 97) or a single DMARD (SINGLE, n = 98). Remission was defined according to modified American College of Rheumatology (ACR) remission criteria and Disease Activity Score 28 joint count (DAS28) < or = 2.6, and sustained remission as presence of remission at 6, 12, and 24 months. Good treatment response was defined as DAS28 (3/4) 3.2 and decrease of DAS28 >1.2. RESULTS: In 169 patients with complete data, 33 (42%) COMBI and 18 (20%) SINGLE patients achieved modified ACR remission at 2 years, which was sustained in 11 (14%) COMBI and 3 (3%) SINGLE patients. Fifty-four (68%) COMBI and 37 (41%) SINGLE patients were in DAS28 remission at 2 years, which was sustained in 40 (51%) COMBI and 14 (16%) SINGLE patients. Good treatment response was sustained in 67% of COMBI and 27% of SINGLE patients. Over 2 years, the Larsen score increased by a median of 1 (95% CI 0-2) in patients in sustained DAS28 remission compared to 4 (95% CI 2-16) in patients who were in DAS28 remission at 6 months but lost it later; and by 6 (95% CI 2-10) in patients who were not in remission at 6 months. CONCLUSION: A remarkable proportion of patients with early RA treated with combinations of DMARD were in remission at 2 years, and remission was more often sustained compared to patients treated with a single DMARD. Sustained remission protects against radiographic joint damage.

Decreased muscle strength and mobility of the neck in patients with rheumatoid arthritis and atlantoaxial disorders.

OBJECTIVE: To compare neck muscle strength and mobility of the cervical spine in rheumatoid arthritis (RA) patients with and without atlantoaxial (AA) disorders (anterior atlantoaxial subluxation [AAS], AA impaction). DESIGN: Clinical cross-sectional study. SETTING: Outpatient rheumatology and rehabilitation clinics in a Finnish hospital. PARTICIPANTS: Patients with RA (N=124; mean age +/- standard deviation, 62+/-12y [corrected]) on a waiting list for orthopedic surgery. Thirty (24%) patients presented with AA disorders (16 with anterior AAS, 8 with AA impaction, 6 with a combination of anterior AAS and AA impaction). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Neck function was measured by isometric neck strength and mobility tests, neck pain by a visual analog scale, erosion of the hands and feet by radiography, and the patients' function by the Health Assessment Questionnaire (HAQ). RESULTS: Maximal neck muscle strength against flexion, extension, and rotation was lower in patients with AA disorders compared with the other patients in both women (P=.012) and men (P=.017). Mobility was lowest in the AA impaction group in all measured directions (P<.001). Peripheral erosive disease was more frequent in the group with AA disorders. They also had longer disease duration and were more disabled (HAQ) than the other patients. CONCLUSIONS: Neck muscle strength is significantly decreased in patients with AA disorders. Mobility of the cervical spine is most limited in patients with AA impaction, but can be normal in cases with solitary anterior AAS.

Frequency of remissions in early rheumatoid arthritis defined by 3 sets of criteria. a 5-year followup study.

OBJECTIVE: To study the frequency of remission using 3 sets of criteria in patients with rheumatoid arthritis (RA) at 5 years after the diagnosis. METHODS: All adult patients with recent onset inflammatory arthritis who did not meet criteria or show clinical signs of other specific arthritides were included in the RA1997 inception cohort at Jyväskylä Central Hospital, Finland, and were assessed for remission at 5-year control examination. Remission was defined as (1) American College of Rheumatology (ACR) remission (fatigue excluded), (2) clinical remission with no tender and no swollen joints and normal erythrocyte sedimentation rate, and (3) radiographic remission with no worsening of erosions and no new erosions from baseline to 5 years. RESULTS: The study included 127 patients with early RA (mean age 56 yrs, 61% female, 54% with positive rheumatoid factor, and 25% with erosions). At 5 years, 111 patients were examined, 17% (95% CI 11%-25%) of whom met ACR remission criteria, 37% (95% CI 28%-47%) met clinical remission criteria, and 55% (95% CI 49%-68%) met radiographic remission criteria. Only 13 (12%) patients met all 3 sets of remission criteria. The rate of remission was statistically significantly different (p < 0.001) using the 3 sets. CONCLUSION: The rate of remission in RA depends on the criteria used. No gold standard exists for defining remission in RA. A set of criteria including no sign of inflammatory activity and no radiographic progression might be a basis for development of clinically relevant remission criteria for RA.