Suzanne M. M. Verstappen

Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial)

Background: To investigate whether intensive treatment with methotrexate (MTX) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis. Methods: In a two-year multicentre open label strategy trial, 299 patients with early rheumatoid arthritis were randomly assigned to the intensive strategy group or the conventional strategy group. Patients in both groups received MTX, the aim of treatment being remission. Patients in the intensive treatment group came to the outpatient clinic once every month; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria, using a computerised decision program. Patients of the conventional strategy group came to the outpatient clinic once every three months; they were treated according to common practice. Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses. Results: Seventy six (50%) patients in the intensive strategy group achieved at least one period of remission during the two year trial, versus 55 patients (37%) in the conventional strategy group (p = 0.03). Areas under the curve for nearly all clinical variables were significantly lower—that is, there was a better clinical effect for the intensive treatment group compared with the conventional treatment group. Conclusion: The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX, aiming for remission, tailored to the individual patient. Furthermore, participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice.

Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial

BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. OBJECTIVE To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. DESIGN A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) SETTING 7 hospitals in the Netherlands. PATIENTS 236 patients with early RA (duration <1 year). INTERVENTION Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. PRIMARY FUNDING SOURCE Catharijne Foundation.

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 ⩽3.2 was found in the majority of patients in seven sites in five countries; in eight sites in five other countries, >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.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: Data from 32 countries in the QUEST-RA Study

IntroductionWork disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries.MethodsThe Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses.ResultsAt the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score.ConclusionsWork disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility

Objective: To evaluate the available evidence on the efficacy and feasibility of the new concept of tight control in randomised trials in patients with rheumatoid arthritis (RA). Tight control is a treatment strategy tailored to the individual patient with RA, which aims to achieve a predefined level of low disease activity or remission within a certain period of time. Methods: The literature database PubMed was searched and yielded four trials: the FIN-RACo trial, the TICORA study, the BeSt study and the CAMERA study. Results: Tight control resulted in greater improvement and a higher percentage of patients meeting the preset aim of low disease activity or remission when compared to the control intervention. In the FIN-RACo trial, aimed at DAS28<2.6, 51% of patients in the tight control group achieved remission versus 16% in the contrast group (p<0.001). In the TICORA study, 65% of patients in the tight control group versus 16% of the contrast group achieved remission, based on DAS<1.6 (p<0.0001). In the CAMERA study, 50% of patients in the tight control group using a computer decision model achieved remission, versus 37% in the contrast group (p = 0.029). The BeSt study consisted of only tight control groups aimed at a DAS<1.6; remission was achieved in 38–46% of patients. This is higher than the range of remission in earlier trials of 13–36%. Conclusion: Tight control aiming for low disease activity or even better still, remission, seems a promising option in treating patients with RA in clinical trials and probably also in daily practice.

Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis

Objectives: To systematically analyse the literature on reported adverse events of low- to medium-dose glucocorticoids during ⩾1 month for inflammatory diseases. Methods: Data were systematically retrieved and selected from PUBMED, EMBASE and CINAHL databases (6097 hits). Results: A total of 28 studies (2382 patients) met the inclusion criteria. The risk of adverse events over all studies was 150 per 100 patient-years (95% confidence interval (CI) 132 to 169). Psychological and behavioural adverse events (eg, minor mood disturbances) were most frequently reported, followed by gastrointestinal events (eg, dyspepsia, dysphagia). In 14 studies comprising 796 patients with rheumatoid arthritis the risk of adverse events was 43/100 patient-years (95% CI 30 to 55), in 4 studies of 167 patients with polymyalgia rheumatica the risk of adverse events was 80/100 patient-years (95% CI 15 to146), and in 10 studies of 1419 patients with inflammatory bowel disease the risk of adverse events was 555/100 patient-years (95% CI 391 to 718). High rates of adverse events were reported in high-quality studies with short follow-up, notably in studies of patients with inflammatory bowel disease. Conclusions: The risk of adverse events depends on study design and disease. Studies on inflammatory bowel disease were often of short duration with frequent documentation of adverse events which resulted in higher adverse event rates whereas, in studies of rheumatoid arthritis, the longer follow-up may have resulted in lower adverse event rates. In most studies aimed at efficacy of glucocorticoids or other drugs, adverse events were not systematically assessed. Clear guidelines on assessment of adverse events are lacking.

Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register

Objective The British Society for Rheumatology Biologics Register (BSRBR) has collected data on adverse events including pregnancies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor (anti-TNF) therapy. The purpose of this report is to summarise the pregnancy outcomes in women treated with anti-TNF in the BSRBR. Methods Patients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and to methotrexate (MTX) and/or leflunomide (LEF) at conception (n=21 pregnancies); (2) exposure to anti-TNF at conception (n=50); (3) exposure to anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (control group; n=10). Results Eighty-eight live births in a total of 130 pregnancies were reported in patients who received anti-TNF before or during pregnancy. The rate of spontaneous abortion was highest among patients exposed to anti-TNF at the time of conception (with MTX/LEF 33% and without MTX/LEF 24%). This compared with 17% spontaneous abortions in those with prior exposure to anti-TNF and 10% spontaneous abortions in the control group. Ten terminations were performed. Conclusion Although the results to date have been promising, no firm conclusions can be drawn about the safety of anti-TNF during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception cannot yet be changed.

Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial

Objective To evaluate whether treating patients with very early inflammatory polyarthritis (IP) with a 3-week course of intramuscular (IM) methylprednisolone acetate may postpone the need for disease-modifying antirheumatic drugs (DMARDs) and prevent IP from evolving into rheumatoid arthritis (RA). Methods Patients with very early IP (4–10 weeks’ duration) were randomised to receive three injections of either 80 mg IM methylprednisolone acetate or placebo, given at weekly intervals. Assessments were monthly until 6 months after the first injection, and then concluded at 12 months. The primary outcome was the need to start DMARDs by the 6-month assessment. Secondary outcomes included disease activity and final clinical diagnosis by the rheumatologist at 12 months. Results Patients in the placebo group (76%) were more likely to need DMARDs during the first 6 months of the trial than patients in the glucocorticoid group (61%) (adjusted OR = 2.11, 95% CI 1.16 to 3.85, p = 0.015). Disease activity did not differ between the two groups at 12 months, probably because many patients in the placebo group started DMARDs early in the study. After 12 months, the arthritis had resolved without the need for DMARDs in 9.9% (11/111) of the patients in the placebo group and in 19.8% (22/111) in the glucocorticoid-treated group (adjusted OR = 0.42, 95% CI 0.18 to 0.99, p = 0.048). Conclusion Treatment of patients with very early IP with IM methylprednisolone acetate appears to postpone the prescription of DMARDs and prevent one in 10 patients from progressing into RA.

The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register

Objectives The development of new classification criteria for rheumatoid arthritis (RA) calls for a re-estimation of RA incidence rates. The objectives of this study were to estimate the age and sex-specific incidence rates (IR) of RA in Norfolk, England using the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism criteria, and to compare those with IRs estimated using the 1987 ACR criteria. Setting The Norfolk Arthritis Register (NOAR), a large primary care inception cohort of patients with inflammatory oligo- and polyarthritis (IP) aged ≥ 16. Methods All patients notified to NOAR from 1990-5 with symptom onset in 1990 were included. The former Norwich Health Authority population was the denominator. Age and sex specific IRs using 1987 and 2010 classification criteria were calculated at baseline visit, annually for the first 3 years and at 5 years. Results 260 patients were notified to NOAR with symptom onset in 1990 and without an alternative diagnosis. IRs applying the 2010 criteria at baseline were 54/100 000 for women and 25/100 000 for men. Age and sex-specific IRs using the 2010 classification criteria at baseline were similar to cumulative IRs applying the 1987 criteria up to 5 years. However, some patients only ever satisfied one set of criteria and a proportion of IA patients (20%) did not satisfy either criteria set over 5 years. Conclusions The 2010 criteria classify similar numbers of patients as having RA at baseline, as the 1987 criteria would have taken up to 5 years to identify.

Biologic therapies and pregnancy: the story so far

Biologic therapies have revolutionized treatment outcomes for patients with inflammatory arthritis. However, there remains a concern regarding their safety during conception, pregnancy and breastfeeding. Data on the safety of these treatments are largely limited to uncontrolled case reports. Collective evidence from many hundreds of pregnancies in inflammatory arthritis and IBD have suggested that exposure to anti-TNF therapies at the time of conception or during the first trimester does not result in an increased risk of adverse pregnancy and fetal outcomes. Monoclonal antibodies, and to a lesser extent recombinant fusion proteins, do cross the placenta during the second and third trimester and are functional in the fetus, as evidence by lymphopaenia reported at birth in children exposed to rituximab in utero. In addition, live vaccines should be avoided in children with in utero exposure to biologics for at least the first 6 months of life. The longer-term effects of in utero exposure remain unknown. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which they are absorbed by the infant is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies or rituximab at the time of conception. Data on other biologic therapies, including anakinra, abatacept and tocilizumab, in both men and women remain extremely limited.