Pekka Hannonen

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial

BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis. METHODS 199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat. FINDINGS 87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events were similar in both treatment groups. INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.

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.

A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis

OBJECTIVE To evaluate the impact of a 2-year program of strength training on muscle strength, bone mineral density (BMD), physical function, joint damage, and disease activity in patients with recent-onset (<2 years) rheumatoid arthritis (RA). METHODS In this prospective trial, 70 RA patients were randomly assigned to perform either strength training (all major muscle groups of the lower and upper extremities and trunk, with loads of 50-70% of repetition maximum) or range of motion exercises (without resistance) twice a week; all were encouraged to engage in recreational activities 2-3 times a week. All patients completed training diaries (evaluated bi-monthly) and were examined at 6-month intervals. All were treated with medications to achieve disease remission. Maximum strength of the knee extensors, trunk flexors and extensors, and grip strength was measured with dynamometers. BMD was measured at the femoral neck and lumbar spine by dual x-ray densitometry. Disease activity was determined by the Disease Activity Score, the extent of joint damage by the Larsen score, and functional capacity by the Health Assessment Questionnaire (HAQ); walking speed was also measured. RESULTS Sixty-two patients (31 per group) completed the study. Strength training compliance averaged 1.4-1.5 times/week. The maximum strength of all muscle groups examined increased significantly (19-59%) in the strength-training group, with statistically significant improvements in clinical disease activity parameters, HAQ scores, and walking speed. While muscle strength, disease activity parameters, and physical function also improved significantly in the control group, the changes were not as great as those in the strength-training group. BMD in the femoral neck and spine increased by a mean +/- SD of 0.51 +/- 1.64% and by 1.17 +/- 5.34%, respectively, in the strength-training group, but decreased by 0.70 +/- 2.25% and 0.91 +/- 4.07% in the controls. Femoral neck BMD in the 17 patients with high initial disease activity (and subsequent use of oral glucocorticoids) remained constantly at a statistically significantly lower level than that in the other 45 patients. CONCLUSION Regular dynamic strength training combined with endurance-type physical activities improves muscle strength and physical function, but not BMD, in patients with early RA, without detrimental effects on disease activity.

Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis

Objectives: To study which cut off point of DAS28 corresponds to fulfilment of the American Rheumatism Association (ARA) preliminary remission criteria, and clinical remission criteria in patients with rheumatoid arthritis (RA). Methods: All adult patients diagnosed with RA at Jyväskylä Central Hospital 1997–98 were assessed for remission at 5 years. Remission was defined as (a) ARA remission; (b) clinical remission (defined as no tender or swollen joints and normal erythrocyte sedimentation rate). DAS28 was used to measure disease activity. A receiver operating characteristics curve analysis was performed to calculate a cut off point of DAS28 that best corresponds to the ARA remission criteria and the clinical remission criteria. Results: 161 patients (mean age 57 years, 107 (66%) female, 98 (61%) with positive rheumatoid factor, and 51 (32%) with erosions) were studied. At 5 years, 19 (12%) patients met the ARA remission criteria, and 55 (34%) met the clinical remission criteria. The cut off value of DAS28 was 2.32 for the ARA remission criteria, and 2.68 for the clinical remission criteria. In patients with DAS28 <2.32, 11/57 (19%) had tender joints, 6/57 (11%) had swollen joints, and 4/57 (7%) had both tender and swollen joints (66 joint count). Conclusion: In this study the DAS28 cut off point for the ARA remission was lower than in previous studies. The cut off point for DAS28 remission remains controversial. A substantial proportion of patients below the DAS28 cut off point for remission have tender or swollen joints, or both. DAS28 may not be an appropriate tool for assessment of remission in RA.

Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with “sawtooth” strategy

OBJECTIVES To investigate the prognostic significance of clinical and genetic markers on the outcome of patients with recent-onset rheumatoid arthritis (RA) treated actively with slow acting antirheumatic drugs (SAARDs). METHODS A total of 142 consecutive patients with early RA (median disease duration of 7 months) were treated according to the “sawtooth” strategy and prospectively followed up for an average of 6.2 years. Several clinical parameters at start as well as genetic markers were related to the functional outcome (ARA Functional class and HAQ disability score) and radiographic joint damage (Larsen’s score) at the latest visit. RESULTS In logistic regression analysis only Mallya score (including morning stiffness, pain scale, grip strength, Ritchie’s articular index, haemoglobin, and erythrocyte sedimentation rate) at baseline, and Mallya score and rheumatoid factor (RF) positivity at one year were found to be of significance with respect to the radiographic outcome of the patients. Furthermore, at the latest visit HAQ score was related to radiographic score. At baseline the mean ages of the DR4 positive patients and the patients with RA associated DR alleles were statistically significantly lower than those without the above mentioned risk factors (44 v 49, p=0.03 and 41 v 53, p=0.04, respectively). However, these genetic markers had no prognostic significance on the functional or radiographic outcome of the patients. CONCLUSION High clinical disease activity at baseline and RF positivity especially at one year after the institution of SAARD treatment are the best predictors of poor prognosis in early RA. However, from the clinical point of view, the disease outcome of an individual patient with early RA, cannot be predicted accurately enough by present means.

Scores for functional disability in patients with rheumatoid arthritis are correlated at higher levels with pain scores than with radiographic scores.

OBJECTIVE To analyze correlations of functional disability scores with other measures of clinical status, in particular, Larsen radiographic scores and pain scores, in patients with rheumatoid arthritis (RA). METHODS The functional capacity of 141 patients with RA (102 women, 39 men; median age 57 years; median disease duration 11.8 years; 83% rheumatoid factor positive) was assessed according to the Stanford Health Assessment Questionnaire (HAQ). Other variables studied included Larsen scores for radiographic damage of the small joints of the hands, wrists, and feet, pain scores by visual analog scale (VAS), Disease Activity Scores, general health scores by VAS, and Beck Depression Inventory (BDI) scores. RESULTS The Spearman correlation coefficient comparing HAQ and Larsen scores was 0.277 (P = 0.001) and between HAQ and pain scores 0.652 (P < 0.001). In regression analysis, pain scores explained 41.4% of the variation in HAQ scores, normalized Larsen scores explained 7.3%, and BDI scores explained 5.5%; other variables were not significant in the model. CONCLUSION Functional capacity scores of patients with RA are correlated at higher levels with pain scores than with radiographic scores of small joints.

Smoking-gender interaction and risk for rheumatoid arthritis.

The present case–control study was conducted to investigate the relationship between smoking and rheumatoid arthritis, and to investigate formally the interaction between sex, smoking, and risk for developing rheumatoid arthritis. The study was performed in the Central District of Finland. Cases were patients with rheumatoid arthritis and the control group was a random sample of the general population. Logistic regression models were used to evaluate the effect of smoking on risk for rheumatoid arthritis, after adjusting for the effects of age, education, body mass index, and indices of general health and pain. Overall, 1095 patients with rheumatoid arthritis and 1530 control individuals were included. Patients were older, less well educated, more disabled, and had poorer levels of general health as compared with control individuals (all P < 0.01). Preliminary analyses revealed the presence of substantial statistical interaction between smoking and sex (P < 0.001). In separate multivariable analyses, past history of smoking was associated with increased risk for rheumatoid arthritis overall in men (odds ratio 2.0, 95% confidence interval 1.2–3.2) but not in women. Among men, this effect was seen only for rheumatoid factor-positive rheumatoid arthritis. There were significant interactions between smoking and age among women but not among men. We conclude that sex is a biologic effect modifier in the association between smoking and rheumatoid arthritis. The role of menopause in the etiology of rheumatoid arthritis merits further research.

Stable occurrence of knee and hip total joint replacement in Central Finland between 1986 and 2003: an indication of improved long-term outcomes of rheumatoid arthritis

Background: Total joint replacement (TJR) surgery is an important severe long-term outcome of rheumatoid arthritis, but relatively little is known about changes of its incidence in patients with rheumatoid arthritis over the past two decades. Methods: A population-based, retrospective, incidence case review was conducted to analyse the frequency of primary TJR surgery of the knee and hip in all patients, and specifically in patients with rheumatoid arthritis in Central Finland between 1986 and 2003. Patients with TJR surgery of the knee and hip were identified in hospital databases over the 18-year period. Age-standardised incidence rate ratios for the primary TJR of the knee and hip were calculated, stratified to sex and diagnosis, with 1986 as the reference value. Results: In patients without rheumatoid arthritis the age-adjusted incidence rate ratios (with 95% CI) for TJR of the knee increased 9.8-fold from 1986 to 2003 in women and men, and for TJR of the hip 1.8-fold in women and 2-fold in men. By contrast, no meaningful change was seen over this period, in age-adjusted incidence rate ratios for TJR of the knee or hip in patients with rheumatoid arthritis, ranging from 0.7 to 1.2 in 2003 compared with 1986. Conclusion: The prevalence of TJR surgery has increased 2–10-fold in patients without rheumatoid arthritis patients, associated with an ageing population, but has not increased in patients with rheumatoid arthritis between 1986 and 2003. These data are consistent with emerging evidence that long-term outcomes of rheumatoid arthritis have improved substantially, even before the availability of biological agents.

Effects of Strength Training on Neuromuscular Function and Disease Activity in Patients with Recent-onset Inflammatory Arthritis

Thirty-nine consecutive patients with recent-onset rheumatoid or psoriatic arthritis were randomly allotted for six months period either to the experimental progressive dynamic strength training group (EG, 10 women and 11 men; 41 +/- 10 yrs), or to the control group (CG, 10 women and 8 men; 45 +/- 11 yrs) who just maintained their habitual physical activities. All patients received antirheumatic medication throughout the experimental period. During the study period significant improvements took place in the EG in maximal muscle strength of all examined muscle groups (31.5% for the knee extensors, p < 0.001; 14.8% and 10.7% for the trunk flexors and extensors, p < 0.01; 27.8% and 20.4% for grip strength, p < 0.001) as well as in erytrocyte sedimentation rate (p < 0.05). Ritchies articular index (RI) (p < 0.001) and HAQ (p < 0.01). In the CG only the decrease in RI was statistically significant (p < 0.05). Erosive changes in joints increased only slightly and less in the EG than in the CG. The present results suggest that dynamic strength training in early arthritis increases the neuromuscular performance without detrimental effects on disease activity or joint damage.

Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial.

IntroductionEarly treatment of rheumatoid arthritis (RA) has been shown to retard the development of joint damage for a period of up to 5 years. The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs (DMARDs) or a single DMARD.MethodsA cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone (FIN-RACo), or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone (SINGLE). After 2 years, the drug-treatment strategy became unrestricted, but still targeted remission. The radiographs of hands and feet were analyzed by using the Larsen score at baseline, 2, 5, and 11 years, and the radiographs of large joints, at 11 years.ResultsSixty-five patients in the FIN-RACo and 65 in the SINGLE group had radiographs of hands and feet available at baseline and at 11 years. The mean change from baseline to 11 years in Larsen score was 17 (95% CI, 12 to 26) in the FIN-RACo group and 27 (95% CI, 22 to 33) in the SINGLE group (P = 0.037). In total, 87% (95% CI, 74 to 94) and 72% (95% CI, 58 to 84) of the patients in the FIN-RACo and the SINGLE treatment arms, respectively, had no erosive changes in large joints at 11 years.ConclusionsTargeting to remission with tight clinical controls results in low radiologic progression in most RA patients. Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy.Trial registrationCurrent Controlled Trials ISRCTN18445519.