Timo Möttönen

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.

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.

Effect of a three month course of ciprofloxacin on the outcome of reactive arthritis

BACKGROUND Treatment of reactive arthritis (ReA) with antibiotics has so far remained controversial. Eradication of the causative microbe appears logical, but short term antibiotic treatment has no beneficial effect on the outcome of ReA. OBJECTIVE To evaluate the effect of a three month course of ciprofloxacin on ReA. METHODS In a randomised, double blind, placebo controlled trial, between December 1992 and February 1996, 71 patients with acute ReA triggered by a gastrointestinal or a urogenital infection were randomly assigned to receive ciprofloxacin 500 mg or placebo twice daily for three months. Patients were assessed at study entry, at 6 weeks, 3 months, 6 months, and 12 months. Sixty two patients were valid for the efficacy analysis. The primary outcome measures were erythrocyte sedimentation rate, number of swollen joints, patients self assessment, and complete recovery. RESULTS Adverse events were mostly mild and occurred in both treatment groups. There were no statistically significant differences in any of the primary or secondary efficacy variables between the study groups at baseline or during the 12 month follow up. All primary outcome measures indicated that the condition of the patients improved during the study. CONCLUSION Both groups tended to recover. Ciprofloxacin, given as a three month course, had no advantage over placebo treatment.

Combination drug therapy retards the development of rheumatoid atlantoaxial subluxations

OBJECTIVE To compare the efficacy of combination therapy with disease-modifying antirheumatic drugs (DMARDs) versus single therapy with DMARDs in the prevention of early cervical spine changes in patients with rheumatoid arthritis (RA). METHODS One hundred ninety-five patients with recent-onset RA (mean disease duration 8 months) were randomly assigned to receive a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or a single DMARD with or without prednisolone. After 2 years of followup, cervical spine radiographs were taken of 176 of these patients (85 in the combination-therapy group and 91 in the single-therapy group). These radiographs were evaluated, and the findings were correlated with the therapy strategies as well as with peripheral joint destruction and clinical and laboratory variables describing the disease activity. RESULTS Anterior atlantoaxial subluxation (aAAS), atlantoaxial impaction (AAI; i.e., vertical subluxation), and subaxial subluxation (SAS) were found in only 6 (3.4%), 2 (1.1%), and 5 (2.8%) of the patients, respectively. Interestingly, none of the patients in the combination-therapy group had aAAS or AAI. The incidences of aAAS and AAI in the single-therapy group were 6.6% and 2.2%, respectively. SAS was present in 2 patients (2.2%) in the single-therapy group and in 3 patients (3.5%) in the combination-therapy group. The difference in the incidence of aAAS between the treatment groups was statistically significant (P = 0.029). None of the patients with cervical spine changes achieved remission of RA during the study. CONCLUSION In the present study, the incidence of cervical spine subluxations in patients treated with single-drug therapy was in accord with findings of previous studies. However, none of the patients in the combination-therapy group had aAAS or AAI. These findings suggest that early, aggressive combination-DMARD therapy with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone can prevent or retard the development of rheumatoid atlantoaxial disorders.

Monetary value of lost productivity over a five year follow up in early rheumatoid arthritis estimated on the basis of official register data on patients’ sickness absence and gross income: experience from the FIN-RACo trial

Objective: To explore the monetary value of rheumatoid arthritis related loss of productivity in patients with early active disease. Methods: In a prospective cohort substudy of the FIN-RACo Trial, 162 patients with recent onset rheumatoid arthritis, aged 18 to 65 years and available to the workforce, were followed up for five years. Loss of work productivity in euros 2002 was estimated by data on absence for sickness and on income (human capital approach) from official databases. Treatment responses were evaluated by area under the curve (AUC) of the ACR-N measure and by increase in number of erosions in radiographs of hands and feet. The health assessment questionnaire (HAQ) at six months was linked to the International Classification of Functioning, Disability and Health (ICF). Results: In all, 120 (75%) patients, women more often (82%) than men (61%) (p = 0.002), lost work days. The mean lost productivity per patient-year was €7217 (95% confidence interval (CI), 5561 to 9148): for women, €6477 (4858 to 8536) and for men, €8443 (5389 to 12 898). There was an inverse correlation with improvement: €1101 (323 to 2156) and €14 952 (10 662 to 19 852) for the highest and lowest quartiles of AUC of ARC-N, respectively. Lost productivity was associated with increase in the number of erosions and with disability in “changing and maintaining body position” subcategory of the ICF. Conclusions: Despite remission targeted treatment with disease modifying antirheumatic drugs, early rheumatoid arthritis results in substantial loss of productivity. A good improvement in the disease reduces the loss markedly.

The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial.

OBJECTIVE To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. METHODS A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. RESULTS At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group (P=0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P=0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P=0.017), respectively. CONCLUSION Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

Single values of serum transferrin receptor and transferrin receptor ferritin index can be used to detect true and functional iron deficiency in rheumatoid arthritis patients with anemia

OBJECTIVE To elucidate the use of serum transferrin receptor (sTfR) to distinguish between iron-deficiency anemia (IDA) and anemia of chronic disease (ACD), and to establish an improved scheme to identify functional iron deficiency (FID) in rheumatoid arthritis (RA) patients with anemia. METHODS We studied 30 anemic RA patients whose iron status was confirmed by bone marrow examination and determination of the sTfR level, serum ferritin level, and sTfR-log ferritin index (TfR-F Index). All patients with diminished or exhausted iron stores (n = 18) received oral iron supplementation. RESULTS Baseline values of sTfR and the TfR-F Index predicted the response correctly in all patients who received supplementation treatment and were normal in 10 of 11 patients with normal initial iron stores (ACD). CONCLUSION The results of this study elucidate the roles of sTfR and the TfR-F Index in the differential diagnosis between IDA and ACD and provide direct evidence that these parameters are useful in detecting FID, irrespective of the concurrent iron storage status.

Salmonella-triggered reactive arthritis. Use of polymerase chain reaction, immunocytochemical staining, and gas chromatography-mass spectrometry in the detection of bacterial components from synovial fluid

OBJECTIVE To investigate whether microbial components are present in the cells of synovial fluid or peripheral blood from patients with Salmonella-triggered reactive arthritis (ReA). METHODS Synovial fluid cells and/or peripheral blood cells from 23 patients with Salmonella-triggered ReA and from 19 control patients with newly diagnosed rheumatoid arthritis were studied using 3 different polymerase chain reaction (PCR) techniques and immunocytochemical staining. Muramic acid from the synovial fluid was studied by gas chromatography-mass spectrometry. RESULTS Salmonella chromosomal DNA was not detectable in the synovial fluid cells and peripheral blood leukocytes of patients with Salmonella ReA. Initially, positive reactions were observed in the synovial fluid cells and peripheral blood leukocytes of 3 of 17 and 3 of 18 patients with ReA, respectively, but in the subsequent PCR studies, these findings were not reproducible. Salmonella-specific antigen was detectable by immunofluorescence in the synovial fluid cells and peripheral blood leukocytes of 4 of 11 and 2 of 7 patients with ReA, respectively. Muramic acid was present in 2 of 15 synovial fluid samples from patients with ReA, but the bacterial cultures from synovial fluid were negative. CONCLUSION These findings indicate the presence of bacterial degradation products, but not bacterial DNA, in the inflamed joints of patients with Salmonella-triggered ReA.

Value of joint scintigraphy in the prediction of erosiveness in early rheumatoid arthritis.

The value of scintigraphy in predicting development of new erosions in small peripheral joints was studied by visual evaluation of scintigrams and by three computerised methods. In 13 patients with newly diagnosed rheumatoid arthritis a total of 387 joints were examined clinically, scintigraphically, and radiographically. The follow up period was 24 months. Four eroded joints in three patients were found at the onset. Of the joints which were to become eroded, 46/47 were scintigraphically active at all the check ups. Erosions were detected earlier in foot joints than in finger joints. New erosions were especially prone to appear in joints with persisting and high scintigraphic activity. On the contrary, inactive joints by repeated scanning never eroded. Scintigraphic and clinical activity and radiographic erosiveness correlated significantly with each other. The sensitivity and specificity of visual scintigraphic assessment and the relative pixel activity method proved to be superior to the region of interest methods and clinical evaluation for prediction of erosiveness.

Estrogen–progestin contraceptive use during adolescence prevents bone mass acquisition: a 4-year follow-up study

BACKGROUND Estrogen-progestin contraception may affect estrogen production and alter the development of peak bone mass. STUDY DESIGN A 4-year follow-up with 122 adolescent women aged 12-19 years. The data were divided into three groups based on estrogen-progestin contraceptive (EPC) use: (i) nonusers (n=52), (ii) 1-2 years of use (n=24) and (iii) use for more than 2 years (n=46). The estrogen dose of the preparations was < or =35 mcg. Height, weight, and the amount of exercise (ratio of work metabolic rate, h/week) as well as bone mineral content (BMC) of lumbar spine and femoral neck were measured repeatedly. RESULTS There was a significant trend showing less of an increase in the mean adjusted BMC of lumbar spine in the group of adolescent women who had used EPC for more than 2 years compared with the two other groups. In the mean adjusted BMC of the femoral neck, there was a significant trend of a smaller increase in EPC users for more than 2 years compared with 1-2 years of use. CONCLUSIONS Long-term EPC with low-dose estrogen preparations seems to suppress normal bone mineral accrual in adolescent women.