Nonsteroidal antiinflammatory drug withdrawal in patients with stable rheumatoid arthritis.

OBJECTIVE: To evaluate the effect of nonsteroidal antiinflammatory drug (NSAID) withdrawal on blood pressure (BP), 44-joint Disease Activity Score (DAS44), and functional assessments in patients with stable rheumatoid arthritis (RA). METHODS: NSAID was withdrawn from 30 patients with stable RA (DAS44 ≤ 2.8). Other prescribed medication continued. Clinical and laboratory measures were taken at baseline, 6 weeks, and 12 weeks. RESULTS: No participants required NSAID reintroduction during the study period. Significant improvement in systolic BP was noted: maximal median reduction was 7 mm Hg (baseline to 12 weeks). There was no significant deterioration in DAS44 or function. Eleven participants required additional intervention. CONCLUSION: NSAID withdrawal resulted in improvement in BP without loss of disease control.

Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs.

Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate-sulfasalazine, methotrexate-chloroquine, methotrexate-cyclosporin, methotrexate-leflunomide, methotrexate-intramuscular-gold and methotrexate-doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.

Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study.

BACKGROUND: Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. AIM: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. METHODS: A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. RESULTS: At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy. CONCLUSIONS: In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.

The frequency and distribution of minocycline induced hyperpigmentation in a rheumatoid arthritis population.

OBJECTIVE: Minocycline is particularly useful in patients with rheumatoid arthritis (RA) with previous major sepsis, where anti-tumor necrosis factor is relatively contraindicated. Pigmentation is a documented side effect, but predisposing factors in an RA population have not been established. We investigated minocycline induced pigmentation in a population with RA to determine whether skin type and eye color influence predisposition to this side effect. METHODS: Patients with RA attending a rheumatology unit who had received minocycline were contacted by telephone and some were also interviewed in the clinic. Those receiving therapy for more than 3 months were assessed. Hair color, eye color, tendency to burn in the sun, and dose and duration of therapy were documented. The frequency, type, and distribution of pigmentation were established. RESULTS: Of 37 patients identified, 10 were excluded because the duration of therapy was less than 3 months. Of the remaining 27 patients, 85% were female, with median age 64 years (range 44-88) and median disease duration 23.5 years (range 4-51). Eleven patients (41%) developed pigmentation after a median of 12 months. Four of the 11 stopped their minocycline due to pigmentation. Hair color, eye color, and tendency to burn in the sun did not predict patients who developed pigmentation. CONCLUSION: Pigmentation is a common side effect in patients receiving minocycline therapy for more than 3 months. Most patients do not stop therapy due to pigmentation. Those who stop are more likely to be female, less than 70 years of age, and have facial pigmentation.

Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial.

BACKGROUND: Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs, but a minority of patients achieve a good response. We aimed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis--for sustained, tight control of disease activity--compared with routine outpatient care. METHODS: We designed a single-blind, randomised controlled trial in two teaching hospitals. We screened 183 patients for inclusion. 111 were randomly allocated either intensive management or routine care. Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response (defined as a disease activity score <2.4 and a fall in this score from baseline by >1.2). Analysis was by intention-to-treat. FINDINGS: One patient withdrew after randomisation and seven dropped out during the study. Mean fall in disease activity score was greater in the intensive group than in the routine group (-3.5 vs -1.9, difference 1.6 [95% CI 1.1-2.1], p<0.0001). Compared with routine care, patients treated intensively were more likely to have a good response (definition, 45/55 [82%] vs 24/55 [44%], odds ratio 5.8 [95% CI 2.4-13.9], p<0.0001) or be in remission (disease activity score <1.6; 36/55 [65%] vs 9/55 [16%], 9.7 [3.9-23.9], p<0.0001). Three patients assigned routine care and one allocated intensive management died during the study; none was judged attributable to treatment. INTERPRETATION: A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity, radiographic disease progression, physical function, and quality of life at no additional cost.

Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial.

BACKGROUND: Rheumatoid arthritis is characterised by inflammatory synovitis, articular destruction, and accelerated atherogenesis. HMG-CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitors (statins) mediate clinically significant vascular risk reduction in patients without inflammatory disease and might have immunomodulatory function. We postulated that statins might reduce inflammatory factors in rheumatoid arthritis and modify surrogates for vascular risk. METHODS: 116 patients with rheumatoid arthritis were randomised in a double-blind placebo-controlled trial to receive 40 mg atorvastatin or placebo as an adjunct to existing disease-modifying antirheumatic drug therapy. Patients were followed up over 6 months and disease activity variables and circulating vascular risk factors were measured. Coprimary outcomes were change in disease activity score (DAS28) and proportion meeting EULAR (European League Against Rheumatism) response criteria. Analysis was by intention to treat. FINDINGS: At 6 months, DAS28 improved significantly on atorvastatin (-0.5, 95% CI -0.75 to -0.25) compared with placebo (0.03, -0.23 to 0.28; difference between groups -0.52, 95% CI -0.87 to -0.17, p=0.004). DAS28 EULAR response was achieved in 18 of 58 (31%) patients allocated atorvastatin compared with six of 58 (10%) allocated placebo (odds ratio 3.9, 95% CI 1.42-10.72, p=0.006). C-reactive protein and erythrocyte sedimentation rate declined by 50% and 28%, respectively, relative to placebo (p<0.0001, p=0.005, respectively). Swollen joint count also fell (-2.69 vs -0.53; mean difference -2.16, 95% CI -3.67 to -0.64, p=0.0058). Adverse events occurred with similar frequency in patients allocated atorvastatin and placebo. INTERPRETATION: These data show that statins can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.

Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis.

There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation-risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.

A longitudinal study of lung function in nonsmoking patients with rheumatoid arthritis.

STUDY OBJECTIVE: s: Patients with rheumatoid arthritis (RA) have a high prevalence of pulmonary function test (PFT) abnormality, but the long-term significance of this is unknown. We performed a longitudinal study of pulmonary function in asymptomatic, nonsmoking patients with active RA requiring disease-modifying drugs. We looked for temporal change in lung function and characteristics that would predict subsequent development of PFT abnormality or respiratory symptoms. METHODS: In 1990, 52 patients (44 women; age range, 29 to 78 years; median, 56 years) underwent clinical assessment (drug history, RA severity, immunologic, and inflammatory markers) and PFTs (spirometry, body plethysmography, gas transfer). PFT results were expressed as standardized residuals (SRs). Thirty-eight patients were reassessed in 2000. A self-administered questionnaire was used to identify respiratory symptoms. RESULTS: The prevalence of pulmonary function abnormality was higher than expected compared with a reference population, but there was no significant increase in number over 10 years (8.7% in 1990 and 8.8% in 2000). When assessed by group means and compared with reference values, reduced diffusing capacity of the lung for carbon monoxide (DLCO) and increased ratio of residual volume (RV) to total lung capacity (TLC) [RV/TLC] were the only abnormalities to develop over the study period (mean DLCO in 2000, - 0.47 SR; 95% confidence interval [CI], - 0.91 to - 0.01; RV/TLC, 0.49 SR; 95% CI, 0.13 to 0.84). However, rates of change of pulmonary function variables were not significantly different from zero. Logistic regression did not identify any meaningful relationship between disease characteristics and PFT abnormality. CONCLUSIONS: Asymptomatic patients with RA have a higher prevalence of PFT abnormality than expected, but these do not increase in number over time. We did not identify any patient or disease-specific characteristic that could predict the development of respiratory disease in patients with RA. Analysis using percentage of predicted values, rather than SRs, is misleading as it exaggerates the extent of abnormality present. Abnormal lung function is a common and probably benign finding in nonsmoking, asymptomatic patients with RA.

Longterm maintenance therapy with disease modifying antirheumatic drugs.

Longterm safety and efficacy of disease modifying antirheumatic drugs (DMARD) have been challenging to assess. There are few studies that have evaluated patient outcome beyond 5 years. As patients may receive several DMARD over the course of their disease a long with nonsteroidal antiinflammatory drugs, corticosteroids, and other drugs for comorbidities, it is difficult to design and implement a trial to define a specific drug's longterm effect. Based on the findings of several key studies, however, it does appear that DMARD are safe when taken longterm, and that they are more likely to be discontinued because of inefficacy than toxicity. Although DMARD are often discontinued because of lack of efficacy, 12 year data suggest that DMARD can provide benefit over this period. The toxicity profiles vary significantly between DMARD. In addition, the time during therapy when the majority of these adverse effects most frequently appear is DMARD-specific. Prospective studies are needed to further clarify longterm safety and efficacy of the newer DMARD.

"5D" Outcome in 52 patients with rheumatoid arthritis surviving 20 years after initial disease modifying antirheumatic drug therapy.

OBJECTIVE: Evaluation of a complex and variable disease such as rheumatoid arthritis (RA) poses a challenge particularly over the medium to long term. A practical framework to evaluate clinically relevant outcomes over the long term is the "5D" approach of Fries, described in 1980. We describe the 20 year outcome in 52 survivors of a 123 patient cohort in terms of change in discomfort, disability, drug side effects, dollar costs, and deaths. METHODS: We studied 123 patients with RA allocated to their first disease modifying antirheumatic drug (DMARD) between 1977 and 1979. All were under the overall care of one physician over the 20 years and were maintained where possible taking a single DMARD. Baseline demographic variables, the Ritchie Articular Index (RAI), Lee functional index, and erythrocyte sedimentation rate (ESR) were initially recorded. The extent to which the demographic and disease variables contributed to need for joint replacement surgery was assessed. Therapies for comorbidity were also documented. RESULTS: At cohort inception mean age was 50 years, RAI was 35, and median disease duration 5.5 years. F:M ratio was 90:33; 96% of patients were positive for rheumatoid factor (RF). Initial median ESR was 55 mm/h. At 20 years, 9 patients (7% of original cohort, 14% of survivors) were lost to followup and 62 (50%) had died. In the 52 survivors RAI, a surrogate for disability, showed a significant improvement (p < 0.0001), but disability measured by Lee functional index showed a deterioration (p = 0.018); 50% underwent joint replacement surgery. Initial ESR and mean ESR over the first 10 years of followup were significantly higher in those who required surgery. Nonsteroidal antiinflammatory drug (NSAID) use declined, but at least 2 deaths and 4 renal deaths that may have been related to therapy were attributed to NSAID use. No unexpected DMARD toxicity or mortality occurred. Concomitant therapy for comorbidity, in particular for cardiovascular disease, osteoporosis, and gastrointestinal disease, increased: more than 60% were on these therapies at 20 year followup. CONCLUSION: Strategies to improve the outcome of RA in all dimensions should include: earlier referral for expert assessment; avoidance of NSAID gastrointestinal and nephrotoxicity; a more intensive effort to identify effective management of comorbidity and those likely to have a poor outcome. Such patients require sustained, intensive therapy to minimize later disability.