The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions.

OBJECTIVE: To identify the proportion of patients with inflammatory arthritis who remain on methotrexate in the medium to long term and the incidence of side-effects in clinical practice. METHOD: The study population comprised all patients with inflammatory arthritis treated with methotrexate and monitored in clinics under the auspices of Staffordshire Rheumatology Centre. Two clinical auditors collected data retrospectively from the computer database used to support monitoring of patients on disease-modifying anti-rheumatic drugs. Information was collected on duration of treatments and reasons for stopping treatment. For patients identified as having potentially serious side-effects or who died whilst taking methotrexate, further information on their outcome was collected from patients' medical notes and where applicable post mortem reports and death registers. RESULTS: Between 1986 and 1999, 673 patients were treated with methotrexate, of whom 551 had a diagnosis of rheumatoid arthritis. From the Kaplan-Meier analysis, the probability of patients remaining on treatment 5 yr after starting methotrexate was 0.74. Three hundred and sixteen patients stopped methotrexate between 1986 and 1999. In 117 patients, the methotrexate was restarted. Seventy-two patients (10.7% of all patients) stopped because of inefficacy or patient choice or situation. Thirty-seven patients (5.5%) stopped methotrexate due to abnormal haematology (usually low neutrophils). Thirty-seven patients (5.5%) stopped methotrexate due to abnormalities in liver function tests. Life-threatening side-effects were identified in 12 patients (1.8%). These included six pneumonitis, five cytopenias and one disseminated varicella zoster. Two of these patients (0.3%) died, one from pneumonitis and one from disseminated varicella zoster. A total of 25 patients (3.7%) died while taking methotrexate and four died (0.6%) within 3 months of stopping methotrexate. One death (0.15%) was directly attributable to methotrexate (methotrexate pneumonitis). CONCLUSION: This study has shown that methotrexate is well tolerated in clinical practice in the medium to long term. It has produced accurate data on the incidence of adverse effects of methotrexate in a local population in a non-research setting. It has identified the incidence of life-threatening side-effects to be 1.7% with one death (0.15%) directly due to methotrexate. This information should prove useful when recommending such treatment to patients with inflammatory arthritis.

A comparison of four shoulder-specific questionnaires in primary care.

OBJECTIVES: To compare the validity, responsiveness to change, and user friendliness of four self completed, shoulder-specific questionnaires in primary care. METHODS: A cross sectional assessment of validity and a longitudinal assessment of responsiveness to change of four shoulder questionnaires was carried out: the Dutch Shoulder Disability Questionnaire (SDQ-NL); the United Kingdom Shoulder Disability Questionnaire (SDQ-UK); and two American instruments, the Shoulder Pain and Disability Index (SPADI) and the Shoulder Rating Questionnaire (SRQ). 180 primary care consulters with new shoulder region pain each completed two of the questionnaires, as well as EuroQoL and 10 cm visual analogue scales (VAS) for overall pain and difficulty due to the shoulder problem. Each participant was assessed by a standardised clinical schedule. Postal follow up at 6 weeks included baseline measures and self rated assessment of global change of the shoulder problem (seven point Likert scale). RESULTS: Strongest correlations were found for SDQ-UK with EuroQoL 5 score, and for SPADI and SRQ with shoulder pain and difficulty VAS. All shoulder questionnaires correlated poorly with active movement at the painful shoulder. SPADI and SRQ performed better on ROC analysis than SDQ-NL and SDQ-UK (areas under the curve of 0.87, 0.85, 0.77, and 0.77, respectively). However, SRQ scores changed significantly over time in stable subjects. CONCLUSIONS: Cross sectional comparison of the four shoulder questionnaires showed they had similar overall validity and patient acceptability. SPADI and SRQ were most responsive to change. Additionally, SPADI was the quickest to complete and scores did not change significantly in stable subjects.

Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice.

We analysed computerized records of disease-modifying anti-rheumatic drug (DMARD) monotherapy to determine how long rheumatoid arthritis (RA) patients continued on five commonly prescribed DMARDs, and the incidence and time-course of adverse drug reactions (ADRs) they experienced. We studied the records for 3923 courses of DMARDs given to a cohort of 2170 patients monitored for a total of 9378 treatment-years. Methotrexate (MTX) was the DMARD most likely to be continued long-term; <45% of patients had discontinued the drug after 96 months. For the other DMARDs, the time until 50% discontinued due to ADRs or inefficacy was 43.3 months for sulphasalazine (SAS), 33.9 months for D-penicillamine (DPN) and 26 months for myocrisin. Most monitored ADRs requiring drug discontinuation were seen early in therapy, with a median time to onset of <6 months; the important exceptions to this were haematological ADRs to MTX, where the median delay to neutropenia was 16.9 months, and that to thrombocytopenia was 9.4 months. Monitored ADRs (identified by blood or urine tests) were seen least frequently with SAS (one ADR in every 35 patient-years of monitoring) but this apparent advantage was offset by a high incidence of gastrointestinal ADRs and inefficacy. Overall, one toxicity reaction requiring drug discontinuation was identified for every 15.9 patient-years of monitoring.

Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term?

BACKGROUND: It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof that it decreases the toxicity of methotrexate and there is a theoretical risk that it may decrease the efficacy of methotrexate. OBJECTIVES: To look at the effect of stopping FA supplementation in UK rheumatoid arthritis (RA) patients established on methotrexate <20 mg weekly and FA 5 mg daily, to report all toxicity (including absolute changes in haematological and liver enzyme indices) and to report changes in the efficacy of methotrexate. METHODS: In a prospective, randomized, double-blind, placebo-controlled study, 75 patients who were established on methotrexate <20 mg weekly and FA 5 mg daily were asked to stop their FA and were randomized to one of two groups: placebo or FA 5 mg daily. Patients were evaluated for treatment toxicity and efficacy before entry and then at intervals of 3 months for 1 yr. RESULTS: Overall, 25 (33%) patients concluded the study early, eight (21%) in the group remaining on FA and 17 (46%) in the placebo group (P = 0.02). Two patients in the placebo group discontinued because of neutropenia. At 9 months there was an increased incidence of nausea in the placebo group (45 vs. 7%, P = 0.001). The placebo group had significantly lower disease activity on a few of the variables measured, but these were probably not of clinical significance. CONCLUSIONS: It is important to continue FA supplementation over the long term in patients on methotrexate and FA in order to prevent them discontinuing treatment because of mouth ulcers or nausea and vomiting. Our data suggest that FA supplementation is also helpful in preventing neutropenia, with very little loss of efficacy of methotrexate.

Management of oral complications of disease-modifying drugs in rheumatoid arthritis.

Stomatitis is a troublesome adverse effect of disease-modifying anti-rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA) patients. This review presents data to examine the incidence, clinical features and consequences of DMARD-related stomatitis, and suggests an algorithm for its clinical management. The specific objectives of the two studies presented here were to determine the incidence of DMARD-related stomatitis and its effect on DMARD continuation, and secondly to identify the clinical and laboratory risk factors. We investigated two cohorts of patients: (i) a retrospective survey of data collected from drug monitoring clinics run for patients on DMARDs from 1987 to 1994 involving 1539 patients and 2394 drug exposures; (ii) a prospective study of 25 consecutive RA patients presenting with DMARD-related stomatitis compared to 29 RA controls with no history of DMARD stomatitis. The retrospective survey showed that 2% of DMARD patients stopped therapy because of stomatitis, but 55% of these were able to resume the same therapy. In the case control study. 24% of patients discontinued temporarily and 8% permanently. Cases of DMARD-related stomatitis differed from controls in that they had a higher incidence of previous mouth ulcers (40% vs 14%), they smoked less (8% vs 31%) and Schirmer's test was more often abnormal (44% vs 21%). There were no differences in RA severity, disease activity or oral hygiene. Haematinic deficiencies were equally common in cases and controls: 30% for iron, 8% for vitamin B12 and 24% for folic acid. Herpes simplex virus was involved in a minority (8%) of cases. In conclusion, the occurrence of stomatitis in RA patients on DMARD should not lead to cessation of drug therapy, but to a careful evaluation so that patients may be maintained on effective treatment.

Small joint synovitis in rheumatoid arthritis: should it be assessed separately?

In the assessment of disease activity in rheumatoid arthritis (RA) small joint synovitis is traditionally included only as a component of active, tender or swollen joint counts. By contrast, in the assessment of disease damage in RA, the X-ray score of hands and feet represents one of the most common parameters used and is regarded as a major indicator of outcome. Data presented in this study lead us to hypothesize that the small joints require separate assessment in any study of disease activity or outcome in RA: (i) there is clear evidence that small joint synovitis often occurs in the absence of an abnormal acute phase response (ESR or C-reactive protein) and (ii) measured synovitis is an individual (PIP) joint has been shown to be reliable and to be related to subsequent X-ray changes in the same joint. Our findings show that, in a study of a treatment of RA, it is quite possible for disease activity measures to appear controlled while inflammation continues in the small joints causing radiological damage. This radiological damage is reflected as an adverse outcome. Hence the paradox of improving disease activity but not outcome. We argue that small joint inflammation and damage should be recognized as one aspect of the RA disease process offering unique information and as such should be assessed independently.

Combination therapy for rheumatoid arthritis and drug-induced systemic lupus erythematosus.

Development of drug-induced systemic lupus erythematosus (SLE) is an uncommon complication of the use of D-penicillamine and sulphasalazine. We report two cases of patients with rheumatoid arthritis (RA) who developed symptoms and signs of SLE and suggest that increasing use of these two agents as combination therapy in RA may cause an additive risk to the occurrence of this complication.

Use of the Stoke Index to differentiate between disease-modifying agents and non-steroidal anti-inflammatory drugs in rheumatoid arthritis.

The Stoke Index is a validated composite algorithm that has been designed to give a global measure of disease activity in rheumatoid arthritis (RA). The use of this single measure of disease activity in RA simplifies the critical evaluation of drug therapy. 368 patients with RA of varying duration and severity, entered into comparative drug trials between 1980 and 1987, had the algorithm calculated four weeks prior to therapy, at the start of treatment, and bi-monthly to six months. The index score was significantly improved by drugs with known slow acting anti-rheumatic drug (SAARD) activity and improvement could be seen as early as two months after the beginning of treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) did not improve the score. The index differentiates between treatments in patients with minor or major disease activity. We conclude that this composite index of disease activity provides a sensitive, meaningful measure for the evaluation of therapy in RA.

The relationship between serial measures of disease activity and outcome in rheumatoid arthritis.

Disease activity was measured annually over a median period of 7 years (range 5-9) in a cohort of 127 patients with rheumatoid arthritis. The measurements were plotted, and the area under the resultant curve measured. The relationship of serial measures of disease activity (area under the curve) to outcome (measured radiologically, functionally and by global assessment) was investigated. A significant correlation was found between persistent disease activity and radiographic deterioration. Similar results were found for functional outcome, as measured by Steinbrocker grade, health assessment questionnaire score or global assessment (by analogue score). Single measures of disease activity did not predict outcome. Although imprecise, current methods of measuring disease activity in RA, if measured serially, are valuable in predicting outcome over a 5-10 year period.

Rifampicin in early rheumatoid arthritis.

Sixteen patients with definite or classical Rheumatoid Arthritis (RA) of less than twelve months duration were recruited into a randomised, open twelve month study comparing Rifampicin 600 mg daily (9 patients) with Hydroxychloroquine (HCQ) 400 mg daily (7 patients). Ten patients completed twelve months of treatment (4 Rifampicin, 6 HCQ). Five patients were withdrawn from the study due to lack of efficacy (1 HCQ, 4 on Rifampicin). One further patient on rifampicin was withdrawn due to development of abnormal liver function tests. Significant improvement (p < 0.03) was noted in the Stoke Index (SI) at six and twelve months in the HCQ group which was not seen in the rifampicin group. In both groups there was no significant improvement in the single variables (Ritchie index, morning stiffness, grip strength, synovitis score, ESR, CRP). The results fail to confirm that Rifampicin may be useful in the treatment of RA in early stages of disease.

Should disease-modifying agents be used in mild rheumatoid arthritis?

A 12-month double-blind controlled study comparing hydroxychloroquine 400 mg daily with placebo in 104 patients with mild RA was conducted to see whether patients with mild rheumatoid arthritis (RA) benefit from treatment with disease-modifying agents. Mild RA was defined as synovitis limited to the hands and feet, an ESR less than 30 mm/h and C-reactive protein less than 20 mg/l, a situation where accepted clinical practice is to use a non-steroidal anti-inflammatory agent alone. By 6 months, the improvement of clinical and laboratory parameters in the hydroxychloroquine treated patients was significant compared with pretreatment levels and significantly greater than the control group. This improvement was maintained at 12 months. In addition, fewer patients withdrew through lack of efficacy, eight on hydroxychloroquine versus 18 on placebo. The implications of treating this well defined group of patients is discussed.

Raised epidermal phospholipase A2 activity in rheumatoid arthritis.

Epidermal phospholipase A2 (PLA2) in RA patients was significantly higher than in normals (p less than 0.0001) but lower than in psoriatic patients (p less than 0.05). No relationship was observed between PLA2 activity and commonly used measures of rheumatoid disease activity in a cross-sectional study. However, in a longitudinal study change in PLA2 activity correlated strongly with changes in disease activity.

The association and predictive value of the complex immunoglobulin A-alpha 1-antitrypsin in the development of erosions in early rheumatoid arthritis.

Immunoglobulin A-alpha 1 antitrypsin complex (IgA-AT), its constituent components and nine other clinical or laboratory variables were measured in thirty-three patients with early, non-erosive rheumatoid arthritis (RA) in order to assess their value in predicting the subsequent development of erosions. After 12 months, eighteen patients had developed erosions. Comparison of variables measured at outset between the group of patients subsequently developing erosions and those not, showed only the complex IgA-AT level to be significantly different, the mean being higher in the erosive group. In the subgroup of patients with high IgA-AT levels (greater than 3.0 arbitary units) all developed erosions. The possible therapeutic implications of these findings are discussed.

Comparison and evaluation of a disease activity index for use in patients with rheumatoid arthritis.

An algorithm (Stoke index) has been designed to give a global measure of disease activity in rheumatoid arthritis. This algorithm has been created as an easy to use flow diagram based on two objective laboratory measures (C-reactive protein and erythrocyte sedimentation rate), one subjective and two semi-objective clinical measures (morning stiffness, synovitis score and Ritchie articular index). Results of six clinical markers and seven laboratory markers of disease activity on a cohort of 371 rheumatoid patients have been used to evaluate the algorithm and compare it with a previously described index of disease activity (Mallya-Mace index). Principal component analysis validates its ability to measure disease activity. Sensitivity is described by the distribution of patients between the two index scores. Change in index score by patients over a 6-month period indicates reversibility. The Stoke index demonstrates greater sensitivity and reversibility than the Mallya-Mace index. These findings indicate that the algorithm described provides a useful index of global disease activity for use in the assessment of rheumatoid arthritis.

Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study.

We studied combination therapy with two slow-acting antirheumatic drugs given concurrently in active rheumatoid arthritis (RA). A 12-month prospective randomized controlled trial compared gold and hydroxychloroquine in 52 patients to gold and placebo in 49. The patients continued to receive non-steroidal anti-inflammatory drugs and analgesics. They were selected from three rheumatology centres in the West Midlands. Combination therapy led to a greater number of withdrawals due to adverse reactions (18 cases compared to 10 receiving gold/placebo). Patients completing 12 months' therapy (27 taking gold/hydroxychloroquine and 32 on gold/placebo) were compared using five clinical, seven laboratory, and one radiological measure. All 13 variables favoured gold/hydroxychloroquine with an overall advantage of 20-25% for the combination. This only reached statistical significance (at the 1% level) for C-reactive protein. An overall disease activity index was better at 12 months (at the 5% level) and showed a more rapid response with gold/hydroxychloroquine. This is the first randomized prospective placebo-controlled trial to show a significant advantage from a combination of two slow-acting drugs. There are many different ways of giving such combinations and we consider these should be explored to maximize the effectiveness of treatment for RA.

Measurement of natural killer cell cytotoxicity by area under a cytotoxic curve. A method suitable for rheumatoid arthritis.

Calculation of the area under a curve derived from a 51Cr cellular release assay gives a reproducible expression of cellular cytotoxicity and correlates well with results at fixed lymphocyte-to-target cell ratios and with lytic units at 20% and 30% cytotoxicity. This method is suitable for quantifying the low cytotoxicity seen in rheumatoid arthritis. The area under the cellular cytotoxic curve may be calculated using a simple mathematical formula or by computer analysis.

The relationship between the complex of immunoglobulin A and alpha-1-antitrypsin, its constituent components and the acute-phase response as measured by C-reactive protein in rheumatoid arthritis treated with gold or D-penicillamine.

Serum levels of immunoglobulin A (IgA), alpha 1-antitrypsin (AT), their complex (IgA-alpha 1AT) and C-reactive protein (CRP) were measured prior to treatment and at 6 months, in 45 rheumatoid arthritis (RA) patients. Twenty-five patients were treated with D-penicillamine (DPA) and 20 patients with gold (sodium aurothiomalate). The level of circulating complex was reduced by both treatments (p less than 0.001). There was a significant correlation between the circulating levels of IgA-alpha 1AT complex and serum IgA (p less than 0.05). No relationship was observed between the level of circulating complex and CRP. These findings suggest that formation of IgA-alpha 1AT complex in RA is dependent on the level of IgA. The complex is reduced by gold and DPA but it does not reflect an acute phase response as measured by CRP.