Leucopenia during sulphasalazine treatment for rheumatoid arthritis.

Leucopenia appears to be a more frequent complication of sulphasalazine treatment in rheumatoid arthritis than in inflammatory bowel disease and poses a management problem. In this study leucopenia was found in 20 patients, 14 of whom were participating in prospective studies (252 patients), giving an incidence of 5.6%. Treatment had to be discontinued in half of these patients. Most (14) episodes of leucopenia occurred early in treatment (less than 24 weeks) but some occurred late and sustained monitoring seems necessary. No predictive factors for leucopenia were elucidated. All patients recovered fully with dose adjustment or, in more severe cases, after withdrawal of sulphasalazine and appropriate supportive therapy. The incidence of leucopenia may be higher in Glasgow than in other units in Britain.     

Effect of sulphasalazine on the radiological progression of rheumatoid arthritis.

We have investigated the influence of sulphasalazine, a second line antirheumatic drug, on the radiological progression of erosions in rheumatoid arthritis over a two year period in 41 patients. Hand radiograph scores deteriorated significantly over this period, but in a group of 31 patients in whom one year films were also available this deterioration was limited to the first year. This slowing of radiological deterioration was not related to 'normalisation' of the erythrocyte sedimentation rate (ESR). Compared with a 'control' group of 10 patients who had refused offers of second line therapy, sulphasalazine treated patients showed less deterioration over the two year period, and this difference was more marked than in previous studies of gold or penicillamine. No significant change was seen in large joint radiographs in sulphasalazine treated patients over two years, but this probably represents the poor sensitivity of the method of assessment. No significant correlation was seen between changes in inflammatory indices and slowing of radiological deterioration in erosion score. Thus sulphasalazine appears to slow the progression of radiological disease of the hands over the second year of treatment in a representative sample of patients who continue to receive treatment for two years.     

Cell-mediated immunity in rheumatoid arthritis.

Cell-mediated immunity in rheumatoid arthritis (RA) was assessed by skin testing with six antigens in 107 patients, 94 of whom were age, sex, and race-matched with healthy individuals or patients with diseases unrelated to immunological abnormalities. 20% of RA patients were anergic. Impaired cell-mediated immunity in the RA patients was manifested by a decrease in the magnitude of skin reactivity as well as a decrease in the incidence of positive reactions to multiple antigens. Depression in cell-mediated immunity was related to age but not to sex, duration of disease, or disease activity. A slight correlation was found between absolute peripheral lymphocyte counts and the number of positive skin tests, and was confirmed by finding an association between lymphocyte counts and the size of skin reactions. A correlation was also found between lymphocyte counts and disease activity. Four explanations of the observed depression in cell-mediated immunity in RA were considered: (1) a preoccupation of the immune mechanism of the host with cell-mediated immunity reactions related to the pathogenesis of the disease; (2) a depression of cell-mediated immune reactivity by a virus infection; (3) depression of cell-mediated immunity by therapy; and (4) immune complex suppression of cell-mediated immunity. No effect of gold therapy was found. The near universal use of salicylates or other anti-inflammatory drugs did not permit investigation of the effect of these drugs on cell-mediated immunity.     

Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis.

A group of 54 patients with rheumatoid arthritis (31 fast, 23 slow acetylators) treated with sulphasalazine 3 g/day were studied retrospectively. At 24 weeks no difference in the efficacy of the drug could be shown between fast and slow acetylators. In a second prospective study 40 fast acetylators were allocated to 3 g/day and 20 slow acetylators to 1.5 g/day. At 24 weeks marked improvement was seen in the fast acetylators given high dose but not the slow acetylators given low dose. It was also noted in this study that the usual ratio of fast : slow acetylators was reversed, and there is some suggestion that fast acetylators may be predisposed to more severe rheumatoid arthritis. The toxicity pattern in a total of 149 patients (83 fast, 66 slow acetylators) was also studied. Significantly more slow acetylators stopped treatment because of nausea or vomiting, or both, but serious toxicity was not confined to either group. Acetylator phenotype therefore appears important in determining the incidence of nausea and/or vomiting associated with sulphasalazine therapy in patients with rheumatoid arthritis but has no effect on the occurrence of potentially serious toxicity or efficacy. Thus prior measurement of acetylator phenotype in patients with rheumatoid arthritis confers little practical benefit in their management.     

Does sulphasalazine cause folate deficiency in rheumatoid arthritis?

Sulphasalazine impairs folic acid absorption and metabolism but rarely leads to folate deficiency in inflammatory bowel disease (IBD). In rheumatoid arthritis (RA), however, serum and red cell folate concentrations are often low and sulphasalazine might stress folate metabolism. In a prospective study, 2 g sulphasalazine was compared with 500 mg penicillamine daily in 30 patients over 24 weeks. Pre-treatment serum and red cell folate concentrations were low-normal. Improvements in disease activity and haemoglobin occurred in both treatment groups, but MCV increased only in patients taking sulphasalazine. Serum and red cell folate concentrations did not change in either group. Increased MCV with sulphasalazine might therefore reflect reticulocytosis secondary to drug-induced haemolysis. The mechanisms by which sulphasalazine antagonizes folate metabolism are dose-dependent and, consequently, higher doses might precipitate folate deficiency.     

Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms

OBJECTIVE: Insulin resistance is increased by inflammation, but the mechanisms are unclear. The present study was undertaken to test the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: We measured fasting insulin, glucose, and lipid levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and coronary artery calcification in 103 patients with SLE and in 124 patients with RA. Insulin sensitivity was measured using the homeostasis model assessment (HOMA) index. RESULTS: The HOMA value was higher in RA patients (median 2.05 [interquartile range (IQR) 1.05-3.54]) than in SLE patients (1.40 [0.78-2.59]) (P = 0.007). CRP and ESR did not differ significantly in RA and SLE patients. Body mass index (BMI) was significantly correlated with the HOMA index in both RA (rho = 0.20) and SLE (rho = 0.54), independently of age, sex, race, and current use of corticosteroids. In RA patients, the HOMA index was also significantly positively correlated with IL-6 (rho = 0.63), TNFalpha (rho = 0.50), CRP (rho = 0.29), ESR (rho = 0.26), coronary calcification (rho = 0.26), and Disease Activity Score in 28 joints (rho = 0.21); associations adjusted for age, sex, race, BMI, and current use of corticosteroids remained significant (P < 0.05). In SLE patients, the HOMA index was also significantly correlated with ESR (rho = 0.35) and CRP (rho = 0.25), but not with other variables. The association between the ESR and the HOMA value in patients with SLE remained significant after adjustment for confounding covariates (P = 0.008). In multivariable models, the major contributing factors to the HOMA index were the BMI in SLE patients, and IL-6 and TNFalpha levels in RA patients. CONCLUSION: The pathogenesis of insulin resistance and its contribution to atherogenesis varies in different inflammatory settings.     

Influence of acetylator status on sulphasalazine efficacy and toxicity in patients with rheumatoid arthritis.

The influence of acetylator status on the therapeutic efficacy and the toxicity of sulphasalazine (SASP) was assessed in 106 patients with rheumatoid arthritis (RA). Changes of indices of disease activity after 6 months, and progression of erosions after 2 years of SASP treatment were similar in fast and slow acetylators. Incidence and nature of withdrawals and side-effects, and requirement for intra-articular steroid injections or combination therapy due to poor response to SASP were almost identical in the two groups. A significant increase of the hepatic enzyme aspartate transaminase was noted mainly in slow acetylators, but was not associated with clinical disease. These results suggest that acetylator status does not relate significantly to either the efficacy or the toxicity of SASP in RA. It is possible that hepatic metabolism is affected by SASP, particularly in slow acetylators, but this does not lead to clinically identifiable problems.     

The effect of sulphasalazine on neutrophil superoxide generation in rheumatoid arthritis

The production of superoxide by the peripheral blood neutrophils of 19 patients with active rheumatoid arthritis was measured during treatment with sulphasalazine (SASP). The response to drug treatment was determined by change in plasma viscosity, CRP, early morning stiffness and articular index over a 10-point scale. Of the 19 patients studied, eight were considered to have responded well to SASP and seven to have responded poorly or not at all. Over the treatment period, plateau levels of superoxide production fell in seven of the eight responders (P = 0.028) compared with a non-significant fall in 3/7 of the non- responder groups. The initial rate of superoxide production also fell in the responder group, but this was not statistically significant. Initial values in both the responder and non-responder groups were comparable with those seen for normal controls. Analysis of drug levels showed all patients to be compliant with drug treatment; however, drug levels and neutrophil activity were not correlated. Studies of the effect of SASP and sulphapyridine on superoxide production in vitro showed no difference between good and poor responders. These results suggest that there is no inherent difference between good and poor responders regarding the susceptibility of their neutrophils to SASP. SASP's action on neutrophils, therefore, appears not to be its main mechanism of disease-modifying activity in RA.      

Infections in systemic lupus erythematosus and rheumatoid arthritis.

Patients with systemic lupus erythematosus have a higher infection rate than the general population. It is estimated that at least 50% of them will suffer a severe infectious episode during the course of the disease. Improvements in the control of the disease are discussed in this article.     

Low dose desensitisation does not reduce the toxicity of sulphasalazine in rheumatoid arthritis.

OBJECTIVE: To examine the proposal that pretreatment low dose desensitisation may reduce the incidence of toxicity of sulphasalazine in the treatment of rheumatoid arthritis (RA). METHODS: A double blind, placebo controlled trial was performed with 422 patients satisfying the American College of Rheumatology criteria for RA who required sulphasalazine treatment because of increased disease activity. Patients received either sulphasalazine desensitisation, or placebo, for three weeks before commencement of sulphasalazine treatment. The frequency and nature of adverse effects and changes in clinical and laboratory parameters of disease activity were measured after three and six months. RESULTS: Improvement in the efficacy of sulphalasazine (measured by clinical and laboratory parameters) was significant and similar in magnitude in both groups. There was no significant difference between actively and placebo desensitised patients as regards the incidence or profile of adverse effects (toxicity). CONCLUSION: Pretreatment low dose desensitisation is unhelpful in reducing the toxicity associated with sulphasalazine treatment of RA.     

A double blind comparative study of sulphasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulphasalazine.

In a double blind, single observer, 48 week study the effects of sulphasalazine (2 g daily) and hydroxychloroquine (400 mg daily months 0-6, thereafter 200 mg daily) were compared in 60 patients with definite or classical rheumatoid arthritis. They had not been treated previously with second line drugs. The onset of response with sulphasalazine was earlier than with hydroxychloroquine. After 48 weeks a comparison of the treatments showed no statistically significant differences in disease activity variables. Adverse reaction was the main reason for withdrawal in the sulphasalazine group and lack of efficacy in the hydroxychloroquine group. All adverse reactions, one being agranulocytosis after eight weeks of sulphasalazine treatment, appeared in the first three months of treatment and were completely reversible.     

Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis

BACKGROUND: Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti-tumour necrosis factor (anti-TNF) agents. OBJECTIVE: To study acquired drug resistance to anti-TNF agents in rheumatoid arthritis (RA). METHODS: Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co-therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co-therapy and time to discontinuation of the three anti-TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model. RESULTS: 1198 patients contributing 1450 patient-years of anti-TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co-therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti-TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months' treatment. CONCLUSIONS: In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy than the other anti-TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.     

The long term effects of sulphasalazine in the treatment of rheumatoid arthritis and a comparative study with penicillamine

Summary The long term efficacy and tolerability of sulphasalazine (SASP) in the treatment of 21 patients with active classical or definite rheumatoid arthritis (RA) were examined and compared with the effects of penicillamine in a similarly active group of RA patients. Nineteen of the 21 patients treated with SASP improved during the first 6 months as shown by significant changes in the clinical and laboratory variables. Clinical improvement was maintained for the remainder of the year. Improvement in laboratory variables was maintained at 9 months but showed some deterioration at 1 year. Six patients went into remission by the ARA criteria, and 16 were able to continue the drug at the end of 1 year. In addition SASP had a steroidsparing effect in 4 of the patients on systemic steroids. No potentially dangerous side effects were encountered by the end of the first year, although 5 patients were withdrawn. Dyspepsia, nausea and abdominal discomfort were the most common side-effects, although rashes (3) and macrocytosis (2) also occurred. Eighteen of the 21 patients treated with penicillamine improved during 9 months,although there was some deterioration at 1 year. Eight patients were withdrawn because of side-effects — thrombocytopenia (5), nephrotic syndrome (1) and proteinuria(2). This study suggests that SASP has a disease modifying action maintained over a year and associated with low toxicity. It is a useful addition to the small number of second-line drugs with a possibly different mode of action.