M. Farr

Side Effect Profile of 200 Patients with Inflammatory Arthritides Treated with Sulphasalazine

SummaryThe side effect profile of sulphasalazine was documented in 200 patients with inflammatory joint disease treated with the drug for at least 1 year. Fifty-eight percent of patients developed one or more adverse reactions and in 21.5% the drug was withdrawn. A further 28% continued taking the drug at a reduced dose. Five percent of the side effects were judged to be potentially serious. In all patients the reactions subsided on either discontinuation of the drug or reduction of the dose. Gastrointestinal (33%) and central nervous system reactions (19%) were the most common, but all were relatively minor. Neutropenia (2%), thrombocytopenia (1%) and pan-hypogammaglobulinaemia (1%) were potentially the most serious effects.The side effect profile of sulphasalazine in inflammatory joint disease appeared to be similar to that in inflammatory bowel disease, but reactions were more frequent in inflammatory joint disease. Enteric-coated sulphasalazine is a useful addition to the small number of slow acting antirheumatic drugs, and in view of its established efficacy, its level of toxicity was found to be ‘acceptable ’ as long as patients were carefully monitored and regular blood tests were carried out.

Plasma and synovial fluid concentrations of sulphasalazine and two of its metabolites in rheumatoid arthritis

SummaryA study was made of plasma and synovial fluid levels of sulphasalazine, one of its dissociation products — sulphapyridine and a metabolite of the latter — acetyl sulphapyridine in patients with rheumatoid arthritis (RA) who were in a steady state on sulphasalazine therapy. Combined sulphapyridine levels were significantly higher than those of sulphasalazine both in plasma and synovial fluid. Synovial fluid levels of both drugs correlated with their plasma levels and were generally slightly lower. Some patients accumulated sulphasalazine and sulphapyridine in the synovial fluid and the mean concentration of sulphasalazine was higher in the fluid than in the plasma. The explanation for this is uncertain. The concentration of combined sulphapyridine in synovial fluid was related to local joint inflammation and more active systemic disease. No consistent association was found between sulphasalazine levels and local or systemic activity. The higher sulphapyridine levels in synovial fluid found in this study suggest the possibility that this moiety could play a more active role in RA than it does in inflammatory bowel disease.

Platelets in the synovial fluid of patients with rheumatoid arthritis

SummaryIn a study of synovial fluid from 110 patients with various forms of arthritis, platelets were identified in the synovial fluid of all the 50 rheumatoids, in 18 out of the 25 (72%) with osteoarthritis and in all 35 of those with other forms of inflammatory osteoarthrosis. Identification of platelets by light microscopy was confirmed by electron microscopy. Platelet counts were significantly higher in rheumatoid fluid (mean 14 988/mm3; range 1000–65 000/mm3) compared with fluid from patients with osteoarthrosis (mean 1592/mm3; 0–10 000/mm3). In addition, significantly higher platelet counts were found in the synovial fluid (SF) of inflamed joints. There was a positive correlation between the SF platelet count and the total white cell count, polymorph count, hydrogen ion concentration, knee score, acid phosphatase and 5-nucleotidase activity and a negative correlation with the glucose level. All these factors indicate joint activity. Finally, platelet numbers correlated with SF levels of immunoglobulin M, and seropositive patients had significantly higher platelet counts in the SF compared with seronegative patients. Rheumatoid patients with thrombocytosis also had higher SF platelet counts. The close relationship of the SF platelet count to other indices of inflammation supports the concept that platelets may directly contribute to synovial inflammation by a variety of pathways.

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

SummaryThe 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.

Plasma exchange for Guillain-Barré syndrome.

Lymphopenia is a recognized but poorly studied feature of rheumatoid arthritis (RA). We set out to establish the prevalence and significance of lymphopenia in RA. A group of 66 RA patients was studied for one year. During this time 10 (15%) had persistent lymphopenia (lymphocyte count less than 1.00 X 10(9)/l) without evidence of Feltys syndrome. A separate study of lymphocyte subsets in 13 lymphopenic RA patients showed marked reduction in T-cell numbers with normal circulating B-cell numbers. The numbers of CD4 and CD8 positive T-cells were equally depressed. Lymphopenia may indicate more severe disease. It was not influenced by changes in disease activity or therapy.

Sulphasalazine in rheumatoid arthritis: Combination therapy with D-penicillamine or sodium aurothiomalate

SummaryThis open study examined the safety of adding a second slow-acting antirheumatic drug (SARD) — D-penicillamine or sodium aurothiomalate — to the therapy of 38 rheumatoid patients already established on sulphasalazine. Combined anti-rheumatic therapy given in this way was generally well-tolerated and the incidence of adverse reactions was not increased. During the first year none of the reactions were serious although 9 of the 29 patients (31%) given D-penicillamine and 3 of the 9 patients receiving aurothiomalate developed side-effects requiring withdrawal of the second SARD. Reactions attributed to D-penicillamine were: gastro-intestinal-6, rashes-2, and blurring of vision-1. All 3 reactions occurring with gold were rashes, 2 associated with proteinuria and one with increased liver enzymes. During the second year D-penicillamine was withdrawn in 4 patients due to thrombocytopenia-2, and rashes-2. In addition an overall favourable clinical response was achieved in 70% of patients. This approach for combination therapy whereby a second SARD is given to patients already established on a single SARD, appears to minimise the toxicity which is a problem when 2 SARDs are started simultaneously.

Treatment of psoriatic arthritis with sulphasalazine: A one year open study

SummarySulphasalazine (SASP) has recently become established as an effective treatment for active rheumatoid arthritis (RA), but has not previously been used in psoriatic arthritis in which remission-inducing drugs have proved disappointing. In this one year open study, 34 patients with active psoriatic arthritis were treated with sulphasalazine. An overall favourable clinical response was observed in 23 patients (67%). Nine patients (26%) achieved a very good therapeutic response and these either had arthritis associated with spondylitis or the symmetrical type of joint disease. Evaluation at 3,6 and 12 months showed a significant improvement in inflammatory indices including a reduction in the C-reactive protein level and ESR. The drug was well-tolerated and side-effects were mild. Eight patients (23.5%) stopped the drug because of reactions and one patient with a rash was successfully desensitised. Fifty-three percent continued the drug into the second year. No apparent exacerbation of the psoriasis was observed. These results suggest that sulphasalazine is a safe and potentially effective drug in the treatment of psoriatic arthritis. A double-blind placebocontrolled trial has been set up to determine its true efficacy.

T-cell functional defects in rheumatoid arthritis: Intrinsic or extrinsic?

This study investigated two mechanisms which may underlie abnormal T-cell function [lymphocyte proliferation and interleukin-2 (IL-2) production] in rheumatoid arthritis (RA). These were: (a) a possible lack of the IL-2-producing CD4+2H4+ lymphocytes and (b) the possible inhibitory role of monocytes and neutrophils. Numbers of CD4+2H4+ cells did not differ between normal controls and patients with RA, although IL-2 produced by the peripheral blood mononuclear cells (PBMC) of the same individuals was markedly reduced in the patient group (P less than 0.001). Many rheumatoid peripheral blood mononuclear cell preparations, but very few control, were contaminated with neutrophils (P less than 0.001). This was more marked in patients with active RA than in those with inactive disease (P less than 0.001). Numbers of monocytes were similar in all groups. Monocyte depletion, or addition of indomethacin and/or catalase in PBMC, caused a significantly greater increase of responses in RA patients than in controls. This effect was significantly higher in patients with active disease than in the inactive group. These findings suggest that activated monocytes and neutrophils found in the rheumatoid PBMC preparations exert inhibitory effects mediated, in part, by the production of prostaglandins and reactive oxygen intermediates. Monocyte depletion and partial reconstitution resulted in significant increase of lymphocyte proliferation and IL-2 production in both controls and patients. None of the manipulations performed succeeded in normalizing the deficient rheumatoid T-cell responses. These data support the hypothesis that non-lymphoid cell populations play an important role in the T-cell dysfunction characteristic of RA.(ABSTRACT TRUNCATED AT 250 WORDS)

A Double-Blind Controlled Study Comparing Sulphasalazine with Placebo in Rheumatoid Factor (RF)-Negative Rheumatoid Arthritis.

SummaryThe efficacy and tolerability of sulphasalazine (SASP) was examined in a double blind, placebo-controlled 24-week study of 32 patients with rheumatoid factor (RF)-negative RA. Twelve patients (75%) of the SASP group completed the study; 4 patients were withdrawn because of an adverse event. Ten patients (62.5%) in the placebo group completed the study; 5 dropped out because of lack of response and one because of an adverse reaction.Efficacy was demonstrated by a significant and sustained improvement in the indices of disease activity in the SASP group. It was confirmed by significant intergroup differences in favour of SASP over placebo in the changes in ESR, Ritchie index, number of painful joints and clinical score. There was also a significant difference in favour of SASP in the number of responders and the number of withdrawals due to inefficacy. The character, frequency and timing of side-effects were similar to those previously reported. All were reversible on stopping therapy.This study shows that SASP is an effective second-line drug for treating patients with RF-negative RA.

Long term experience of salazopyrin EN in rheumatoid arthritis (RA).

Our studies have shown that Salazopyrin EN is an effective slow-acting anti-rheumatic drug, improving clinical synovitis, depressing the acute phase response, capable of inducing remissions and possibly influencing the progression of joint damage. It is well-tolerated in the long-term with comparatively few serious side effects. Its mechanism of action, however, is still not entirely clear. We have found that the sulphapyridine moiety penetrates the synovial membrane and also that it can modify immune function. While Salazopyrin undoubtedly has an important role in the therapy of rheumatoid arthritis, it probably also has a place in the treatment of seronegative arthropathies and the spondyloarthritides. Furthermore we suggest that it should be used as an anchor drug in combination therapy to attempt to suppress disease activity further and limit joint damage.