Sulphasalazine therapy in rheumatoid arthritis: qualitative changes in lymphocytes and correlation with clinical response.

Clinical and immunological parameters in 14 patients with rheumatoid arthritis (RA) receiving sulphasalazine (SASP) were evaluated, to determine whether their clinical response was reflected by any quantitative changes in their peripheral blood lymphocytes after 12 weeks. Whilst disease activity markers fell significantly, no such changes were noted in the percentage or absolute numbers of lymphocytes or their subsets. The lymphocytes of a further 21 patients before and after receiving SASP for 12 weeks were then studied qualitatively. The suppression mediated by in vitro SASP on ex vivo PHA stimulated lymphocytes showed a decrease at 12 weeks. This change was more marked and reached statistical significance only in those patients who showed a good clinical response. It is postulated that this may in some way be related to expression of activation markers and concomitant SASP binding.

Effect of sulphasalazine and its metabolites on mitogen induced transformation of lymphocytes--clues to its clinical action?

The effects of sulphasalazine (SASP), sulphapyridine (SP), and 5-aminosalicylic acid (5-ASA) have been studied on mouse spleen cells cultured in the presence of phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and lipopolysaccharide (LPS). SASP exhibited a significant degree of suppression, at doses in the range 25-100 micrograms/ml (p less than 0.01), this suppression being greater than 50% at 50 micrograms/ml. SP exhibited only a minor degree of suppression (10% at 75 micrograms/ml, p less than 0.01). Coadministration of a non-steroidal anti-inflammatory drug (NSAID), indomethacin, produced no evidence of further suppression in the presence of SASP or SP. Administration of SP plus 5-ASA to parallel cultures that were profoundly suppressed by the molecular equivalent amount of SASP resulted in no suppression. This implied requirement of the intact parent molecule (SASP) to produce this effect, at these concentrations. The concentration of SASP required to produce more than 50% suppression was higher than that ever attained in the peripheral blood of humans receiving therapeutic doses of the drug. Human lymphocytes are similarly suppressed by SASP, but only at higher concentrations than are required for murine cells. Thus, if the parent drug is the active moiety and requires these concentrations to be effective in vivo, it follows that the site where these effects may be mediated is likely to be the intestinal tract. The effects described would suggest the gut associated lymphoid tissue as a likely target.

Renal and pancreatic calcification in rheumatoid arthritis with Sjögren's syndrome.

We describe a female patient who developed seropositive rheumatoid arthritis (RA) at the age of 12 years. After 10 years her disease was complicated by Sjögren's syndrome (SS) and distal (type 1) renal tubular acidosis (RTA). Seven years later she was noted to have nephrocalcinosis. At the age of 32, investigation of a short history of weight loss and abdominal pain revealed a benign gastric ulcer and chronic calcific pancreatitis. We believe she is the first patient with RA and SS in whom complicating renal and pancreatic calcification have been reported. Her case emphasizes the good prognosis of type 1 RTA in SS and suggests that pancreatic involvement may be more common than clinically apparent.

Chemonucleolysis of lumbar intervertebral disc prolapse with chymopapain: outcome after 1 year.

One hundred and one consecutive patients with lumbar disc prolapse were treated by chymopapain chemonucleolysis and their response and favourable pre-treatment criteria determined. Most improvement occurred within the first month, and one year after treatment outcome was judged satisfactory (excellent or good) in 71%. Individual patient characteristics associated with a satisfactory response were sciatica of greater severity than back pain (p = 0.005) and duration of symptoms less than 18 months (p = 0.03). Patients fulfilling 3 or 4 of four immediate pre-treatment clinical and radiographic criteria (sciatica more severe than back pain, reduced straight leg raising, neurological deficit, radiographic abnormality) had a satisfactory response more often than others (p less than 0.05). Reported success one year after surgery for disc prolapse is similar. Chemonucleolysis, however, requires less resources and does not preclude subsequent operation. Our results therefore suggest that it might be considered an alternative to surgery when conservative treatment has failed.

Long-term treatment of rheumatoid arthritis with sulphasalazine, gold, or penicillamine: a comparison using life-table methods.

Life-table analysis was applied to the records of 317 patients with rheumatoid arthritis (RA) treated with sulphasalazine (SAS), 201 treated with sodium aurothiomalate (gold), and 163 with penicillamine. They comprised all those treated in our department with these drugs between January 1973 and July 1984. Risks of treatment termination for all reasons were similar for each drug at five years (gold 92%, penicillamine 83%, SAS 81%). The risk of treatment termination due to inefficacy was less for gold (29.5%) than for penicillamine (38.1%) or sulphasalazine (41.2%). Adverse effects, however, led to withdrawal of gold in 57%, penicillamine in 41.2%, and SAS in 37%; the most effective drugs appeared most toxic. Serious adverse effects were much more common in association with gold (17.4%) and penicillamine (12.3%) than with SAS (1.6%). Sulphasalazine appears as well tolerated over long periods in RA as gold or penicillamine and is associated with fewer serious adverse effects; of these drugs, it might therefore be considered the agent of first choice.

Phenytoin in rheumatoid arthritis.

In a prospective open study, 18 patients with active rheumatoid arthritis were treated with phenytoin (300 mg/day) for 32 weeks. Clinical assessments improved significantly and there was no relapse 8 weeks after drug withdrawal. Serum C-reactive protein, plasma viscosity and hemoglobin also improved but changes were not significant. Serum phenytoin concentrations were lower than anticipated. Side effects were mild and caused 2 patients to withdraw. Our observations and the known effects of phenytoin on the immune system and collagen metabolism suggest that further controlled studies using higher doses are warranted.

Serum amyloid A protein during the treatment of rheumatoid arthritis with second-line drugs.

Serum amyloid A protein (SAA), serum C-reactive protein (CRP) and the ESR were measured in 19 patients with rheumatoid arthritis before treatment and during therapy with gold, penicillamine or sulphasalazine for a mean period of 14.8 months (range 6-23 months). All three measurements decreased significantly; however, only 7% of SAA values fell to within the normal range (18-44 mg/l), compared to 38% measurements of serum CRP (less than 10 mg/l) and 32% of the ESR (less than 25 mm/h). In 8 (42%) of the 19 patients, SAA remained high (greater than 400 mg/l) for 3 months or more whilst serum CRP was depressed below 20 mg/l; this discrepancy was not related to particular drugs. We conclude that during treatment of rheumatoid arthritis with gold, penicillamine or sulphasalazine, SAA concentrations can be high when serum CRP and ESR are suppressed. SAA may be a more sensitive index of disease activity.

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.

Anti-rheumatic drugs and joint damage in rheumatoid arthritis.

The effect of second-line anti-rheumatic drugs such as gold on the course and progression of joint damage has been the subject of considerable controversy. We have evaluated the effects of second-line anti-rheumatic drugs in three studies of 46-84 patients with rheumatoid arthritis given a second-line drug continuously for 12 months. Using two different methods of radiographic assessment we found that there was significant progression over the 12-month period when the mean changes in the groups of patients were examined, and there was similar indications of continuing disease activity shown by mean values of acute phase proteins and ESR which were above the normal range at both six and 12 months. But there were subgroups of patients who showed a reduction in ESR and joint tenderness with a related slowing of the rate of radiographic progression in the second six months of treatment. There was no direct relationship between changes in the ESR and radiographic progression in individual patients. Although anti-rheumatic drugs are not ideal and therapy does not cause remission in many patients, some patients respond well. Rheumatoid arthritis may represent a heterogeneous collection of patients who respond individually to different drugs.

Rheumatoid arthritis: the effects of treatment with dapsone on hemoglobin.

Hemoglobin concentration (Hb) was measured at 6 week intervals for up to a year in 84 patients with rheumatoid arthritis treated with dapsone. During the first 6 weeks, mean Hb decreased from 12.0 to 11.0 g/dl (p less than 0.001). Falls in Hb occurred in 81% of patients but exceeded 2 g/dl in only 10%. After more than 6 weeks of treatment mean Hb increased, though a few individuals became anemic during this period. Anemia led to discontinuation of dapsone in 5 (6%) patients. Men and patients receiving corticosteroids had higher pretreatment Hb values; after falls in mean Hb at 6 weeks, recovery was more rapid in these 2 subgroups. Changes in Hb produced by 100 mg and 150 mg dapsone daily were similar.

Outcome of attempts to treat rheumatoid arthritis with gold, penicillamine, sulphasalazine, or dapsone.

The outcome of attempts to continue treatment indefinitely with either gold, penicillamine, sulphasalazine, or dapsone was studied in 240 patients with rheumatoid arthritis (RA). The usual reason for discontinuing treatment was the occurrence of an adverse effect. This led to 53% of patients stopping gold, 33% sulphasalazine, 32% penicillamine, and 17% dapsone. The next most frequent reason was that the drug was ineffective, leading to discontinuation in 37% of patients having dapsone, 24% sulphasalazine, 19% penicillamine, and 16% gold. Other reasons for stopping treatment were infrequent. The high discontinuation rate of these drugs over 2 years in part accounts for the conflict of opinion on whether they can alter the course of RA; their efficacy must to a large extent be governed by their acceptability.

Rheumatoid arthritis: is serum vitamin B12 high in active disease?

Seven clinical and laboratory indices of disease activity were compared with serum vitamin B12 levels in 32 patients with rheumatoid arthritis treated with penicillamine (16 patients) or sulphasalazine (16 patients) for up to 24 weeks. Prior to treatment each patient had active disease but a normal or low serum vitamin B12 concentration. During treatment, significant improvements occurred in all clinical and laboratory measurements but vitamin B12 levels were unchanged. We have been unable to confirm a reported positive association between rheumatoid disease activity and serum B12 concentration.