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.

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.

Grip strength: peak or sustained pressure in rheumatoid arthritis?

The intra-observer reproducibility of three methods of measuring grip strength with a standard sphygmomanometer cuff was studied in 26 patients with rheumatoid arthritis (RA). Two techniques involved the measurement of peak pressure but differed in the period of time between consecutive attempts with each hand. The third method measured sustained grip. All three methods were highly reproducible. However, peak pressure recordings (either the best or the mean of three readings) were associated with least patient discomfort, were easier to read, and are suggested as the methods of choice for serial assessment of grip strength in RA.

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.

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.

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.

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.

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.

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.

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.

The assessment of radiological changes in the hands and wrists in rheumatoid arthritis.

Two methods of assessing changes in hand and wrist radiographs, the Larsen Index and Amos Index, were compared and contrasted in 48 patients with rheumatoid arthritis (RA). X-rays were taken before and after 1 year of treatment with remission-inducing drugs and scored independently by three observers using both methods. Single readings of radiographs using the Larsen Index were highly reproducible (intra- and inter-observer correlations greater than 0.90 on all occasions), but reproducibility fell when changes were determined from paired films (intra- and inter-observer correlations 0.47-0.82). Variability was greatest in the proximal interphalangeal and wrist joints. The Amos Index, which assesses erosive progression and not the appearance of single films, was more reproducible (intra- and inter-observer correlations 0.72-0.94); it would therefore be better able to detect small changes in groups of patients. The scoring systems were significantly correlated (r = 0.63; P less than 0.001), and with both different observers scored the films at the same "level'. The Amos Index is simple, reproducible, and does not require standard films. It is the assessment of choice.

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.

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.

Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial.

Sulphasalazine was first formulated by Svartz in the early 1940s, specifically for use as a remission inducing drug in rheumatoid arthritis. After the publication of an unfavourable trial, however, the drug was restricted to patients with ulcerative colitis. In the late 1970s sulphasalazine was re-examined in rheumatoid arthritis and favourable results reported in "open" trials. A double blind controlled trial was therefore conducted comparing enteric coated sulphasalazine and D-penicillamine in patients with active rheumatoid arthritis. A total of 63 patients were recruited in two centres; 31 were treated with sulphasalazine and 32 received penicillamine. After 16 weeks' treatment both drugs had produced significant improvements in clinical score, pain score measured on a visual analogue scale, grip strength, Ritchie articular index, erythrocyte sedimentation rate, and serum C reactive protein concentration. Nausea was the major side effect in the sulphasalazine treated group. No potentially dangerous effects of sulphasalazine were encountered in contrast with those seen in the penicillamine group. The results suggest that sulphasalazine is an effective and safe drug capable of producing remissions in active rheumatoid arthritis. They also lend confidence to the use of preliminary "open" trials as a means of screening for remission inducing drugs in rheumatoid arthritis.

High-dose intravenous methylprednisolone in rheumatoid arthritis.

Fourteen patients with severe rheumatoid arthritis (RA) were given 27 courses of methylprednisolone intravenously, each of 3 infusions of 1 g on alternate days. After 7 days there was marked improvement in clinical state and most laboratory tests; levels of ESR and 4 serum acute-phase proteins, C3, C, IgG, and IgA, fell significantly. Serum IgM and rheumatoid factor titre were unchanged. 125I C1q binding fell in all instances where it was initially raised. Clinical remission lasted a mean of 10 weeks. Serum C-reactive protein (CRP) fell to less than 30 mg/l after all courses except one within 7 days and rose above this figure after a mean of 7 weeks. The ESR fell below 30 mm/h within seven days in 17 courses and remained below this value for a mean of 7 weeks. Three patients had clinical remissions, with serum CRP less than 30 mg/l and ESR less than 30 mm/h, lasting more than 42 weeks.

A comparison between clinical and laboratory tests in rheumatoid arthritis.

Five clinical measurements (clinical score, articular index, visual analogue pain score, visual analogue function score, grip strength) were compared with two laboratory tests (the erythrocyte sedimentation rate and serum C-reactive protein concentration) in 68 patients with rheumatoid arthritis (RA). Patients treated with nonsteroid anti-inflammatory drugs showed clinical deterioration when treatment was interrupted, followed by improvement on resumption; there was no change in the laboratory tests. Patients treated with remission-inducing drugs (RIDs) had improved clinical measurements and also reduced erythrocyte sedimentation rate and serum C-reactive protein levels. Treatment with RID's led to similar trends in both clinical and laboratory tests, but correlation coefficients between the tests at intervals rarely attained statistical significance. The different response times for each test and probably also errors inherent in clinical measurements introduced sufficient variability to account for the discrepancy. Of the clinical tests, 'clinical score' appeared the most satisfactory.