Alclofenac and D-penicillamine. Comparative trial in rheumatoid arthritis.

Forty-six patients with rheumatoid arthritis, 22 receiving D-penicillamine and 2j alclofenac, took part in a 6-month single-bind external observer trial to compare the efficacy and toxicity of these drugs in the treatment of severe rheumatoid arthritis. Both drugs were active and similar in their efficacy at 6 months as judged by clinical and laboratory measurements. Penicillamine was active therapeutically by 3 months, one month before alclofenac. 9 patients, 8 on alclofenac and one on D-penicillamine, had to stop treatment because of lack of effect or toxic effects. Skin rashes within the first week of treatment were a major problem with alclofenac and led to 6 withdrawals.     

A double blind trial to assess the value of alclofenac compared with phenylbutazone in the management of rheumatoid arthritis.

A double-blind cross-over study using a double placebo technique was employed to compare the effectiveness of daily alclofenac 3 g and phenylbutazone 300 mg in rheumatoid arthritis. (2) Thirty-one patients with classical or definite rheumatoid arthritis entered the trial. Twenty-three patients completed the trial; eight patients were withdrawn while on alclofenac, six developing a rash and two having inadequate analgesia. (3) Relief of pain on both drugs was comparable. (4) When questioned at the end of the trial, sixteen patients preferred phenylbutazone, four preferred alclofenac. (5) No significant changes in laboratory values were found, apart from a slight mean fall in haemoglobin on phenylbutazone. (6) There were significantly more side effects on alclofenac and rashes were particularly prominent.     

A study of the influence of various antirheumatic drug regimens on serum acute-phase proteins, plasma tryptophan, and erythrocyte sedimentation rate in rheumatoid arthritis.

In patients with rheumatoid arthritis neither indomethacin nor aspirin influenced the levels of the erythrocyte sedimentation rate (e.s.r) or serum acute-phase proteins fibrinogen, haptoglobin, C-reactive protein and alphaI acid-glycoprotein). Treatment with D-penicillamine, sodium aurothiomalate, or alclofenac produced a significant reduction both in acute-phase protein levels and in e.s.r. Each of the drugs displaced L-tryptophan from plasma proteins in vivo but withdrawal of indomethacin and aspirin was followed immediatley by excessive binding of this amino acid to circulating proteins:this phenomenon was not observed when alclofenac, sodium aurothiomalate or D-penicillamine were withdrawn. It has been demonstrated that disease activity in rheumatoid arthritis is reflected in acute-phase protein concentrations and in the extent to which L-tryptophan is bount to plasma protein. It is suggested that drugs which profoundly affect these parameters provide not only symptomatic relieft but also possible beneficial effects upon the disease process itself.     

A STUDY OF THE INFLUENCE OF VARIOUS ANTIRHEUMATIC DRUG REGIMENS ON SERUM ACUTE-PHASE PROTEINS, PLASMA TRYPTOPHAN, AND ERYTHROCYTE SEDIMENTATION RATE IN RHEUMATOID ARTHRITIS

In patients with rheumatoid arthritis neither indomethacin noraspirin influenced the levels of the erythrocyte sedimentationrate (e.s.r.) or serum acute-phase proteins (fibrinogen, hapto-globin,C-reactive protein and alpha₁ acid-glycoprotein). Treatmentwith D-penicillamine, sodium aurothiomalate, or alclofenac produceda significant reduction both in acute-phase protein levels andin e.s.r. Each of the drugs displaced L-tryptophan from plasmaproteins in vivo but withdrawal of indomethacin and aspirinwas followed immediately by excessive binding of this aminoacid to circulating proteins: this phenomenon was not observedwhen alclofenac, sodium aurothiomalate or D-penicillamine werewithdrawn. It has been demonstrated that disease activity inrheumatoid arthritis is reflected in acute-phase protein concentrationsand in the extent to which L-tryptophan is bound to plasma protein.It is suggested that drugs which profoundly affect these parametersprovide not only symptomatic relief but also possible beneficialeffects upon the disease process itself.     

HEPATITIS AND NEUTROPENIA SECONDARY TO GOLD THIOMALATE THERAPY FOR RHEUMATOID ARTHRITIS

Abstract A 37 year old female with rheumatoid arthritis developed clinical and biochemical evidence of hepatitis after receiving 80 mg of sodium aurothiomalate. Inadvertent rechallenge with sodium aurothiomalate led to recurrence of the biochemical abnormalities and a profound neutropenia and eosinophilia.     

Intestinal absorption in patients with rheumatoid arthritis treated with methotrexate

Summary Twelve patients with rheumatoid arthritis treated for at least 12 months with methotrexate and 11 matched rheumatoid arthritis controls underwent a standard d-xylose absorption test. No patients had any pre-existing clinical of biochemical evidence of malabsorption. No significant difference was observed in the 1 hour plasma d-xylose estimation between methotrexate treated patients and controls. The 2 to 5 hour urinary excretion ratio, however, was significantly lower in the methotrexate-treated group compared with controls indicating a minor degree of malabsorption. Six of the methotrexate treated patients and 5 of the controls underwent endoscopic duodenal biopsy but neither group demonstrated any significant histological changes. In conclusion, methotrexate therapy in patients with rheumatoid arthritis produces mild intestinal malabsorption.     

A clinical and biochemical evaluation of etretinate in rheumatoid arthritis

Summary Etretinate (Tigason; Roche), which is effective in the treatment of psoriatic arthritis has immunomodulating activity in vivo. We have therefore assessed this drug in an open clinical and biochemical assessment of 24 weeks duration in rheumatoid arthritis. The treatment dose was 1.0 mg/kg/day for the first 4 weeks reducing to 0.5 mg/kg/day thereafter. There was a modest clinical improvement though this only reached statistical significance for joint circumference at 12 and 16 weeks (P<0.05). Biochemical improvement only reached levels of statistical significance for IgM at week 16 (P<0.01). Eight out of 15 patients had discontinued the drug because of side-effects by week 12 and only three out of 15 patients showed individual improvement by week 24. Some biochemical parameters (ESR) worsened. These results suggest only modest clinical efficacy and use of the drug in rheumatoid arthritis is likely to be curtailed by unacceptable side-effects. The improvement in biochemical variables that occurs when the drug is used in psoriatic arthritis does not occur in rheumatoid arthritis.     

Corticosteroids in rheumatoid arthritis

This report has presented evidence to support a disease-modifying role for corticosteroids in rheumatoid arthritis. It would appear that the efficacy of these agents in retarding the destructive course of rheumatoid disease has been substantially underestimated. Consideration for more liberal use of corticosteroids in the management of rheumatoid arthritis is warranted. Further study on new approaches to corticosteroid delivery is proposed.     

A comparison of prednisolone with azathioprine and prednisolone with intramuscular gold in rheumatoid arthritis

Summary Pulse prednisolone hemisuccinate therapy (500 mg given intravenously on three occasions over two weeks) has been combined with either intramuscular sodium aurothiomalate or azathioprine in an assessment of 30 patients with rheumatoid arthritis. Significant improvement in a variety of clinical and biochemical assessments was seen in both groups. Both treatments were well tolerated by the patients and prednisolone appeared to accelerate the response to sodium aurothiomalate and azathioprine but there was no great evidence that it enhanced it.     

Siebrandus Sixtius: evidence of rheumatoid arthritis of the robust reaction type in a seventeenth century Dutch priest.

Rheumatoid arthritis of the robust reaction type has been diagnosed in a seventeenth century Dutch priest, Siebrandus Sixtius, based on pictorial evidence of typical hand deformities and historical evidence affirming that he had chronic nodular rheumatism for many years. This case report, in conjunction with other pictorial depictions of probable rheumatoid arthritis, questions the view that rheumatoid arthritis is a modern disease which prevailed in the New World and was found in the Old World only after the discovery of America.     

Serum histidine in rheumatoid arthritis: a family study

We have compared free serum histidine in patients with rheumatoid arthritis, their blood relatives, and their non-blood relatives. The hypohistidinaemia of rheumatoid arthritis is acquired with the disease and does not provide a biochemical marker of those at risk.     

The evaluation of bone changes in patients with rheumatoid arthritis

Some biochemical and radiological parameters of bone loss associated with rheumatoid arthritis were compared with changes observed in patients suffering from osteoarthrosis. In patients with rheumatoid arthritis increased elimination of hydroxyproline correlated with hypercalciuria and elevated total serum alkaline phosphatase were found. It is suggested that in cases where special methods of assessment of bone changes are not available these biochemical values could serve as satisfactory screening method for detection of bone loss.     

Diffuse large-cell lymphoma of B-cell origin and deficient T-cell function in a patient with rheumatoid arthritis

An increased incidence of non-Hodgkin's lymphoma has been described in patients with rheumatoid arthritis. Mechanisms related to abnormal immune regulation have been postulated, but no patients with rheumatoid arthritis and lymphoma have been previously well characterized immunologically. We describe here a patient with long-standing rheumatoid arthritis in whom a B-cell diffuse large-cell lymphoma developed. He was found to have a severe T-cell immunodeficiency and evidence of persistent Epstein-Barr virus infection. Epstein-Barr nuclear antigen was not found to be present within lymphoma cells. The combination of defective T-cell function and persistent Epstein-Barr virus infection may have predisposed this patient with rheumatoid arthritis to the development of a malignant clone of B lymphocytes.     

Aetiology of rheumatoid arthritis: an attempt to transmit an infective agent from patients with rheumatoid arthritis to baboons.

Thirty baboons were injected intravenously and intra-articularly with material from the joints of 19 patients with active rheumatoid arthritis or with control material. Fifteen of the 30 animals received synovial fluid cells or synovial membrane cells from 3 patients with seronegative arthritis. Ten animals received pooled cells from a total of 16 cases of seropositive arthritis. Five animals were given nonrheumatoid cells. No signs of arthritis were recognised in the 27 surviving animals during 3 years of observation. No significant biochemical, haematological, or serological changes occurred during this period, and no gross or microscopic evidence of synovial or systemic disease was found post mortem.     

Studies on the frequency and pathogenesis of liver involvement in rheumatoid arthritis.

A systematic prospective survey of 100 outpatients with rheumatoid arthritis revealed that 45 had biochemical evidence of liver disease. In most cases this was due to increases in total serum alkaline phosphatase (ALP) and/or gammaglutamyl transpeptidase (GGT). Examination of serum ALP isoenzyme profiles in 50 of the patients showed that the liver isoenzyme was the sole or major component in 44 patients, including many with normal total ALP levels. 18% had raised serum liver ALP together with raised GGT, suggestive of an underlying hepatobiliary lesion. No correlation could be detected between raised serum levels of liver enzymes and the age or sex of the patient, duration or severity of arthritis, and drug or alcohol history. However, there was a significant correlation between raised serum ALP and lacrimal or salivary gland dysfunction. It is suggested that immunological mechanisms may be involved in the development of hepatic abnormalities in rheumatoid arthritis.     

End-stage liver disease developing with the use of methotrexate in heterozygous α1-antitrypsin deficiency

We report a case of cirrhosis developing in a man who was heterozygous for α₁-antitrypsin deficiency and who was receiving methotrexate for severe rheumatoid arthritis. The α₁-antitrypsin phenotype PiMZ has been associated with cryptogenic cirrhosis. Our patient had no biochemical or histologic evidence of chronic liver disease during the first year of receiving methotrexate. We postulate that the PiMZ state may result in enhanced susceptibility to methotrexate-induced hepatic toxicity and should be screened for if liver function abnormalities occur during methotrexate therapy.     

Actin cytoskeleton dynamics linked to synovial fibroblast activation as a novel pathogenic principle in TNF-driven arthritis

Rheumatoid arthritis is a chronic inflammatory disorder whose origin of defect has been the subject of extensive research during the past few decades. While a number of immune and non-immune cell types participate in the development of chronic destructive inflammation in the arthritic joint, synovial fibroblasts have emerged as key effector cells capable of modulating both joint destruction and propagation of inflammation. Ample evidence of aberrant changes in the morphology and biochemical behaviour of rheumatoid arthritis synovial fibroblasts have established the tissue evading and "transformed" character of this cell type. We have recently demonstrated that actin cytoskeletal rearrangements determine the pathogenic activation of synovial fibroblasts in modelled TNF-mediated arthritis, a finding correlating with similar gene expression changes which we observed in human rheumatoid arthritis synovial fibroblasts. Here, we show that pharmacological inhibition of actin cytoskeleton dynamics alters potential pathogenic properties of the arthritogenic synovial fibroblast, such as proliferation, migration and resistance to apoptosis, indicating novel opportunities for therapeutic intervention in arthritis. Recent advances in this field of research are reviewed and discussed.     

Psychogenesis of rheumatoid arthritis--what do we really know?

Empirical studies concerning the psychogenesis of rheumatoid arthritis are critically reviewed. Alexander's thesis that patients' suppressed aggressive impulses lead to increased muscle tension and hence to articular lesions has not thus far been given sufficient empirical support; there is not much evidence that people with rheumatoid arthritis show specific personality features, either. Human studies have not yet clearly demonstrated a connection between stressful life events and the onset or exacerbation of the disease; animal studies, in which the influence of stress on the development of rheumatoid symptoms was examined experimentally, have not yielded unambiguous results. However, these somewhat disappointing findings should not lead to the premature conclusion that psychological factors play no part in the development of rheumatoid arthritis.     

Absence of Rheumatoid Arthritis in Schizophrenia*

Summary: Middle-aged women with a substantiated diagnosis of schizophrenia from Victorian Psychiatric Hospitals were examined for clinical, radiological and serological evidence of rheumatoid arthritis. Clinical or radiological evidence of rheumatoid arthritis was detected in none of the 301 patients studied, where-as the expected prevalences would be 7.7%; this difference is highly significant (p < 0.001). On the other hand, the prevalence of serologically demonstrable rheumatoid factor in the women with schizophrenia was similar to that in subnormal women in hospital under the same conditions and in women from a normal Australian population. The demonstrable polarity of schizophrenia and clinical rheumatoid arthritis in women might be explained either on a genetic basis or through the “protective” effects of one disease, schizophrenia, on the occurrence of the other, rheumatoid arthritis.