SULPHOXIDATION ABILITY AND THIOL STATUS IN RHEUMATOID ARTHRITIS PATIENTS

EDITORIAL 7. 8. 9. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. assays using affinity purified antigens. Arthritis Rheum 1983;26:146-55. Emlen W, Pisetsky DS, Taylor RP. Antibodies to DNA: a perspective. Arthritis Rheum 1986;29:1417-26. Shoenfeld Y, Rauch J, Massicotte H, et al. Polyspecificity of monoclonal lupus antibodies produced by human-human hybridomas. NEngUMed 1983;3O8:414-20. Harris EN, Gharavi AE, Tincani A, et al. Affinity purified anti-cardiolipin and antiDNA antibodies. / Clin Lab Immunol 1985; 17:155-62. Isenberg D, Feldman R, Dudeney C, et al. A study of antipolynucleotide antibodies, antiKlebsiella (K30) antibodies and anti-DNA antibody idiotypes in ankylosing spondylitis. Br J Rheumatol 1987;26:168-171. Naparstek Y, Duggan D, Schattner A, et al. Immunochemical similarities between monoclonal antibacterial Waldenstrom's macroglobulins and monoclonal anti-DNA lupus antibodies. J Exp Med \99,5\\6\: 152538. Isenberg DA, Shoenfeld Y, Madaio MP, et al. Anti-DNA antibody idiotypes in systemic lupus erythematosus. Lancet 1984;ii:417-22. El-Roiey A, Sela I, Isenberg DA, et al. The sera of patients with Klebsiella infections contain a common anti-DNA idiotype (16/6) and anti-polynucleotide activity. Clin Exp Immunol 1987;67:507-15. Radoux V, Chen PP, Sorge JA, Carson DA. A conserved human germline Vk-gene directly encodes rheumatoid factor light chains. J Exp Med 1986;164:2119-24. Cairns E, Block J, Bell DA. Anti-DNA autoantibody-producing hybridomas of normal human lymphoid cell origin. J Clin Invest 1984;74:880-7. Reuter R, Luhrmann R. Immunization of mice with purified Ul small nuclear ribonucleoprotein induces a pattern-of antibody specificities characteristic of the anti-Sm and anti-RNP autoimmune responses of patients with lupus erythematosus, as measured by monoclonal antibodies. Proc Nail Acad Set 1986;83:8689-93. SULPHOXIDATION ABILITY AND THIOL STATUS IN RHEUMATOID ARTHRITIS PATIENTS IT has been known for some time that polymorphisms exist in some metabolic pathways. Furthermore adverse reactions to certain drugs occur predominantly in the minority of individuals who are poor metabolizers of these drugs. As a consequence the risk of side-effects may be predicted from knowledge of patients' metabolic status. For example, by using a compound such as debrisoquine as a probe-drug the hydroxylation status can be determined. If impaired, there is an increased risk of toxicity with drugs such as phenformin or perhexilinc which are metabo- 10. antibodies in patients with systemic vasculitis. Lancet 1987;i:716-20. Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986;13:486-9. Blatt PM, Martin SE. The lupus anticoagulant. Arch Palhol Lab Med 1987;111:113—14. Mathews MB, Bernstein RM. Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity. Nature 1983;3O4: 177-9. Mathews MB, Bernstein RM, Franza Jr BR, Garrels JI. Identity of the proliferating cell nuclear antigen and cyclin. Nature 1984;309: 374-6. Rinke J, Steitz JA. Precursor molecules of both human 5S ribosomal RNA and transfer RNAs are bound by a cellular protein reactive with anti-La lupus antibodies. Cell 1982; 29:149-59. Lerner MR, Steitz JA. Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc Natl Acad Set USA 1979;76:5495-9. Lerner MR, Steitz J A. Snurps and scyrps. Cell 1981;25:298-3O0. Billings PB, Hoch SO, White PJ, Carson DA, Vaughan JH. Antibodies to the EpsteinBarr virus nuclear antigen and to rheumatoid arthritis nuclear antigen identify the same polypeptide. Proc Nail Acad Sci USA 1983;80:7104-8. Sculley TB, Pope JH, Hazelton RA. Correlation between the presence of antibodies to the Epstein-Barr virus nuclear antigen type 2 and antibodies to the rheumatoid arthritis nuclear antigen in patients with rheumatoid arthritis. Arthritis Rheum 1986;29:964-70. Tipping PG, Dimech WJ, Littlejohn GO, Holdsworth SR. Comparison of immunofluorescence and immunoperoxidase for demonstration of anti-nuclear antibodies on HEp-2 substrate. Br J Rheumatol 1987;26: 188-92. Venables PJW, Charles PJ, Buchanan RRC, et al. Quantitation and detection of isotypes of anti-SS-B antibodies by ELISA and Farr 163 164 BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXVI NO. 3 might act in the reverse direction (vide infra). Sequential measurements of sulphoxidation ability in patients on various medications and with fluctuating disease activity are required before this test can acquire practical value. It has been reported that myasthenia gravis induced by D-penicillamine occurs exclusively in individuals who exhibit poor sulphoxidization [9], exemplifying the need for such data. In all three studies [5-7] the prevalence of poor sulphoxidizers was higher in patients with rheumatoid arthritis than had been previously noted in healthy individuals, raising the possibility that poor sulphoxidation may have a role in the pathogenesis of this disease. In support of the general concept is the observation that there is an increase of poor hydroxylation phenotype in systemic lupus erythematosus [10]. However, the prevalence of poor sulphoxidation in a group of patients with rheumatoid arthritis was not significantly different from that of a group of patients with osteoarthritis, matched for age and drug therapy (unpublished observations). A second article in this journal [11] documents the change in 'thiol status' of patients with rheumatoid arthritis undergoing treatment with sulphasalazine, a disease-modifying drug which does not possess a thiol group. It was demonstrated that, as the disease activity of patients improved, the changes in thiol status were the same as those observed with other disease-modifying drugs. Thus, changes in thiol status do not merely reflect therapy with a thiol-containing drug but rather are related to changes in disease state. It is appropriate to note, therefore, that the possession of a thiol group is not a prerequisite for a drug to possess a (noncytotoxic) disease-modifying action, and, as has been recently shown for methylcysteine, is alone insufficient for this action [12]. The thiol status of patients with rheumatoid arthritis is complex both in assessment and comprehension. A particular difficulty is the relationship, confirmed in this paper [11], between plasma thiol levels, which are low in active disease and rise as the disease remits, and the intracellular thiol levels, which are increased in active disease. Whether any or all the alteration in thiol status after drug treatment is primary or secondary remains unknown [13]. There is also evidence that in rheumatoid disease there is an uncoupling of the normal association between intracellular thiol levels and superoxide dismutase activity [11]. Accentuation of this deviation from normal occurs after initiation of treatment with a lized by hydroxylation [1,2]. Similarly, poor acety (...truncated)