Abstract
OBJECTIVE--To study the effects of sulphasalazine (SASP) on the systemic and mucosal humoral immune systems in patients with rheumatoid arthritis (RA). METHODS--Serum concentrations of interleukin 6 (IL-6), class and subclass specific IgG, IgA and IgM, IgA and IgG antigliadin antibodies and rheumatoid factors (RF) of IgG, IgA (including IgA1 and IgA2 subclasses) and IgM isotypes were measured before and 16 weeks after sulphasalazine (SASP) therapy in 15 female and three male patients with RA. Amounts of immunoglobulins in saliva and jejunal fluid were measured as estimates of mucosal humoral immunity. RESULTS--Serum concentrations of IgA and IgG decreased significantly during SASP therapy and correlated with reduced concentrations of IL-6. In addition, levels of circulating IgA RF, IgA anti-gliadin antibodies and IgM RF decreased significantly after the treatment. In contrast, immunoglobulin levels in saliva and jejunal fluid were unaltered. CONCLUSION--SASP exerts powerful but selective inhibitory effects on systemic immunoglobulin production, whereas no effects on mucosal immunoglobulin production were observed. The decreased systemic B cell activity may be mediated by downregulation of the production of IL-6, a cytokine with Ig switching properties.
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Selected References
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- Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
- Alarcón G. S., Schrohenloher R. E., Bartolucci A. A., Ward J. R., Williams H. J., Koopman W. J. Suppression of rheumatoid factor production by methotrexate in patients with rheumatoid arthritis. Evidence for differential influences of therapy and clinical status on IgM and IgA rheumatoid factor expression. Arthritis Rheum. 1990 Aug;33(8):1156–1161. doi: 10.1002/art.1780330816. [DOI] [PubMed] [Google Scholar]
- Bird H. A., Dixon J. S., Pickup M. E., Rhind V. M., Lowe J. R., Lee M. R., Wright V. A biochemical assessment of sulphasalazine in rheumatoid arthritis. J Rheumatol. 1982 Jan-Feb;9(1):36–45. [PubMed] [Google Scholar]
- Bjarnason I., Hopkinson N., Zanelli G., Prouse P., Smethurst P., Gumpel J. M., Levi A. J. Treatment of non-steroidal anti-inflammatory drug induced enteropathy. Gut. 1990 Jul;31(7):777–780. doi: 10.1136/gut.31.7.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bluestone R., Goldberg L. S. Effect of D-penicillamine on serum immunoglobulins and rheumatoid factor. Ann Rheum Dis. 1973 Jan;32(1):50–52. doi: 10.1136/ard.32.1.50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brandtzaeg P., Halstensen T. S., Kett K., Krajci P., Kvale D., Rognum T. O., Scott H., Sollid L. M. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology. 1989 Dec;97(6):1562–1584. doi: 10.1016/0016-5085(89)90406-x. [DOI] [PubMed] [Google Scholar]
- Chalmers I. M., Sitar D. S., Hunter T. A one-year, open, prospective study of sulfasalazine in the treatment of rheumatoid arthritis: adverse reactions and clinical response in relation to laboratory variables, drug and metabolite serum levels, and acetylator status. J Rheumatol. 1990 Jun;17(6):764–770. [PubMed] [Google Scholar]
- Claman H. N., Merrill D. Serum immunoglobulins in rheumatoid arthritis. J Lab Clin Med. 1966 May;67(5):850–854. [PubMed] [Google Scholar]
- Colombel J. F., Mascart-Lemone F., Nemeth J., Vaerman J. P., Dive C., Rambaud J. C. Jejunal immunoglobulin and antigliadin antibody secretion in adult coeliac disease. Gut. 1990 Dec;31(12):1345–1349. doi: 10.1136/gut.31.12.1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Comer S. S., Jasin H. E. In vitro immunomodulatory effects of sulfasalazine and its metabolites. J Rheumatol. 1988 Apr;15(4):580–586. [PubMed] [Google Scholar]
- Corkill M. M., Jobanputra P., Gibson T., Macfarlane D. G. A controlled trial of sulphasalazine treatment of chronic ankylosing spondylitis: failure to demonstrate a clinical effect. Br J Rheumatol. 1990 Feb;29(1):41–45. doi: 10.1093/rheumatology/29.1.41. [DOI] [PubMed] [Google Scholar]
- Cowling P., Ebringer R., Ebringer A. Association of inflammation with raised serum IgA in ankylosing spondylitis. Ann Rheum Dis. 1980 Dec;39(6):545–549. doi: 10.1136/ard.39.6.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crabbé P. A., Heremans J. F. The distribution of immunoglobulin-containing cells along the human gastrointestinal tract. Gastroenterology. 1966 Sep;51(3):305–316. [PubMed] [Google Scholar]
- Davis M. J., Dawes P. T., Beswick E., Lewin I. V., Stanworth D. R. Sulphasalazine therapy in ankylosing spondylitis: its effect on disease activity, immunoglobulin A and the complex immunoglobulin A-alpha-1-antitrypsin. Br J Rheumatol. 1989 Oct;28(5):410–413. doi: 10.1093/rheumatology/28.5.410. [DOI] [PubMed] [Google Scholar]
- Delacroix D. L., Dive C., Rambaud J. C., Vaerman J. P. IgA subclasses in various secretions and in serum. Immunology. 1982 Oct;47(2):383–385. [PMC free article] [PubMed] [Google Scholar]
- Delamere J. P., Farr M., Grindulis K. A. Sulphasalazine induced selective IgA deficiency in rheumatoid arthritis. Br Med J (Clin Res Ed) 1983 May 14;286(6377):1547–1548. doi: 10.1136/bmj.286.6377.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dougados M., Boumier P., Amor B. Sulphasalazine in ankylosing spondylitis: a double blind controlled study in 60 patients. Br Med J (Clin Res Ed) 1986 Oct 11;293(6552):911–914. doi: 10.1136/bmj.293.6552.911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Elkon K. B., Gharavi A. E., Patel B. M., Hughes G. R., Frankel A. IgA and IgM rheumatoid factors in serum, saliva and other secretions: relationship to immunoglobulin ratios in systemic sicca syndrome and rheumatoid arthritis. Clin Exp Immunol. 1983 Apr;52(1):75–84. [PMC free article] [PubMed] [Google Scholar]
- Engström P. E., Sundin U., Lavö B., Norhagen G., Hällgren R., Smith C. I., Hammarström L. Class and subclass-associated specificity differences of anti-gliadin antibodies from mucosa and serum. Immunology. 1992 Dec;77(4):604–608. [PMC free article] [PubMed] [Google Scholar]
- Engvall E., Perlmann P. Enzyme-linked immunosorbent assay, Elisa. 3. Quantitation of specific antibodies by enzyme-labeled anti-immunoglobulin in antigen-coated tubes. J Immunol. 1972 Jul;109(1):129–135. [PubMed] [Google Scholar]
- Farr M., Kitas G. D., Tunn E. J., Bacon P. A. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. Br J Rheumatol. 1991 Dec;30(6):413–417. doi: 10.1093/rheumatology/30.6.413. [DOI] [PubMed] [Google Scholar]
- Feltelius N., Gudmundsson S., Wennersten L., Sjöberg O., Hällgren R., Klareskog L. Enumeration of IgA producing cells by the enzyme linked immunospot (ELISPOT) technique to evaluate sulphasalazine effects in inflammatory arthritides. Ann Rheum Dis. 1991 Jun;50(6):369–371. doi: 10.1136/ard.50.6.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feltelius N., Hällgren R., Sjöberg O. T lymphocytes in ankylosing spondylitis and the influence of sulphasalazine treatment. Clin Rheumatol. 1987 Dec;6(4):545–552. doi: 10.1007/BF02330592. [DOI] [PubMed] [Google Scholar]
- Grodzinsky E., Hed J., Liedén G., Sjögren F., Ström M. Presence of IgA and IgG antigliadin antibodies in healthy adults as measured by micro-ELISA. Effect of various cutoff levels on specificity and sensitivity when diagnosing coeliac disease. Int Arch Allergy Appl Immunol. 1990;92(2):119–123. doi: 10.1159/000235201. [DOI] [PubMed] [Google Scholar]
- Haneberg B., Aarskog D. Human faecal immunoglobulins in healthy infants and children, and in some with diseases affecting the intestinal tract or the immune system. Clin Exp Immunol. 1975 Nov;22(2):210–222. [PMC free article] [PubMed] [Google Scholar]
- Hanly J. G., Hassan J., Whelan A., Feighery C., Bresnihan B. Effects of gold therapy on the synthesis and quantity of serum and synovial fluid IgM, IgG, and IgA rheumatoid factors in rheumatoid arthritis patients. Arthritis Rheum. 1986 Apr;29(4):480–487. doi: 10.1002/art.1780290404. [DOI] [PubMed] [Google Scholar]
- Helle M., Boeije L., Aarden L. A. Functional discrimination between interleukin 6 and interleukin 1. Eur J Immunol. 1988 Oct;18(10):1535–1540. doi: 10.1002/eji.1830181010. [DOI] [PubMed] [Google Scholar]
- Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6;324(6092):73–76. doi: 10.1038/324073a0. [DOI] [PubMed] [Google Scholar]
- Hirsch H. Z., Tarkowski A., Koopman W. J., Mestecky J. Local production of IgA- and IgM-rheumatoid factors in adult periodontal disease. J Clin Immunol. 1989 Jul;9(4):273–278. doi: 10.1007/BF00918658. [DOI] [PubMed] [Google Scholar]
- Imai F., Suzuki T., Ishibashi T., Dohi Y. Effect of sulfasalazine on B cells. Clin Exp Rheumatol. 1991 May-Jun;9(3):259–264. [PubMed] [Google Scholar]
- Jonard P. P., Rambaud J. C., Dive C., Vaerman J. P., Galian A., Delacroix D. L. Secretion of immunoglobulins and plasma proteins from the jejunal mucosa. Transport rate and origin of polymeric immunoglobulin A. J Clin Invest. 1984 Aug;74(2):525–535. doi: 10.1172/JCI111450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kanerud L., Hafström I., Berg A. Effects of antirheumatic treatment on gastric secretory function and salivary flow in patients with rheumatoid arthritis. Clin Exp Rheumatol. 1991 Nov-Dec;9(6):595–601. [PubMed] [Google Scholar]
- Kanerud L., Hafström I., Ringertz B. Effect of sulphasalazine and sulphapyridine on neutrophil superoxide production: role of cytosolic free calcium. Ann Rheum Dis. 1990 May;49(5):296–300. doi: 10.1136/ard.49.5.296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kanerud L., Scheynius A., Hafström I. Evidence of a local intestinal immunomodulatory effect of sulfasalazine in rheumatoid arthritis. Arthritis Rheum. 1994 Aug;37(8):1138–1145. doi: 10.1002/art.1780370805. [DOI] [PubMed] [Google Scholar]
- Kanerud L., Scheynius A., Nord C. E., Hafström I. Effect of sulphasalazine on gastrointestinal microflora and on mucosal heat shock protein expression in patients with rheumatoid arthritis. Br J Rheumatol. 1994 Nov;33(11):1039–1048. doi: 10.1093/rheumatology/33.11.1039. [DOI] [PubMed] [Google Scholar]
- Komatsubara Y., Hiramatsu S., Hongo I., Maeda A., Soda T. Multi-variate analysis of serum protein rheumatoid arthritis. Scand J Rheumatol. 1976;5(2):97–102. doi: 10.3109/03009747609099898. [DOI] [PubMed] [Google Scholar]
- Koopman W. J., Schrohenloher R. E., Crago S. S., Spalding D. M., Mestecky J. IgA rheumatoid factor synthesis by dissociated synovial cells. Characterization and relationship to IgM rheumatoid factor synthesis. Arthritis Rheum. 1985 Nov;28(11):1219–1227. doi: 10.1002/art.1780281105. [DOI] [PubMed] [Google Scholar]
- Kutteh W. H., Prince S. J., Mestecky J. Tissue origins of human polymeric and monomeric IgA. J Immunol. 1982 Feb;128(2):990–995. [PubMed] [Google Scholar]
- Leickly F. E., Buckley R. H. Development of IgA and IgG2 subclass deficiency after sulfasalazine therapy. J Pediatr. 1986 Mar;108(3):481–482. doi: 10.1016/s0022-3476(86)80907-6. [DOI] [PubMed] [Google Scholar]
- Lúthvíksson B. R., Jónsson T., Erlendsson K., Sigfússon A. Disease manifestations in patients with isolated elevation of IgA rheumatoid factor. Scand J Rheumatol. 1992;21(1):1–4. doi: 10.3109/03009749209095053. [DOI] [PubMed] [Google Scholar]
- Mestecky J., McGhee J. R., Arnold R. R., Michalek S. M., Prince S. J., Babb J. L. Selective induction of an immune response in human external secretions by ingestion of bacterial antigen. J Clin Invest. 1978 Mar;61(3):731–737. doi: 10.1172/JCI108986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol. 1987 Jul;7(4):265–276. doi: 10.1007/BF00915547. [DOI] [PubMed] [Google Scholar]
- Nissilä M., Lehtinen K., Leirisalo-Repo M., Luukkainen R., Mutru O., Yli-Kerttula U. Sulfasalazine in the treatment of ankylosing spondylitis. A twenty-six-week, placebo-controlled clinical trial. Arthritis Rheum. 1988 Sep;31(9):1111–1116. doi: 10.1002/art.1780310905. [DOI] [PubMed] [Google Scholar]
- Nuver-Zwart I. H., van Riel P. L., van de Putte L. B., Gribnau F. W. A double blind comparative study of sulphasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulphasalazine. Ann Rheum Dis. 1989 May;48(5):389–395. doi: 10.1136/ard.48.5.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Olsen N. J., Callahan L. F., Pincus T. In vitro rheumatoid factor synthesis in patients taking second-line drugs for rheumatoid arthritis. Independent associations with disease activity. Arthritis Rheum. 1988 Sep;31(9):1090–1096. doi: 10.1002/art.1780310902. [DOI] [PubMed] [Google Scholar]
- Otten H. G., Daha M. R., de Rooij H. H., Breedveld F. C. Quantitative detection of class-specific rheumatoid factors using mouse monoclonal antibodies and the biotin/streptavidin enhancement system. Br J Rheumatol. 1989 Aug;28(4):310–316. doi: 10.1093/rheumatology/28.4.310. [DOI] [PubMed] [Google Scholar]
- Ottèn H. G., Daha M. R., van Laar J. M., de Rooy H. H., Breedveld F. C. Subclass distribution and size of human IgA rheumatoid factor at mucosal and nonmucosal sites. Arthritis Rheum. 1991 Jul;34(7):831–839. doi: 10.1002/art.1780340708. [DOI] [PubMed] [Google Scholar]
- Panush R. S., Stroud R. M., Webster E. M. Food-induced (allergic) arthritis. Inflammatory arthritis exacerbated by milk. Arthritis Rheum. 1986 Feb;29(2):220–226. doi: 10.1002/art.1780290210. [DOI] [PubMed] [Google Scholar]
- Pelísková Z., Vácha J., Trnavský K. Sulphasalazine in the treatment of rheumatoid arthritis. Z Rheumatol. 1985 Nov-Dec;44(6):263–266. [PubMed] [Google Scholar]
- Pillemer S. R., Reynolds W. J., Yoon S. J., Perera M., Newkirk M., Klein M. IgA related disorders in rheumatoid arthritis. J Rheumatol. 1987 Oct;14(5):880–886. [PubMed] [Google Scholar]
- Samanta A., Webb C., Grindulis K. A., Fleming J., Sheldon P. J. Sulphasalazine therapy in rheumatoid arthritis: qualitative changes in lymphocytes and correlation with clinical response. Br J Rheumatol. 1992 Apr;31(4):259–263. doi: 10.1093/rheumatology/31.4.259. [DOI] [PubMed] [Google Scholar]
- Schrohenloher R. E., Koopman W. J., Alarcón G. S. Molecular forms of IgA rheumatoid factor in serum and synovial fluid of patients with rheumatoid arthritis. Arthritis Rheum. 1986 Oct;29(10):1194–1202. doi: 10.1002/art.1780291003. [DOI] [PubMed] [Google Scholar]
- Segal A. W., Isenberg D. A., Hajirousou V., Tolfree S., Clark J., Snaith M. L. Preliminary evidence for gut involvement in the pathogenesis of rheumatoid arthritis? Br J Rheumatol. 1986 May;25(2):162–166. doi: 10.1093/rheumatology/25.2.162. [DOI] [PubMed] [Google Scholar]
- Sheldon P., Pell P. Comparison of the effect of oral sulphasalazine, sulphapyridine and 5-amino-salicylic acid on the in vivo antibody response to oral and systemic antigen. Br J Clin Pharmacol. 1993 Mar;35(3):261–264. doi: 10.1111/j.1365-2125.1993.tb05693.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sheldon P., Webb C., Grindulis K. A. Effect of sulphasalazine and its metabolites on mitogen induced transformation of lymphocytes--clues to its clinical action? Br J Rheumatol. 1988 Oct;27(5):344–349. doi: 10.1093/rheumatology/27.5.344. [DOI] [PubMed] [Google Scholar]
- Stenson W. F., Mehta J., Spilberg I. Sulfasalazine inhibition of binding of N-formyl-methionyl-leucyl-phenylalanine (FMLP) to its receptor on human neutrophils. Biochem Pharmacol. 1984 Feb 1;33(3):407–412. doi: 10.1016/0006-2952(84)90233-8. [DOI] [PubMed] [Google Scholar]
- Symmons D. P., Salmon M., Farr M., Bacon P. A. Sulfasalazine treatment and lymphocyte function in patients with rheumatoid arthritis. J Rheumatol. 1988 Apr;15(4):575–579. [PubMed] [Google Scholar]
- Tarkowski A., Bjursten L. M., Nilsson L. A., Nygren H. False positive results in class-specific rheumatoid factor (RF) assays due to interaction between RF and Fc fragments of anti-immunoglobulin indicator reagents. J Immunol Methods. 1983 Mar 11;58(1-2):171–182. doi: 10.1016/0022-1759(83)90273-9. [DOI] [PubMed] [Google Scholar]
- Tarkowski A., Nilsson L. A. Isotype-specific measurement of rheumatoid factor with reference to clinical features of rheumatoid arthritis. J Clin Lab Immunol. 1983 Nov;12(3):129–135. [PubMed] [Google Scholar]
- Teitsson I., Withrington R. H., Seifert M. H., Valdimarsson H. Prospective study of early rheumatoid arthritis. I. Prognostic value of IgA rheumatoid factor. Ann Rheum Dis. 1984 Oct;43(5):673–678. doi: 10.1136/ard.43.5.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Trollmo C., Carlsten H., Tarkowski A. Intra-articular immunization induces strong systemic immune response in humans. Clin Exp Immunol. 1990 Nov;82(2):384–389. doi: 10.1111/j.1365-2249.1990.tb05458.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Trollmo C., Sollerman C., Carlsten H., Tarkowski A. The gut as an inductive site for synovial and extra-articular immune responses in rheumatoid arthritis. Ann Rheum Dis. 1994 Jun;53(6):377–382. doi: 10.1136/ard.53.6.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Veys E. M., Claessens H. E. Serum levels of IgG, IgM, and IgA in rheumatoid arthritis. Ann Rheum Dis. 1968 Sep;27(5):431–440. doi: 10.1136/ard.27.5.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wernick R., Merryman P., Jaffe I., Ziff M. IgG and IgM rheumatoid factors in rheumatoid arthritis. Quantitative response to penicillamine therapy and relationship to disease activity. Arthritis Rheum. 1983 May;26(5):593–598. doi: 10.1002/art.1780260503. [DOI] [PubMed] [Google Scholar]
- Westedt M. L., Daha M. R., Baldwin W. M., 3rd, Stijnen T., Cats A. Serum immune complexes containing IgA appear to predict erosive arthritis in a longitudinal study in rheumatoid arthritis. Ann Rheum Dis. 1986 Oct;45(10):809–815. doi: 10.1136/ard.45.10.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zrein M., Weiss E., Van Regenmortel M. H. Detection of rheumatoid factors of different isotypes by ELISA using biotinylated avian antibodies. Immunol Invest. 1988 May;17(3):165–181. doi: 10.3109/08820138809052958. [DOI] [PubMed] [Google Scholar]
- van Zeben D., Hazes J. M., Zwinderman A. H., Cats A., van der Voort E. A., Breedveld F. C. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis. 1992 Sep;51(9):1029–1035. doi: 10.1136/ard.51.9.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
