Abstract
Rheumatic diseases are mostly chronic in nature and often require long term drug treatment. An increasing number of disease-modifying antirheumatic drugs (DMARDs) are used earlier in the course of disease and increasingly in combination with each other. Often there is comorbidity with ensuing pharmacotherapy, especially in the elderly, and therefore the risk of unwanted drug interactions increases. Awareness of these interactions is important in order to either avoid or manage them.
Antimalarials, gold, penicillamine (D-penicillamine), sulfasalazine and azathioprine have few clinically important drug interactions. The renal excretion of the antifolate methotrexate is affected by drugs that influence kidney function. This is of particular importance in patients with compromised renal function, e.g. the elderly. Other drugs with influence on folate metabolism, such as trimethoprim, should not be given concomitantly.
Cyclosporin is an agent recently introduced in rheumatological practice, and shows a myriad of clinically significant drug interactions mainly based on interference with its metabolic degradation by cytochrome P450 3A, leading to increased or decreased blood concentrations and toxicity or lack of effect. Although most of these interactions with cyclosporin are described in organ transplant patients, they may apply to rheumatological practice as well.
Similar content being viewed by others
References
Pincus T. Long-term outcomes in rheumatoid arthritis. Br J Rheumatol 1994; 34Suppl. 2: 59–73
Borgini MJ, Pualus HE. Combination therapy. In: Brook PM, Furst DE, editors. Innovative treatment approaches for rheumatoid arthritis. Ballieres Clin Rheumatol 1995; 9: 689–710
Bannwarth B, Pehourcq F, Scaeverbeke T, et al. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet 1996; 30: 194–210
Rooney RW, Furst DE, Koehnke R, et al. Aspirin is not associated with more toxicity than other NSAIDs in patients with RA treated with methotrexate. J Rheumatol 1993; 20: 1297–302
Van de Putte, van Riel PLCM. Do disease-modifying antirheumatic drugs actually modify disease course in rheumatoid arthritis? Clin Immunother 1994; 1: 319–22
Morand EF, McCloud PI, Littlejohn GO. Life table analysis of 879 treatment episodes with slow acting antirheumatic drugs in community rheumatology practice. J Rheumatol 1992; 19: 704–8
Situnayake RD, Grindulis KA, McConkey B. Long term treatment of rheumatoid arthritis with suphasalazine, gold, or penicillamine: a comparison using life-table methods. Ann Rheum Dis 1987; 46: 177–83
Tett SE. Clinical pharmacokinetics of slow-acting antirheumatic drugs. Clin Pharmacokinet 1993; 25: 392–407
Barrera P, Boerbooms AMT, van de Putte LBA, et al. Effects of antirheumatic agents on cytokines. Semin Arthritis Rheum 1995; 25: 234–53
Seideman P, Albertoni F, Beck O, et al. Chloroquine reduces the bioavailability of methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1994; 37: 830–3
Seideman P, Kindstrom B. Pharmacokinetic interactions of penicillamine in rheumatoid arthritis. J Rheumatol 1989; 16: 473–4
Leden I. Digoxin-hydroxychloroquine interaction. Acta Med Scand 1982; 211: 411–2
Ette EI, Brown-Awala EA, Essien EE. Chloroquine elimination in humans: effect of low-dose cimetidine. J Clin Pharmacol 1987; 27: 813–6
El-Yazigi A, Wahab FA. Pharmacokinetics of azathioprine after repeated oral and single intravenous administration. J Clin Pharmacol 1993; 33: 522–6
Barrera P, Boerbooms AMTh, Janssen EM, et al. Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor α, and interleukin-6 levels in rheumatoid arthritis: longitudinal evaluation during methotrexate and azathioprine therapy. Arthritis Rheum 1993; 36: 1070–9
Zimm S, Collins JM, O’Neill D, et al. Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther 1983; 34: 810–6
Calabresi P, Chabner BA. Antineoplastic agents. In: Goodman Gilman A, Rall TW, Nies AS, et al., editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: McGraw-Hill Inc., 1993
Loadman PM, Bibby MC. Pharmacokinetic drug interactions with anticancer drugs. Clin Pharmacokinet 1994; 26: 486–500
Adkins JC, Peters DH, Markham A. Fludarabine: an update of its pharmacology and use in the treatment of haematological malignancies. Drugs 1997; 53(6): 1005–37
Jain J, McCaffrey PG, Miner Z, et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 1993; 365: 352–5
Somerville MF, Scott DGI. Neoral-new cyclosporin for old? Br J Rheumatol 1997; 36: 1113–5
Turgeon DK, Leichtman AB, Lown KS. P450 3A activity and cyclosporin dosing in kidney and heart transplant recipients. Clin Pharmacol Ther 1994; 56: 253–60
Tugwell P, Bombardier C, Gent M, et al. Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990; 335: 1051–5
Campana C, Regazzi MB, Buggia I, et al. Clinically significant drug interactions with cyclosporin. Clin Pharmacokinet 1996; 30: 141–79
Chitwood KK, Abdul-Haqq AJ, Heim-Duthoy KL. Cyclosporineamiodarone interaction. Ann Pharmacother 1993; 27: 569–71
Ducharma MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporin after administration with grapefruit juice. Clin Pharmacol Ther 1995; 57: 485–91
Grekas D, Nikolaidis P, Karamonzis M, et al. Effects of azathioprine on cyclosporin metabolism. Nephron 1992; 60: 489
Yussim A, Bar-Nathan N, Shaharabani E, et al. Gastrointestinal, hepatorenal, and neuromuscular toxicity caused by cyclosporine-colchicine interaction in renal transplantation. Transplant Proc 1994; 26: 2825–6
Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Successful therapy with danazol in refractory autoimmune thrombocytopenia associated with rheumatic diseases. Br J Rheumatol 1997; 36: 1095–9
Smith PJ, Swinburn WR, Swinson DR, et al. Influence of previous gold toxicity on subsequent development of penicillamine toxicity. BMJ 1982; 285: 595–6
Fort JG, Abruzzo JL. Nitritoid reaction following initiation of ACE inhibitors in patients with rheumatoid arthritis treated with im gold [abstract]. Arthritis Rheum 1992; 35 Suppl.: R10
Jeurissen ME, Boerbooms AM, van de Putte LB. Pancytopenia and methotrexate with trimethoprim-sulphamethoxazole [letter]. Ann Intern Med 1989; 111: 261
Ng HWK, MacFarlane AW, Graham RM, et al. Near fatal drug interactions with methotrexate given for psoriasis [letter]. BMJ 1987; 295: 752–3
Lilly MB, Omura GA. Clinical pharmacology of oral intermediate-dose methotrexate with or without probenecid. Cancer Chemother Pharmacol 1985; 15: 220–2
Morgan SL, Babott JE, Vaugh WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double blind, placebo-controlled trial. Ann Intern Med 1994; 121: 833–41
Shiroky JB, Neville C, Esdaile JM, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis: results of a randomised, double-blind, placebo-controlled trial. Arthritis Rheum 1993; 35:795–803
Bannwarth B, Labat L, Moride Y, et al. Methotrexate in rheumatoid arthritis. Drugs 1994; 47(1): 25–50
Seideman P, Albertioni F, Beck O, et al. Chloroquine reduces bioavailability of methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1994; 37: 830–3
Netter P, Bannwarth B, Pere P, et al. Clinical phannacokinetics of D-penicillamine. Clin Pharmacokinet 1987; 13: 317–33
Hoffman BF, Bigger JT. Digitalis and allied cardiac glycosides. In: Goodman Gilman A, Rall TW, Nies AS et al., editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 816
Bourge RC. Cardiac transplantation. In: Bennet JC, Plum F, editors. Cecil textbook of medicine. 20th ed. Philadelphia: WB Saunders, 1996: 365–6
Billaud EM, Guillemain R, Fortineau N, et al. Interaction between roxithromycin and cyclosporin in heart transplant patients. Clin Pharmacokinet 1990; 19: 499–502
Kessler M, Netter F, Zerrouki M. Spiramycin does not increase plasma cyclosporine concentrations in renal transplant patients. Eur J Clin Pharmacol 1988; 35: 331–2
Blocka K. Auranofin versus injectable gold: comparison of pharmacokinetic properties. Am J Med 1983; 75: 114–22
Tishler M, Caspi D, Fishel B, et al. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988; 31: 906–8
Erttmann R, Landbeck G. Effect of oral cholestyramine on the elimination of high-dose methotrexate. J Cancer Res Clin Oncol 1985; 110: 48–50
Fries J, Singh G, Lenert L, et al. Aspirin, hydroxychloroquine and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis. Arthritis Rheum 1990; 33: 1611–9
Ferraz MB, Pinheiro GRC, Helfenstein M, et al. Combination therapy with methotrexate and chloroquine in rheumatoid arthritis: a randomized, placebo-controlled trial. Scand J Rheumatol 1994; 23: 231–6
Millard RJ, McCredie S. Bladder cancer in patients on low-dose methotrexate and corticosteroids. Lancet 1994; 343: 1222–3
Ferracoli GF, Casatta L, Bartoli E, et al. Epstein-Barr virus-associated Hodgkin’s lymphoma in a rheumatoid arthritis patient treated with methotrexate and cyclosporin A. Arthritis Rheum 1995; 38: 867–8
Taggart AJ, McDermott BJ, Roberts SD. The effect of age and acetylator phenotype on the phannacokinetics of sulfasalazine in patients with rheumatoid arthritis. Clin Phannacokinet 1992; 23: 311–20
Smedegård G, Björk J. Sulphasalazine: mechanism of action in rheumatoid arthritis. Br J Rheumtol 1995; 34Suppl. 2:7–15
Bird HA. Sulphasalazine, sulphapyridine or 5-aminosalicylic acid: which is the active moiety in rheumatoid arthritis? Br J Rheumatol 1995; 34Suppl. 2: 16–9
Awni WM, Braeckman RA, Locke CS, et al. The influence of multiple oral doses of zileuton on the steady-state phannacokinetics of sulfasalazine and its metabolites, sulfapyridine and n-acetylsulfapyridine. Clin Pharmacokinet 1995; 29Suppl. 2: 98–104
Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Phannacol 1995; 39: 456–9
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Haagsma, C.J. Clinically Important Drug Interactions with Disease-Modifying Antirheumatic Drugs. Drugs & Aging 13, 281–289 (1998). https://doi.org/10.2165/00002512-199813040-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-199813040-00004