Summary
It is clear that the rate of infection is increased in most of the more serious forms of autoimmune disease and agents such as high-dose steroids and the alkylating agents increase this risk. Other agents such as MTX, CsA, LEF, AZA and the TNF antagonists do not appear to increase the risk of infection given either alone or in combination. Similarly, the risk of malignancy in certain types of autoimmune disease appears increased. However, other than the alkylating agents, none of the agents used appear to increase this risk. The more recently released agents such as CsA, LEF and the TNF antagonists need longer durations of follow-up to substantiate this, however. It is clear that, unless they are absolutely necessary, one should avoid the alkylating agents used either alone or in combination to avoid problems with infection and malignancy. In addition, the use of steroids should be kept as low as possible to avoid infections. It is possible that the use of the more benign agents alone and in combination earlier in the disease course may help to reduce both infection and the incidence of malignancy in the long run.
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Bachman TR, Sawitzke AD, Perkins SL, Ward JH, Cannon GW (1996) Methotrexate-associated lymphoma in patients with rheumatoid arthritis. Report of two cases. Arthritis Rheum 39:325
Baltus JA, Boersma JW, Hartman AP, Vandenbroucke JP (1983) The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up. Ann Rheum Dis 42:368
Black KA, Zilko PJ, Dawkins RL, Armstrong BK, Mastalgia GL (1982) Cancer in connective tissue disease. Arthritis Rheum 25:1130
Bradley JD, Brandt KD, Katz BP (1989) Infectious complications of cyclophosphamide treatment for vasculitis. Arthritis Rheum 32:45
Bridges SL Jr, Löpez-Medez A, Han KH, Tracy IC, Alarcon GS (1991) Should methotrexate be discontinued before elective orthopedic surgery in patients with rheumatoid arthritis? J Rheumatol 18:984
Cherwinske HM, Cohn RG, Cheung P, Webster DJ, Xu YZ, Caulfield JP, Young JM, Nakano G, Ransom JT (1995) The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine synthesis. J Pharmacol Exp Ther 275:1043
Claman HN (1972) Corticosteroids and lymphoid cells. N Engl J Med 287:388
Cohen JJ (1989) Lymphocyte death induced by glucocorticoids. In: Schleimer RP, Claman HN, Oron-sky A (eds) Anti-inflammatory steroid actin: basic and clinical aspects. Academic Press, San Diego, pp 110–131
Csuka M, Carrera GF, McCarty DJ (1986) Treatment of intractable rheumatoid arthritis with combined cyclophosphamide, azathioprine, and hydroxychloroquine. A follow-up study. JAMA 255:2315
Dougados M, Combe B, Cantagrel A, Goupille P, Olive P (1999) Combination therapy in early rheumatoid arthritis: a randomized, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 58:220
Duncan SC, Winkelmann RK (1979) Cancer and scleroderma. Arch Dermatol 115:950
Ellman MH, Hanauer S, Sitran M, Cohen R (2000) Infliximab treatment for Crohn’s disease arthritis. Arthritis Rheum 43 [Suppl]: S299
Ferraccioli GF, Casatta L, Bartoli E, De Vita S, Dolcetti R, Boiocchi M, Carbone A (1995) Epstein-Barr virus-associated Hodgkin’s lymphoma in a rheumatoid arthritis patient treated with methotrexate and cyclosporine A. Arthritis Rheum 38:867
Fox RI (1998) Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol 25 [Suppl 53]: S20
Godeau B, Coutant-Perronne V, Le Thi Huong D, Guillevin L, Magadur G, De Bandt M, Dellion S, Rossert J, Rostoker G, Piette JC (1994) Pneumocystis carinii pneumonia in the course of connective tissue disease: report of 34 cases. J Rheumatol 21:246
Hakulinen T, Isomaki H, Knekt P (1985) Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med 78 [Suppl 1A]: 29
Harris NL Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 84:1361
Hazleman B (1985) Incidence of neoplasms in patients with rheumatoid arthritis exposed to different treatment regimens. Am J Med 78 [Suppl 1 A]:39
Kahl LE (1994) Herpes zoster infections in systemic lupus erythematosus: risk factors and outcome. J Rheumatol 21:84
Kahn MF, Arlet J, Block-Michel H (1979) Acute leukemia after treatment using cytotoxic agents for rheumatologic purposes. 19 cases among 2006 patients. Nouv Presse Medm 8:1393
Kamel OW, Rijn M van de, Weiss LM, Del Zoppo GJ, Hench PK, Robbins BA, Montgomery PG, Wamke RA, Dorfman RF (1993) Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 328:1317
Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R, Kimberly RP, Budman DR, Costa J, Decker JL, Chused TM (1978) Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89: 888
Lahdenne P, Honkanen V (2000) Infliximab vs etanercept in the treatment of severe juvenile chronic arthritis. Arthritis Rheum 43 [Suppl]: S381
Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, Miller FW (1991) A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 70:360
Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P (1999) Infliximab (chimeric anti-tumor necrosis factor alpha-monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomized phase III trial. Lancet 354:1932
Matteson EL, Hickey AR, Maguire L, Tilson HH, Urowitz MB (1991) Occurrence of neoplasia in patients with rheumatoid arthritis enrolled in a DMARD Registry. J Rheumatol 18:809
McCurley TL, Collins RD, Ball E, Collins RD (1990) Nodal and extranodal lymphoproliferative disorders in Sjögren’s syndrome: a clinical and immunopathologic study. Hum Pathol 21:482
Medsger TA Jr, Masi AT (1979) Epidemiology of progressive systemic sclerosis. Clin Rheum Dis 5:15
Medsger TA Jr (1985) Systemic sclerosis and malignancy — are they related? J Rheumatol 12:1041
Miller ML, Morton GI, Anderson LG (2000) One year community-based experience with leflunomide in the treatment of rheumatoid arthritis. Arthritis Rheum 43 [Suppl]: S343
Mitchell DM, Spitz PW, Young DY, Bloch DA, McShane DJ, Fries JF (1986) Survival, prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum 29:706
Penn I, Halgrimson CG, Starzl TE (1971) De novo malignant tumors in organ transplant recipients. Transplant Proc 3:773
Perez HD, Andron RI, Goldstein IM (1979) Infection in patients with systemic lupus erythematosus. Association with a serum inhibitor of complement-derived chemotactic activity. Arthritis Rheum 22:1326
Perhala RS, Wilke WS, Clough JD, Segal AM (1991) Local infectious complications following large joint replacement in rheumatoid arthritis patients treated with methotrexate versus those not treated with methotrexate. Arthritis Rheum 34:146
Pettersson T, Pukkala E, Teppo L, Friman C (1992) Increased risk of cancer in patients with systemic lupus erythematosus. Ann Rheum Dis 51:437
Pillemer SR, Webb D, Yocum D (1989) Legionnaires disease in a patient with rheumatoid arthritis treated with cyclosporine. J Rheumatol 16:117
Pinals RS (1976) Azathioprine in the treatment of chronic polyarthritis: long-term results and adverse effects in 25 patients. J Rheumatol 3:140
Renier JC, Bregeon C, Bonnette C (1978) The evolution of patients with rheumatoid arthritis receiving immunosuppressors between 1965 and 1973. Rev Rhum Mai Osteoartic 45:453
Reveille JD, Bartolucci A, Alarcon GS (1990) Prognosis in systemic lupus erythematosus. Negative impact of increasing age at onset, black race, and thrombocytopenia, as well as causes of death. Arthritis Rheum 33:37
Roumm AD, Medsger TA Jr (1985) Cancer and systemic sclerosis. Arthritis Rheum 28:1336
Sakon M, Monden M, Fujimoto Y, Nakano H, Tane S, Ogawa M, Mori T, Okada N, Okamura J (1989) Gastric carcinoma associated with dermatomyositis. Acta Chir Scand 155:365
Sany J, Anaya J-M, Canovas F, Combe B, Jorgensen C, Saker S, Thaury MN, Gavroy JP (1993) Influence of methotrexate on the frequency of postoperative infectious complications in patients with rheumatoid arthritis. J Rheumatol 20:1129
Schleimer RP, Freeland HS, Peters SP, Brown KE, Ders CP (1989) An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelial cells and formation of leukotriene B4 by purified human neutrophils. J Pharmacol Exp Ther 250:598
Sigal NH, Dumont FJ (1992) Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol 10:519
Sigurgeirsson B, Lindelof B, Edhag O, Allander E (1992) Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med 326:363
Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, Loew-Friedrich I, Old C, Rosenburg E (1999) Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double blind, randomized, multicentre trial. Lancet 353:259
Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, Fox R, Moreland L, Olsen N, Furst D, Caldwell J, Kaine J, Sharp J, Hurley F, Loew-Friedrich I (1999) Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med 159:2542
Stuck AE, Minder CE, Frey FJ (1989) Risk of infectious complications in patients taking glucocor-ticosteroids. Rev Infect Dis 11:954
Thorpe P, Hassall MB, York JR (1976) Rheumatoid arthritis treated with chlorambucil: a five-year follow-up. Med J Aust 2:197
Thrasher JB, Miller GJ, Wettlaufer JN (1990) Bladder leiomyosarcoma following cyclophosphamide therapy for lupus nephritis. J Urol 143:119
Tolchin SF, Winkelstein A, Rodnan GP, Pan SF, Nankin HR (1974) Chromosome abnormalities from cyclophosphamide therapy in rheumatoid arthritis and progressive systemic selerosis (scleroderma). Arthritis Rheum 17:375
Tugwell P, Pincus T, Yocum DE, Stein M, Gluck O, Kraag G, McKendry R, Tever J, Baker P, Wells G (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 333:137
Uddin J, Kraus AS, Kelly G (1970) Survivorship and death in rheumatoid arthritis. Arthritis Rheum 13:125
Van den Borne BEEM, Landewe RBM, Joukes I (1998) No increased risk of malignancies and mortality in cyclosporine A-treated patients with rheumatoid arthritis. Arthritis Rheum 41:1930
Vignon G, Bied J (1971) Comparative study of the various immunosuppressive agents in rheumatoid arthritis. Rev Rhum Mai Osteoartic 38:785
Wall RL, Clausen KP (1975) Carcinoma of the urinary bladder in patients receiving cyclophosphamide. N Engl J Med 293:271
Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KL, Fleischmann RM, Fox RI, Jackson CG, Lange M, Bürge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253
Weinblatt ME, Kremer JM, Coblyn JS, Maier AL, Helfgott SM, Morrell M, Byrne VM, Kaymakcian MV, Strand V (1999) Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 42:1322
Whitmore SE, Rosenshein NB, Provost TT (1994) Ovarian cancer in patients with dermatomyositis. Medicine 73:153
Willkens RF, Urowitz MB, Stablein DM, Mc Kendry RJ Jr, Berger RG, Box JH, Fiechtner JJ, Fudman EJ, Hudson NP, Marks CR (1992) Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 35:849
Wilske KR, Healey LA (1990) Challenging the therapeutic pyramid: a new look at treatment strategies for rheumatoid arthritis. J Rheumatol 17 [Suppl 25]:4
Wilske KR, Yocum DE (1996) Consensus Statement: RA: the status and future of combination therapy. J Rheumatol 23 [Suppl 44]: 110
Winchester RJ (1997) Systemic lupus erythematosus: pathogenesis. In: Koopman WJ (ed) Arthritis and allied conditions: a textbook of rheumatology, 13th edn. Williams and Wilkins, Baltimore, pp 1361–1391
Zittoun R, Debre P, Gardais J, Thuau FP, Renier JC, Simon F (1972) Small intestine lymphosarcoma after treatment of rheumatoid arthritis by chlorambucil. Nouv Presse Med 1:2477
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Yocum, D.E. Combination therapy: the risks of infection and tumor induction. Springer Semin Immunopathol 23, 63–72 (2001). https://doi.org/10.1007/s002810100061
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DOI: https://doi.org/10.1007/s002810100061