Semin Respir Crit Care Med 2011; 32(3): 346-370
DOI: 10.1055/s-0031-1279831
© Thieme Medical Publishers

Immunosuppressive and Cytotoxic Therapy: Pharmacology, Toxicities, and Monitoring

Tisha Wang1 , S. Sam Weigt1 , John A. Belperio1 , Joseph P. Lynch1
  • 1Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
Further Information

Publication History

Publication Date:
14 June 2011 (online)

ABSTRACT

Treatment strategies for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic AAV. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (eg, methotrexate, azathioprine, mycophenolate mofetil) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening AAV. Recent studies suggest that rituximab may be useful for induction therapy or for CYC-refractory AAV. This article reviews the key agents used to treat AAV, with a focus on pharmacology, toxicities, and monitoring.

REFERENCES

  • 1 Frankel S K, Jayne D. The pulmonary vasculitides.  Clin Chest Med. 2010;  31 (3) 519-536
  • 2 Lynch III J P, White E, Tazelaar H, Langford C A. Wegener's granulomatosis: evolving concepts in treatment.  Semin Respir Crit Care Med. 2004;  25 (5) 491-521
  • 3 Hoffman G S, Kerr G S, Leavitt R Y et al.. Wegener granulomatosis: an analysis of 158 patients.  Ann Intern Med. 1992;  116 (6) 488-498
  • 4 Jayne D, Rasmussen N, Andrassy K European Vasculitis Study Group et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.  N Engl J Med. 2003;  349 (1) 36-44
  • 5 Reinhold-Keller E, Fink C O, Herlyn K, Gross W L, De Groot K. High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate.  Arthritis Rheum. 2002;  47 (3) 326-332
  • 6 Pagnoux C, Mahr A, Hamidou M A French Vasculitis Study Group et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis.  N Engl J Med. 2008;  359 (26) 2790-2803
  • 7 Sneller M C, Hoffman G S, Talar-Williams C, Kerr G S, Hallahan C W, Fauci A S. An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone.  Arthritis Rheum. 1995;  38 (5) 608-613
  • 8 Villa-Forte A, Clark T M, Gomes M et al.. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience.  Medicine (Baltimore). 2007;  86 (5) 269-277
  • 9 Jayne D. Leflunomide versus methotrexate in Wegener's granulomatosis.  Rheumatology (Oxford). 2007;  46 (7) 1047-1048
  • 10 McDonough A K, Curtis J R, Saag K G. The epidemiology of glucocorticoid-associated adverse events.  Curr Opin Rheumatol. 2008;  20 (2) 131-137
  • 11 Stone J H, Merkel P A, Spiera R RAVE-ITN Research Group et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis.  N Engl J Med. 2010;  363 (3) 221-232
  • 12 Jones R B, Tervaert J W, Hauser T European Vasculitis Study Group et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.  N Engl J Med. 2010;  363 (3) 211-220
  • 13 Klemmer P J, Chalermskulrat W, Reif M S, Hogan S L, Henke D C, Falk R J. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis.  Am J Kidney Dis. 2003;  42 (6) 1149-1153
  • 14 Wang C C, Shiang J C, Tsai M K et al.. Prompt plasmapheresis successfully rescue pulmonary-renal syndrome caused by ANCA-negative microscopic polyangiitis.  Clin Rheumatol. 2009;  28 (12) 1457-1460
  • 15 Stone J H, Uhlfelder M L, Hellmann D B, Crook S, Bedocs N M, Hoffman G S. Etanercept combined with conventional treatment in Wegener's granulomatosis: a six-month open-label trial to evaluate safety.  Arthritis Rheum. 2001;  44 (5) 1149-1154
  • 16 Josselin L, Mahr A, Cohen P et al.. Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long-term follow-up of 15 patients.  Ann Rheum Dis. 2008;  67 (9) 1343-1346
  • 17 Martinez V, Cohen P, Pagnoux C French Vasculitis Study Group et al. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients.  Arthritis Rheum. 2008;  58 (1) 308-317
  • 18 Metzler C, Miehle N, Manger K German Network of Rheumatic Diseases et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis.  Rheumatology (Oxford). 2007;  46 (7) 1087-1091
  • 19 Metzler C, Fink C, Lamprecht P, Gross W L, Reinhold-Keller E. Maintenance of remission with leflunomide in Wegener's granulomatosis.  Rheumatology (Oxford). 2004;  43 (3) 315-320
  • 20 Ghez D, Westeel P F, Henry I, Pruna A, Fournier A, Lassoued K. Control of a relapse and induction of long-term remission of Wegener's granulomatosis by cyclosporine.  Am J Kidney Dis. 2002;  40 (2) E6
  • 21 Koening C L, Hernández-Rodríguez J, Molloy E S, Clark T M, Hoffman G S. Limited utility of rapamycin in severe, refractory Wegener's granulomatosis.  J Rheumatol. 2009;  36 (1) 116-119
  • 22 Schmitt W H, Hagen E C, Neumann I, Nowack R, Flores-Suárez L F, van der Woude F J. European Vasculitis Study Group . Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients.  Kidney Int. 2004;  65 (4) 1440-1448
  • 23 Papo T, Le Thi Huong D, Wiederkehr J L et al.. Etoposide in Wegener's granulomatosis.  Rheumatology (Oxford). 1999;  38 (5) 473-475
  • 24 Flossmann O, Jayne D R. Long-term treatment of relapsing Wegener's granulomatosis with 15-deoxyspergualin.  Rheumatology (Oxford). 2010;  49 (3) 556-562
  • 25 Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H).  Ann Rheum Dis. 2008;  67 (9) 1322-1327
  • 26 Lockwood C M, Thiru S, Stewart S et al.. Treatment of refractory Wegener's granulomatosis with humanized monoclonal antibodies.  QJM. 1996;  89 (12) 903-912
  • 27 Seror R, Pagnoux C, Ruivard M French Vasculitis Study Group et al. Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial.  Ann Rheum Dis. 2010;  69 (12) 2125-2130
  • 28 Meyer K C, Decker C, Baughman R. Toxicity and monitoring of immunosuppressive therapy used in systemic autoimmune diseases.  Clin Chest Med. 2010;  31 (3) 565-588
  • 29 Marder W, McCune W J. Advances in immunosuppressive therapy.  Semin Respir Crit Care Med. 2007;  28 (4) 398-417
  • 30 Lynch III J P, McCune W J. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders.  Am J Respir Crit Care Med. 1997;  155 (2) 395-420
  • 31 de Groot K, Harper L, Jayne D R EUVAS (European Vasculitis Study Group) et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.  Ann Intern Med. 2009;  150 (10) 670-680
  • 32 Levitt M, Warr D, Yelle L et al.. Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, and fluorouracil.  N Engl J Med. 1993;  328 (15) 1081-1084
  • 33 Hoffman G S, Leavitt R Y, Fleisher T A, Minor J R, Fauci A S. Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide.  Am J Med. 1990;  89 (4) 403-410
  • 34 Reinhold-Keller E, Kekow J, Schnabel A et al.. Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with Wegener's granulomatosis.  Arthritis Rheum. 1994;  37 (6) 919-924
  • 35 Guillevin L, Cordier J F, Lhote F et al.. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis.  Arthritis Rheum. 1997;  40 (12) 2187-2198
  • 36 de Groot K, Adu D, Savage C O. EUVAS (European vasculitis study group) . The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review.  Nephrol Dial Transplant. 2001;  16 (10) 2018-2027
  • 37 Wolverton S E, Remlinger K. Suggested guidelines for patient monitoring: hepatic and hematologic toxicity attributable to systemic dermatologic drugs.  Dermatol Clin. 2007;  25 (2) 195-205, vi–ii
  • 38 Pedersen-Bjergaard J, Ersbøll J, Sørensen H M et al.. Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin's lymphomas: comparison with results obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating agents.  Ann Intern Med. 1985;  103 (2) 195-200
  • 39 Faurschou M, Sorensen I J, Mellemkjaer L et al.. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients.  J Rheumatol. 2008;  35 (1) 100-105
  • 40 Campora E, Giudici S, Merlini L, Rubagotti A, Rosso R. Ondansetron and dexamethasone versus standard combination antiemetic therapy. A randomized trial for the prevention of acute and delayed emesis induced by cyclophosphamide-doxorubicin chemotherapy and maintenance of antiemetic effect at subsequent courses.  Am J Clin Oncol. 1994;  17 (6) 522-526
  • 41 Du L T, Rigaud D, Papo T, Godeau P. Cyclophosphamide-induced hepatitis in Wegener's granulomatosis.  Mayo Clin Proc. 1994;  69 (9) 912-913
  • 42 Snyder L S, Heigh R I, Anderson M L. Cyclophosphamide-induced hepatotoxicity in a patient with Wegener's granulomatosis.  Mayo Clin Proc. 1993;  68 (12) 1203-1204
  • 43 Malik S W, Myers J L, DeRemee R A, Specks U. Lung toxicity associated with cyclophosphamide use. Two distinct patterns.  Am J Respir Crit Care Med. 1996;  154 (6 Pt 1) 1851-1856
  • 44 Cupps T R, Silverman G J, Fauci A S. Herpes zoster in patients with treated Wegener's granulomatosis: a possible role for cyclophosphamide.  Am J Med. 1980;  69 (6) 881-885
  • 45 Huynh-Do U, Gantenbein H, Binswanger U. Pneumocystis carinii pneumonia during immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis.  Arch Intern Med. 1995;  155 (8) 872-874
  • 46 Harper L, Savage C O. ANCA-associated renal vasculitis at the end of the twentieth century—a disease of older patients.  Rheumatology (Oxford). 2005;  44 (4) 495-501
  • 47 Charlier C, Henegar C, Launay O et al.. Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients.  Ann Rheum Dis. 2009;  68 (5) 658-663
  • 48 Turnbull J, Harper L. Adverse effects of therapy for ANCA-associated vasculitis.  Best Pract Res Clin Rheumatol. 2009;  23 (3) 391-401
  • 49 Talar-Williams C, Hijazi Y M, Walther M M et al.. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis.  Ann Intern Med. 1996;  124 (5) 477-484
  • 50 Baker G L, Kahl L E, Zee B C, Stolzer B L, Agarwal A K, Medsger Jr T A. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide: long-term case-control follow-up study.  Am J Med. 1987;  83 (1) 1-9
  • 51 Pedersen-Bjergaard J, Ersbøll J, Hansen V L et al.. Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin's lymphoma.  N Engl J Med. 1988;  318 (16) 1028-1032
  • 52 Radis C D, Kahl L E, Baker G L et al.. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year followup study.  Arthritis Rheum. 1995;  38 (8) 1120-1127
  • 53 Travis L B, Curtis R E, Glimelius B et al.. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma.  J Natl Cancer Inst. 1995;  87 (7) 524-530
  • 54 Kinlen L J. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment.  Am J Med. 1985;  78 (1A) 44-49
  • 55 Baltus J A, Boersma J W, Hartman A P, Vandenbroucke J P. The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up.  Ann Rheum Dis. 1983;  42 (4) 368-373
  • 56 Schneider V, Kay S, Lee H M. Immunosuppression as a high-risk factor in the development of condyloma acuminatum and squamous neoplasia of the cervix.  Acta Cytol. 1983;  27 (3) 220-224
  • 57 Knight A, Askling J, Ekbom A. Cancer incidence in a population-based cohort of patients with Wegener's granulomatosis.  Int J Cancer. 2002;  100 (1) 82-85
  • 58 Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients.  Ann Rheum Dis. 1998;  57 (11) 682-686
  • 59 Stone J H, Holbrook J T, Marriott M A Wegener's Granulomatosis Etanercept Trial Research Group et al. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial.  Arthritis Rheum. 2006;  54 (5) 1608-1618
  • 60 Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer.  Cancer. 1977;  39 (4) 1403-1409
  • 61 Chapman R M, Sutcliffe S B. Protection of ovarian function by oral contraceptives in women receiving chemotherapy for Hodgkin's disease.  Blood. 1981;  58 (4) 849-851
  • 62 Somers E C, Marder W, Christman G M, Ognenovski V, McCune W J. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus.  Arthritis Rheum. 2005;  52 (9) 2761-2767
  • 63 Bermas B L, Hill J A. Effects of immunosuppressive drugs during pregnancy.  Arthritis Rheum. 1995;  38 (12) 1722-1732
  • 64 Hoorweg-Nijman J J, Delemarre-van de Waal H A, de Waal F C, Behrendt H. Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage.  Acta Endocrinol (Copenh). 1992;  126 (2) 143-148
  • 65 Masala A, Faedda R, Alagna S et al.. Use of testosterone to prevent cyclophosphamide-induced azoospermia.  Ann Intern Med. 1997;  126 (4) 292-295
  • 66 Dow E, Schulman H, Agura E. Cyclophosphamide cardiac injury mimicking acute myocardial infarction.  Bone Marrow Transplant. 1993;  12 (2) 169-172
  • 67 Bernatsky S, Ramsey-Goldman R, Clarke A E. Malignancies and cyclophosphamide exposure in Wegener's granulomatosis.  J Rheumatol. 2008;  35 (1) 11-13
  • 68 Israel H L, Patchefsky A S, Saldana M J. Wegener's granulomatosis, lymphomatoid granulomatosis, and benign lymphocytic angiitis and granulomatosis of lung: recognition and treatment.  Ann Intern Med. 1977;  87 (6) 691-699
  • 69 Weiner S R, Paulus H E. Treatment of Wegener's granulomatosis.  Semin Respir Med. 1989;  10 156-161
  • 70 Weinblatt M E. Methotrexate for chronic diseases in adults.  N Engl J Med. 1995;  332 (5) 330-331
  • 71 De Groot K, Rasmussen N, Bacon P A et al.. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis.  Arthritis Rheum. 2005;  52 (8) 2461-2469
  • 72 Langford C A, Talar-Williams C, Sneller M C. Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis: long-term renal outcome in patients with glomerulonephritis.  Arthritis Rheum. 2000;  43 (8) 1836-1840
  • 73 Langford C A, Sneller M C, Hoffman G S. Methotrexate use in systemic vasculitis.  Rheum Dis Clin North Am. 1997;  23 (4) 841-853
  • 74 de Groot K, Mühler M, Reinhold-Keller E, Paulsen J, Gross W L. Induction of remission in Wegener's granulomatosis with low dose methotrexate.  J Rheumatol. 1998;  25 (3) 492-495
  • 75 Langford C A, Talar-Williams C, Barron K S, Sneller M C. A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance.  Arthritis Rheum. 1999;  42 (12) 2666-2673
  • 76 Cronstein B N. Molecular mechanism of methotrexate action in inflammation.  Inflammation. 1992;  16 (5) 411-423
  • 77 de Groot K, Reinhold-Keller E, Tatsis E et al.. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener's granulomatosis: methotrexate versus trimethoprim/sulfamethoxazole.  Arthritis Rheum. 1996;  39 (12) 2052-2061
  • 78 Kinder A J, Hassell A B, Brand J, Brownfield A, Grove M, Shadforth M F. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions.  Rheumatology (Oxford). 2005;  44 (1) 61-66
  • 79 van Ede A E, Laan R F, Rood M J et al.. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study.  Arthritis Rheum. 2001;  44 (7) 1515-1524
  • 80 Morgan S L, Baggott J E, Vaughn W H et al.. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial.  Ann Intern Med. 1994;  121 (11) 833-841
  • 81 MacKinnon S K, Starkebaum G, Willkens R F. Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis.  Semin Arthritis Rheum. 1985;  15 (2) 119-126
  • 82 Thomas D R, Dover J S, Camp R D. Pancytopenia induced by the interaction between methotrexate and trimethoprim-sulfamethoxazole.  J Am Acad Dermatol. 1987;  17 (6) 1055-1056
  • 83 Whiting-O'Keefe Q E, Fye K H, Sack K D. Methotrexate and histologic hepatic abnormalities: a meta-analysis.  Am J Med. 1991;  90 (6) 711-716
  • 84 Van Dooren-Greebe R J, Kuijpers A L, Mulder J, De Boo T, Van de Kerkhof P C. Methotrexate revisited: effects of long-term treatment in psoriasis.  Br J Dermatol. 1994;  130 (2) 204-210
  • 85 Walker A M, Funch D, Dreyer N A et al.. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis.  Arthritis Rheum. 1993;  36 (3) 329-335
  • 86 Bergquist S R, Felson D T, Prashker M J, Freedberg K A. The cost-effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate.  Arthritis Rheum. 1995;  38 (3) 326-333
  • 87 Kremer J M, Alarcón G S, Lightfoot Jr R W American College of Rheumatology et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity.  Arthritis Rheum. 1994;  37 (3) 316-328
  • 88 Langford C A, Talar-Williams C, Barron K S, Sneller M C. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse.  Am J Med. 2003;  114 (6) 463-469
  • 89 Zisman D A, McCune W J, Tino G, Lynch III J P. Drug-induced pneumonitis: the role of methotrexate.  Sarcoidosis Vasc Diffuse Lung Dis. 2001;  18 (3) 243-252
  • 90 Carroll G J, Thomas R, Phatouros C C et al.. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate.  J Rheumatol. 1994;  21 (1) 51-54
  • 91 White D A, Rankin J A, Stover D E, Gellene R A, Gupta S. Methotrexate pneumonitis: bronchoalveolar lavage findings suggest an immunologic disorder.  Am Rev Respir Dis. 1989;  139 (1) 18-21
  • 92 Alarcón G S, Kremer J M, Macaluso M Methotrexate-Lung Study Group et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: a multicenter, case-control study.  Ann Intern Med. 1997;  127 (5) 356-364
  • 93 Dawson J K, Graham D R, Desmond J, Fewins H E, Lynch M P. Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests.  Rheumatology (Oxford). 2002;  41 (3) 262-267
  • 94 Kremer J M, Alarcón G S, Weinblatt M E et al.. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review.  Arthritis Rheum. 1997;  40 (10) 1829-1837
  • 95 Jones G, Mierins E, Karsh J. Methotrexate-induced asthma.  Am Rev Respir Dis. 1991;  143 (1) 179-181
  • 96 LeMense G P, Sahn S A. Opportunistic infection during treatment with low dose methotrexate.  Am J Respir Crit Care Med. 1994;  150 (1) 258-260
  • 97 Morice A H, Lai W K. Fatal varicella zoster infection in a severe steroid dependent asthmatic patient receiving methotrexate.  Thorax. 1995;  50 (11) 1221-1222
  • 98 Moder K G, Tefferi A, Cohen M D, Menke D M, Luthra H S. Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study.  Am J Med. 1995;  99 (3) 276-281
  • 99 Nyfors A, Jensen H. Frequency of malignant neoplasms in 248 long-term methotrexate-treated psoriatics: a preliminary study.  Dermatologica. 1983;  167 (5) 260-261
  • 100 Kamel O W, van de Rijn M, LeBrun D P, Weiss L M, Warnke R A, Dorfman R F. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression.  Hum Pathol. 1994;  25 (7) 638-643
  • 101 Kingsmore S F, Hall B D, Allen N B, Rice J R, Caldwell D S. Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review.  J Rheumatol. 1992;  19 (9) 1462-1465
  • 102 Shiroky J B, Frost A, Skelton J D, Haegert D G, Newkirk M M, Neville C. Complications of immunosuppression associated with weekly low dose methotrexate.  J Rheumatol. 1991;  18 (8) 1172-1175
  • 103 Hausknecht R U. Methotrexate and misoprostol to terminate early pregnancy.  N Engl J Med. 1995;  333 (9) 537-540
  • 104 Feldkamp M, Carey J C. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy.  Teratology. 1993;  47 (6) 533-539
  • 105 Kozlowski R D, Steinbrunner J V, MacKenzie A H, Clough J D, Wilke W S, Segal A M. Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease.  Am J Med. 1990;  88 (6) 589-592
  • 106 Blackburn Jr W D, Alarcón G S. Impotence in three rheumatoid arthritis patients treated with methotrexate.  Arthritis Rheum. 1989;  32 (10) 1341-1342
  • 107 Hoffman G S. “Wegener's granulomatosis”: the path traveled since 1931.  Medicine (Baltimore). 1994;  73 (6) 325-329
  • 108 Fauci A S, Haynes B F, Katz P, Wolff S M. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.  Ann Intern Med. 1983;  98 (1) 76-85
  • 109 Hellmich B, Lamprecht P, Gross W L. Advances in the therapy of Wegener's granulomatosis.  Curr Opin Rheumatol. 2006;  18 (1) 25-32
  • 110 Stolk J N, Boerbooms A M, de Abreu R A et al.. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis.  Arthritis Rheum. 1998;  41 (10) 1858-1866
  • 111 Connell W R, Kamm M A, Ritchie J K, Lennard-Jones J E. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience.  Gut. 1993;  34 (8) 1081-1085
  • 112 Present D H, Meltzer S J, Krumholz M P, Wolke A, Korelitz B I. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity.  Ann Intern Med. 1989;  111 (8) 641-649
  • 113 Singh G, Fries J F, Spitz P, Williams C A. Toxic effects of azathioprine in rheumatoid arthritis: a national post-marketing perspective.  Arthritis Rheum. 1989;  32 (7) 837-843
  • 114 Kerstens P J, Stolk J N, De Abreu R A, Lambooy L H, van de Putte L B, Boerbooms A A. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis.  Arthritis Rheum. 1995;  38 (1) 142-145
  • 115 Adler M, Delhaye M, Deprez C et al.. Hepatic vascular disease after kidney transplantation: report of two cases and review of the literature.  Nephrol Dial Transplant. 1987;  2 (3) 183-188
  • 116 Sterneck M, Wiesner R, Ascher N et al.. Azathioprine hepatotoxicity after liver transplantation.  Hepatology. 1991;  14 (5) 806-810
  • 117 Dubinsky M C, Vasiliauskas E A, Singh H et al.. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.  Gastroenterology. 2003;  125 (2) 298-303
  • 118 Refabert L, Sinnassamy P, Leroy B, Fauroux B, de Blic J, Bensman A. Azathioprine-induced pulmonary haemorrhage in a child after renal transplantation.  Pediatr Nephrol. 1995;  9 (4) 470-473
  • 119 Bottomley W W, Ford G, Cunliffe W J, Cotterill J A. Aggressive squamous cell carcinomas developing in patients receiving long-term azathioprine.  Br J Dermatol. 1995;  133 (3) 460-462
  • 120 Balachandran I, Galagan K S. Cervical carcinoma in situ associated with azathioprine therapy: a case report and literature review.  Acta Cytol. 1984;  28 (6) 699-702
  • 121 Wilkinson A H, Smith J L, Hunsicker L G et al.. Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone.  Transplantation. 1989;  47 (2) 293-296
  • 122 Silman A J, Petrie J, Hazleman B, Evans S J. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study.  Ann Rheum Dis. 1988;  47 (12) 988-992
  • 123 Tage-Jensen U, Schlichting P, Thomsen H F, Høybye G, Thomsen A C. Malignancies following long-term azathioprine treatment in chronic liver disease: a report from the Copenhagen Study Group for Liver Diseases.  Liver. 1987;  7 (2) 81-83
  • 124 Kinlen L J. Malignancy in autoimmune diseases.  J Autoimmun. 1992;  5 (suppl A) 363-371
  • 125 Connell W R, Kamm M A, Dickson M, Balkwill A M, Ritchie J K, Lennard-Jones J E. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.  Lancet. 1994;  343 (8908) 1249-1252
  • 126 Amato M P, Pracucci G, Ponziani G, Siracusa G, Fratiglioni L, Amaducci L. Long-term safety of azathioprine therapy in multiple sclerosis.  Neurology. 1993;  43 (4) 831-833
  • 127 Westman K W, Bygren P G, Olsson H, Ranstam J, Wieslander J. Relapse rate, renal survival, and cancer morbidity in patients with Wegener's granulomatosis or microscopic polyangiitis with renal involvement.  J Am Soc Nephrol. 1998;  9 (5) 842-852
  • 128 Voogd C E. Azathioprine, a genotoxic agent to be considered non-genotoxic in man.  Mutat Res. 1989;  221 (2) 133-152
  • 129 Kirk E P. Organ transplantation and pregnancy: a case report and review.  Am J Obstet Gynecol. 1991;  164 (6 Pt 1) 1629-1633, discussion 1633–1634
  • 130 DeWitte D B, Buick M K, Cyran S E, Maisels M J. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone.  J Pediatr. 1984;  105 (4) 625-628
  • 131 Nowack R, Göbel U, Klooker P, Hergesell O, Andrassy K, van der Woude F J. Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement.  J Am Soc Nephrol. 1999;  10 (9) 1965-1971
  • 132 Langford C A, Talar-Williams C, Sneller M C. Mycophenolate mofetil for remission maintenance in the treatment of Wegener's granulomatosis.  Arthritis Rheum. 2004;  51 (2) 278-283
  • 133 Iatrou C, Zerbala S, Revela I et al.. Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement.  Clin Nephrol. 2009;  72 (1) 31-37
  • 134 Joy M S, Hogan S L, Jennette J C, Falk R J, Nachman P H. A pilot study using mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis.  Nephrol Dial Transplant. 2005;  20 (12) 2725-2732
  • 135 Appel G B, Contreras G, Dooley M A Aspreva Lupus Management Study Group et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.  J Am Soc Nephrol. 2009;  20 (5) 1103-1112
  • 136 Walsh M, James M, Jayne D, Tonelli M, Manns B J, Hemmelgarn B R. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis.  Clin J Am Soc Nephrol. 2007;  2 (5) 968-975
  • 137 Knight S R, Russell N K, Barcena L, Morris P J. Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review.  Transplantation. 2009;  87 (6) 785-794
  • 138 European Mycophenolate Mofetil Cooperative Study Group . Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection.  Lancet. 1995;  345 (8961) 1321-1325
  • 139 Bove A A, Kashem A, Cross R C et al.. Factors affecting survival after heart transplantation: comparison of pre- and post-1999 listing protocols.  J Heart Lung Transplant. 2006;  25 (1) 42-47
  • 140 Kobashigawa J A, Miller L W, Russell S D Study Investigators et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report.  Am J Transplant. 2006;  6 (6) 1377-1386
  • 141 Hu W, Liu C, Xie H, Chen H, Liu Z, Li L. Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement.  Nephrol Dial Transplant. 2008;  23 (4) 1307-1312
  • 142 Hiemstra T F, Walsh M, Mahr A et al.. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.  JAMA. 2010;  304 2381-2388
  • 143 Allison A C, Eugui E M. Mycophenolate mofetil and its mechanisms of action.  Immunopharmacology. 2000;  47 (2-3) 85-118
  • 144 Contreras G, Pardo V, Leclercq B et al.. Sequential therapies for proliferative lupus nephritis.  N Engl J Med. 2004;  350 (10) 971-980
  • 145 Nogueras F, Espinosa M D, Mansilla A, Torres J T, Cabrera M A, Martín-Vivaldi R. Mycophenolate mofetil-induced neutropenia in liver transplantation.  Transplant Proc. 2005;  37 (3) 1509-1511
  • 146 Kobashigawa J A, Renlund D G, Gerosa G ERL2401 Heart Study Investigators et al. Similar efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, Myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study.  J Heart Lung Transplant. 2006;  25 (8) 935-941
  • 147 Salvadori M, Holzer H, de Mattos A ERL B301 Study Groups et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients.  Am J Transplant. 2004;  4 (2) 231-236
  • 148 Darji P, Vijayaraghavan R, Thiagarajan C M et al.. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant recipients with gastrointestinal tract disorders.  Transplant Proc. 2008;  40 (7) 2262-2267
  • 149 Oz H S, Hughes W T. Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone.  J Infect Dis. 1997;  175 (4) 901-904
  • 150 Husain S, Singh N. The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials.  Clin Infect Dis. 2002;  35 (1) 53-61
  • 151 Kaczmarek I, Bigdeli A K, Vogeser M et al.. Defining algorithms for efficient therapeutic drug monitoring of mycophenolate mofetil in heart transplant recipients.  Ther Drug Monit. 2008;  30 (4) 419-427
  • 152 McCune W J. Mycophenolate mofetil for lupus nephritis.  N Engl J Med. 2005;  353 (21) 2282-2284
  • 153 van Gelder T, Le Meur Y, Shaw L M et al.. Therapeutic drug monitoring of mycophenolate mofetil in transplantation.  Ther Drug Monit. 2006;  28 (2) 145-154
  • 154 Patel R V, Clark L N, Lebwohl M, Weinberg J M. Treatments for psoriasis and the risk of malignancy.  J Am Acad Dermatol. 2009;  60 (6) 1001-1017
  • 155 Uzel G, Orange J S, Poliak N, Marciano B E, Heller T, Holland S M. Complications of tumor necrosis factor-α blockade in chronic granulomatous disease-related colitis.  Clin Infect Dis. 2010;  51 (12) 1429-1434
  • 156 Helbling D, Breitbach T H, Krause M. Disseminated cytomegalovirus infection in Crohn's disease following anti-tumour necrosis factor therapy.  Eur J Gastroenterol Hepatol. 2002;  14 (12) 1393-1395
  • 157 Lee T W, Fedorak R N. Tumor necrosis factor-α monoclonal antibodies in the treatment of inflammatory bowel disease: clinical practice pharmacology.  Gastroenterol Clin North Am. 2010;  39 (3) 543-557
  • 158 Wallis R S, Broder M S, Wong J Y, Hanson M E, Beenhouwer D O. Granulomatous infectious diseases associated with tumor necrosis factor antagonists.  Clin Infect Dis. 2004;  38 (9) 1261-1265
  • 159 Langford C A. Biologic immunomodulatory therapies in the vasculitic diseases.  Semin Respir Crit Care Med. 2004;  25 (5) 595-607
  • 160 Taylor P C. Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases.  Curr Opin Pharmacol. 2010;  10 (3) 308-315
  • 161 Karampetsou M P, Liossis S N, Sfikakis P P. TNF-α antagonists beyond approved indications: stories of success and prospects for the future.  QJM. 2010;  103 (12) 917-928
  • 162 Sfikakis P P. The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions.  Curr Dir Autoimmun. 2010;  11 180-210
  • 163 Cantini F, Niccoli L, Salvarani C, Padula A, Olivieri I. Treatment of longstanding active giant cell arteritis with infliximab: report of four cases.  Arthritis Rheum. 2001;  44 (12) 2933-2935
  • 164 Tan A L, Holdsworth J, Pease C, Emery P, McGonagle D. Successful treatment of resistant giant cell arteritis with etanercept.  Ann Rheum Dis. 2003;  62 (4) 373-374
  • 165 Sfikakis P P, Theodossiadis P G, Katsiari C G, Kaklamanis P, Markomichelakis N N. Effect of infliximab on sight-threatening panuveitis in Behçet's disease.  Lancet. 2001;  358 (9278) 295-296
  • 166 Sari I, Birlik M, Gonen C et al.. Cytomegalovirus colitis in a patient with Behcet's disease receiving tumor necrosis factor alpha inhibitory treatment.  World J Gastroenterol. 2008;  14 (18) 2912-2914
  • 167 Arbach O, Gross W L, Gause A. Treatment of refractory Churg-Strauss-syndrome (CSS) by TNF-alpha blockade.  Immunobiology. 2002;  206 (5) 496-501
  • 168 White E S, Lynch J P. Pharmacological therapy for Wegener's granulomatosis.  Drugs. 2006;  66 (9) 1209-1228
  • 169 Mukhtyar C, Luqmani R. Current state of tumour necrosis factor alpha blockade in Wegener's granulomatosis.  Ann Rheum Dis. 2005;  64 (suppl 4) iv31-iv36
  • 170 Wegener's Granulomatosis Etanercept Trial (WGET) Research Group . Etanercept plus standard therapy for Wegener's granulomatosis.  N Engl J Med. 2005;  352 (4) 351-361
  • 171 Bartolucci P, Ramanoelina J, Cohen P et al.. Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients.  Rheumatology (Oxford). 2002;  41 (10) 1126-1132
  • 172 Booth A D, Jefferson H J, Ayliffe W, Andrews P A, Jayne D R. Safety and efficacy of TNFalpha blockade in relapsing vasculitis.  Ann Rheum Dis. 2002;  61 (6) 559
  • 173 Booth A, Harper L, Hammad T et al.. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis.  J Am Soc Nephrol. 2004;  15 (3) 717-721
  • 174 Lamprecht P, Voswinkel J, Lilienthal T et al.. Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener's granulomatosis.  Rheumatology (Oxford). 2002;  41 (11) 1303-1307
  • 175 Hermann J, Reittner P, Scarpatetti M, Graninger W. Successful treatment of meningeal involvement in Wegener's granulomatosis with infliximab.  Ann Rheum Dis. 2006;  65 (5) 691-692
  • 176 Seror R, Mahr A, Ramanoelina J, Pagnoux C, Cohen P, Guillevin L. Central nervous system involvement in Wegener granulomatosis.  Medicine (Baltimore). 2006;  85 (1) 54-65
  • 177 Cheung C M, Murray P I, Savage C O. Successful treatment of Wegener's granulomatosis associated scleritis with rituximab.  Br J Ophthalmol. 2005;  89 (11) 1542
  • 178 Dixon W G, Symmons D P, Lunt M, Watson K D, Hyrich K L, Silman A J. British Society for Rheumatology Biologics Register Control Centre Consortium . Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies.  Arthritis Rheum. 2007;  56 (9) 2896-2904
  • 179 Bongartz T, Sutton A J, Sweeting M J, Buchan I, Matteson E L, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.  JAMA. 2006;  295 (19) 2275-2285
  • 180 Dixon W G, Watson K D, Lunt M, Mercer L K, Hyrich K L, Symmons D P. British Society For Rheumatology Biologics Register Control Centre Consortium . Influence of anti-tumor necrosis factor therapy on cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy: results from the British Society for Rheumatology Biologics Register.  Arthritis Care Res (Hoboken). 2010;  62 (6) 755-763
  • 181 Ramos-Casals M, Brito-Zerón P, Muñoz S et al.. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases.  Medicine (Baltimore). 2007;  86 (4) 242-251
  • 182 Dixon W G, Hyrich K L, Watson K D, Lunt M, Symmons D P. BSRBR Control Centre Consortium . Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register.  Ann Rheum Dis. 2010;  69 (6) 1086-1091
  • 183 Utz J P, Limper A H, Kalra S et al.. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis.  Chest. 2003;  124 (1) 177-185
  • 184 Baughman R P, Drent M, Kavuru M Sarcoidosis Investigators et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.  Am J Respir Crit Care Med. 2006;  174 (7) 795-802
  • 185 Khanna D, Liebling M R, Louie J S. Etanercept ameliorates sarcoidosis arthritis and skin disease.  J Rheumatol. 2003;  30 (8) 1864-1867
  • 186 Doty J D, Mazur J E, Judson M A. Treatment of sarcoidosis with infliximab.  Chest. 2005;  127 (3) 1064-1071
  • 187 Baughman R P, Lower E E. Novel therapies for sarcoidosis.  Semin Respir Crit Care Med. 2007;  28 (1) 128-133
  • 188 Panselinas E, Rodgers J K, Judson M A. Clinical outcomes in sarcoidosis after cessation of infliximab treatment.  Respirology. 2009;  14 (4) 522-528
  • 189 Raghu G, Brown K K, Costabel U et al.. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.  Am J Respir Crit Care Med. 2008;  178 (9) 948-955
  • 190 Bargagli E, Galeazzi M, Rottoli P. Infliximab treatment in a patient with rheumatoid arthritis and pulmonary fibrosis.  Eur Respir J. 2004;  24 (4) 708
  • 191 Antoniou K M, Mamoulaki M, Malagari K et al.. Infliximab therapy in pulmonary fibrosis associated with collagen vascular disease.  Clin Exp Rheumatol. 2007;  25 (1) 23-28
  • 192 Ostör A J, Chilvers E R, Somerville M F et al.. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis.  J Rheumatol. 2006;  33 (3) 622-628
  • 193 Kramer N, Chuzhin Y, Kaufman L D, Ritter J M, Rosenstein E D. Methotrexate pneumonitis after initiation of infliximab therapy for rheumatoid arthritis.  Arthritis Rheum. 2002;  47 (6) 670-671
  • 194 Lindsay K, Melsom R, Jacob B K, Mestry N. Acute progression of interstitial lung disease: a complication of etanercept particularly in the presence of rheumatoid lung and methotrexate treatment.  Rheumatology (Oxford). 2006;  45 (8) 1048-1049
  • 195 Huggett M T, Armstrong R. Adalimumab-associated pulmonary fibrosis.  Rheumatology (Oxford). 2006;  45 (10) 1312-1313
  • 196 Schoe A, van der Laan-Baalbergen N E, Huizinga T W, Breedveld F C, van Laar J M. Pulmonary fibrosis in a patient with rheumatoid arthritis treated with adalimumab.  Arthritis Rheum. 2006;  55 (1) 157-159
  • 197 Curtis J R, Patkar N, Xie A et al.. Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists.  Arthritis Rheum. 2007;  56 (4) 1125-1133
  • 198 Keane J, Gershon S, Wise R P et al.. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.  N Engl J Med. 2001;  345 (15) 1098-1104
  • 199 Strangfeld A, Listing J, Herzer P et al.. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents.  JAMA. 2009;  301 (7) 737-744
  • 200 Esteve M, Saro C, González-Huix F, Suarez F, Forné M, Viver J M. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis.  Gut. 2004;  53 (9) 1363-1365
  • 201 Kaur N, Mahl T C. Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases.  Dig Dis Sci. 2007;  52 (6) 1481-1484
  • 202 Warris A, Bjørneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy.  N Engl J Med. 2001;  344 (14) 1099-1100
  • 203 De Rosa F G, Shaz D, Campagna A C, Dellaripa P E, Khettry U, Craven D E. Invasive pulmonary aspergillosis soon after therapy with infliximab, a tumor necrosis factor-alpha-neutralizing antibody: a possible healthcare-associated case?.  Infect Control Hosp Epidemiol. 2003;  24 (7) 477-482
  • 204 True D G, Penmetcha M, Peckham S J. Disseminated cryptococcal infection in rheumatoid arthritis treated with methotrexate and infliximab.  J Rheumatol. 2002;  29 (7) 1561-1563
  • 205 Galandiuk S, Davis B R. Infliximab-induced disseminated histoplasmosis in a patient with Crohn's disease.  Nat Clin Pract Gastroenterol Hepatol. 2008;  5 (5) 283-287
  • 206 Williams G, Khan A A, Schweiger F. Listeria meningitis complicating infliximab treatment for Crohn's disease.  Can J Infect Dis Med Microbiol. 2005;  16 (5) 289-292
  • 207 Martin-Mola E, Balsa A. Infectious complications of biologic agents.  Rheum Dis Clin North Am. 2009;  35 (1) 183-199
  • 208 Vassilopoulos D, Apostolopoulou A, Hadziyannis E et al.. Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.  Ann Rheum Dis. 2010;  69 (7) 1352-1355
  • 209 Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation.  Arthritis Rheum. 2007;  56 (5) 1433-1439
  • 210 Askling J, Bongartz T. Malignancy and biologic therapy in rheumatoid arthritis.  Curr Opin Rheumatol. 2008;  20 (3) 334-339
  • 211 Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study.  Arthritis Rheum. 2007;  56 (9) 2886-2895
  • 212 Lakatos P L, Miheller P. Is there an increased risk of lymphoma and malignancies under anti-TNF therapy in IBD?.  Curr Drug Targets. 2010;  11 (2) 179-186
  • 213 Mariette X. Lymphoma, rheumatoid arthritis, and TNFalpha antagonists.  Joint Bone Spine. 2010;  77 (3) 195-197
  • 214 Brown S L, Greene M H, Gershon S K, Edwards E T, Braun M M. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.  Arthritis Rheum. 2002;  46 (12) 3151-3158
  • 215 Dixon W G, Symmons D P. What effects might anti-TNFalpha treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNFalpha in cardiovascular pathophysiology.  Ann Rheum Dis. 2007;  66 (9) 1132-1136
  • 216 Atzeni F, Turiel M, Caporali R et al.. The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases.  Autoimmun Rev. 2010;  9 (12) 835-839
  • 217 Sidiropoulos P I, Siakka P, Pagonidis K et al.. Sustained improvement of vascular endothelial function during anti-TNFalpha treatment in rheumatoid arthritis patients.  Scand J Rheumatol. 2009;  38 (1) 6-10
  • 218 Dixon W G, Watson K D, Lunt M, Hyrich K L, Silman A J, Symmons D P. British Society for Rheumatology Biologics Register Control Centre Consortium . Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register.  Arthritis Rheum. 2007;  56 (9) 2905-2912
  • 219 Anker S D, Coats A J. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH.  Int J Cardiol. 2002;  86 (2-3) 123-130
  • 220 Chung E S, Packer M, Lo K H, Fasanmade A A, Willerson J T. Anti-TNF Therapy Against Congestive Heart Failure Investigators . Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial.  Circulation. 2003;  107 (25) 3133-3140
  • 221 Mohan N, Edwards E T, Cupps T R et al.. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides.  Arthritis Rheum. 2001;  44 (12) 2862-2869
  • 222 Chung J H, Van Stavern G P, Frohman L P, Turbin R E. Adalimumab-associated optic neuritis.  J Neurol Sci. 2006;  244 (1-2) 133-136
  • 223 Enayati P J, Papadakis K A. Association of anti-tumor necrosis factor therapy with the development of multiple sclerosis.  J Clin Gastroenterol. 2005;  39 (4) 303-306
  • 224 Bensouda-Grimaldi L, Mulleman D, Valat J P, Autret-Leca E. Adalimumab-associated multiple sclerosis.  J Rheumatol. 2007;  34 (1) 239-240, discussion 240
  • 225 Bechtel M, Sanders C, Bechtel A. Neurological complications of biologic therapy in psoriasis: a review.  J Clin Aesthet Dermatol. 2009;  2 (11) 27-32
  • 226 Yamamoto M, Takahashi H, Wakasugi H et al.. Leukoencephalopathy during administration of etanercept for refractory rheumatoid arthritis.  Mod Rheumatol. 2007;  17 (1) 72-74
  • 227 Rutgeerts P, Van Assche G, Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease.  Gastroenterology. 2004;  126 (6) 1593-1610
  • 228 Costa M F, Said N R, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents.  Semin Arthritis Rheum. 2008;  37 (6) 381-387
  • 229 Mohan N, Edwards E T, Cupps T R et al.. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents.  J Rheumatol. 2004;  31 (10) 1955-1958
  • 230 Stasi R, Stipa E, Del Poeta G, Amadori S, Newland A C, Provan D. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab.  Rheumatology (Oxford). 2006;  45 (11) 1432-1436
  • 231 Aries P M, Hellmich B, Voswinkel J et al.. Lack of efficacy of rituximab in Wegener's granulomatosis with refractory granulomatous manifestations.  Ann Rheum Dis. 2006;  65 (7) 853-858
  • 232 Keogh K A, Wylam M E, Stone J H, Specks U. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis.  Arthritis Rheum. 2005;  52 (1) 262-268
  • 233 Memet B, Rudinskaya A, Krebs T, Oelberg D. Wegener granulomatosis with massive intracerebral hemorrhage: remission of disease in response to rituximab.  J Clin Rheumatol. 2005;  11 (6) 314-318
  • 234 Tamura N, Matsudaira R, Hirashima M et al.. Two cases of refractory Wegener's granulomatosis successfully treated with rituximab.  Intern Med. 2007;  46 (7) 409-414
  • 235 Specks U, Fervenza F C, McDonald T J, Hogan M C. Response of Wegener's granulomatosis to anti-CD20 chimeric monoclonal antibody therapy.  Arthritis Rheum. 2001;  44 (12) 2836-2840
  • 236 Omdal R, Wildhagen K, Hansen T, Gunnarsson R, Kristoffersen G. Anti-CD20 therapy of treatment-resistant Wegener's granulomatosis: favourable but temporary response.  Scand J Rheumatol. 2005;  34 (3) 229-232
  • 237 Brihaye B, Aouba A, Pagnoux C, Cohen P, Lacassin F, Guillevin L. Adjunction of rituximab to steroids and immunosuppressants for refractory/relapsing Wegener's granulomatosis: a study on 8 patients.  Clin Exp Rheumatol. 2007;  25 (1, suppl 44) S23-S27
  • 238 Hermle T, Goestemeyer A K, Sweny P, Burns A. Successful therapeutic use of rituximab in refractory Wegener's granulomatosis after renal transplantation.  Clin Nephrol. 2007;  68 (5) 322-326
  • 239 Roccatello D, Baldovino S, Alpa M et al.. Effects of anti-CD20 monoclonal antibody as a rescue treatment for ANCA-associated idiopathic systemic vasculitis with or without overt renal involvement.  Clin Exp Rheumatol. 2008;  26 (3, suppl 49) S67-S71
  • 240 Sharma A, Kumar S, Wanchu A et al.. Successful treatment of hypertrophic pachymeningitis in refractory Wegener's granulomatosis with rituximab.  Clin Rheumatol. 2010;  29 (1) 107-110
  • 241 Taylor S R, Salama A D, Joshi L, Pusey C D, Lightman S L. Rituximab is effective in the treatment of refractory ophthalmic Wegener's granulomatosis.  Arthritis Rheum. 2009;  60 (5) 1540-1547
  • 242 Jones R B, Ferraro A J, Chaudhry A N et al.. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis.  Arthritis Rheum. 2009;  60 (7) 2156-2168
  • 243 Martinez Del Pero M, Chaudhry A, Jones R B, Sivasothy P, Jani P, Jayne D. B-cell depletion with rituximab for refractory head and neck Wegener's granulomatosis: a cohort study.  Clin Otolaryngol. 2009;  34 (4) 328-335
  • 244 Avivi I, Robinson S, Goldstone A. Clinical use of rituximab in haematological malignancies.  Br J Cancer. 2003;  89 (8) 1389-1394
  • 245 McLaughlin P, Grillo-López A J, Link B K et al.. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.  J Clin Oncol. 1998;  16 (8) 2825-2833
  • 246 Marcus R, Imrie K, Belch A et al.. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma.  Blood. 2005;  105 (4) 1417-1423
  • 247 Coiffier B, Lepage E, Briere J et al.. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.  N Engl J Med. 2002;  346 (4) 235-242
  • 248 Selewski D T, Shah G V, Mody R J, Rajdev P A, Mukherji S K. Rituximab (Rituxan).  AJNR Am J Neuroradiol. 2010;  31 (7) 1178-1180
  • 249 Gürcan H M, Keskin D B, Stern J N, Nitzberg M A, Shekhani H, Ahmed A R. A review of the current use of rituximab in autoimmune diseases.  Int Immunopharmacol. 2009;  9 (1) 10-25
  • 250 Hauser S L, Waubant E, Arnold D L HERMES Trial Group et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.  N Engl J Med. 2008;  358 (7) 676-688
  • 251 Reff M E, Carner K, Chambers K S et al.. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.  Blood. 1994;  83 (2) 435-445
  • 252 Pescovitz M D. Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action.  Am J Transplant. 2006;  6 (5 Pt 1) 859-866
  • 253 Falk R J, Jennette J C. Rituximab in ANCA-associated disease.  N Engl J Med. 2010;  363 (3) 285-286
  • 254 Ng C M, Bruno R, Combs D, Davies B. Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial.  J Clin Pharmacol. 2005;  45 (7) 792-801
  • 255 Adeli M M, Eichner B H, Thornburg C, Williams L. Persistent antibody depletion after rituximab in three children with autoimmune cytopenias.  Pediatr Hematol Oncol. 2009;  26 (8) 566-572
  • 256 Quartier P, Brethon B, Philippet P, Landman-Parker J, Le Deist F, Fischer A. Treatment of childhood autoimmune haemolytic anaemia with rituximab.  Lancet. 2001;  358 (9292) 1511-1513
  • 257 Carson K R, Evens A M, Richey E A et al.. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.  Blood. 2009;  113 (20) 4834-4840
  • 258 Goldberg S L, Pecora A L, Alter R S et al.. Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab.  Blood. 2002;  99 (4) 1486-1488
  • 259 Shelton E, Yong M, Cohney S. Late onset Pneumocystis pneumonia in patients receiving rituximab for humoral renal transplant rejection.  Nephrology (Carlton). 2009;  14 (7) 696-699
  • 260 Cohen S B, Emery P, Greenwald M W REFLEX Trial Group et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.  Arthritis Rheum. 2006;  54 (9) 2793-2806
  • 261 van Vollenhoven R F, Emery P, Bingham III C O et al.. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials.  J Rheumatol. 2010;  37 (3) 558-567
  • 262 Sfikakis P P, Boletis J N, Lionaki S et al.. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial.  Arthritis Rheum. 2005;  52 (2) 501-513
  • 263 Lim S H, Esler W V, Zhang Y et al.. B-cell depletion for 2 years after autologous stem cell transplant for NHL induces prolonged hypogammaglobulinemia beyond the rituximab maintenance period.  Leuk Lymphoma. 2008;  49 (1) 152-153
  • 264 Cattaneo C, Spedini P, Casari S et al.. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments.  Leuk Lymphoma. 2006;  47 (6) 1013-1017
  • 265 Aksoy S, Harputluoglu H, Kilickap S et al.. Rituximab-related viral infections in lymphoma patients.  Leuk Lymphoma. 2007;  48 (7) 1307-1312
  • 266 Aksoy S, Dizdar O, Hayran M, Harputluoğlu H. Infectious complications of rituximab in patients with lymphoma during maintenance therapy: a systematic review and meta-analysis.  Leuk Lymphoma. 2009;  50 (3) 357-365
  • 267 Furst D E, Keystone E C, Kirkham B et al.. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008.  Ann Rheum Dis. 2008;  67 (suppl 3) iii2-iii25 (erratum in Ann Rheum Dis 2009;68(3):452, Kavanaugh A [added])
  • 268 Rafailidis P I, Kakisi O K, Vardakas K, Falagas M E. Infectious complications of monoclonal antibodies used in cancer therapy: a systematic review of the evidence from randomized controlled trials.  Cancer. 2007;  109 (11) 2182-2189
  • 269 Kimby E. Tolerability and safety of rituximab (MabThera).  Cancer Treat Rev. 2005;  31 (6) 456-473
  • 270 Genovese M C, Breedveld F C, Emery P et al.. Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients.  Ann Rheum Dis. 2009;  68 (12) 1894-1897
  • 271 Lutt J R, Pisculli M L, Weinblatt M E, Deodhar A, Winthrop K L. Severe nontuberculous mycobacterial infection in 2 patients receiving rituximab for refractory myositis.  J Rheumatol. 2008;  35 (8) 1683-1685
  • 272 Ozgönenel B, Moonka D, Savaşan S. Fulminant hepatitis B following rituximab therapy in a patient with Evans syndrome and large B-cell lymphoma.  Am J Hematol. 2006;  81 (4) 302
  • 273 Tsutsumi Y, Tanaka J, Kawamura T et al.. Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin's lymphoma.  Ann Hematol. 2004;  83 (1) 58-60
  • 274 Yang S H, Kuo S H. Reactivation of hepatitis B virus during rituximab treatment of a patient with follicular lymphoma.  Ann Hematol. 2008;  87 (4) 325-327
  • 275 Wang F, Xu R H, Luo H Y et al.. Clinical and prognostic analysis of hepatitis B virus infection in diffuse large B-cell lymphoma.  BMC Cancer. 2008;  8 115
  • 276 Lok A S. Navigating the maze of hepatitis B treatments.  Gastroenterology. 2007;  132 (4) 1586-1594
  • 277 Fukushima N, Mizuta T, Tanaka M et al.. Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier.  Ann Oncol. 2009;  20 (12) 2013-2017
  • 278 Fabrizi F, Martin P, Elli A et al.. Hepatitis C virus infection and rituximab therapy after renal transplantation.  Int J Artif Organs. 2007;  30 (5) 445-449
  • 279 Ennishi D, Terui Y, Yokoyama M et al.. Monitoring serum hepatitis C virus (HCV) RNA in patients with HCV-infected CD20-positive B-cell lymphoma undergoing rituximab combination chemotherapy.  Am J Hematol. 2008;  83 (1) 59-62
  • 280 García-Suárez J, de Miguel D, Krsnik I, Bañas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies.  Am J Hematol. 2005;  80 (4) 271-281
  • 281 Brooks B R, Walker D L. Progressive multifocal leukoencephalopathy.  Neurol Clin. 1984;  2 (2) 299-313
  • 282 Marzocchetti A, Wuthrich C, Tan C S et al.. Rearrangement of the JC virus regulatory region sequence in the bone marrow of a patient with rheumatoid arthritis and progressive multifocal leukoencephalopathy.  J Neurovirol. 2008;  14 (5) 455-458
  • 283 Molloy E S, Calabrese L H. Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk?.  Autoimmun Rev. 2008;  8 (2) 144-146
  • 284 Ward M M, Donald F. Pneumocystis carinii pneumonia in patients with connective tissue diseases: the role of hospital experience in diagnosis and mortality.  Arthritis Rheum. 1999;  42 (4) 780-789
  • 285 Hugle B, Solomon M, Harvey E et al.. Pneumocystis jiroveci pneumonia following rituximab treatment in Wegener's granulomatosis.  Arthritis Care Res (Hoboken). 2010;  62 (11) 1661-1664
  • 286 Motto D G, Williams J A, Boxer L A. Rituximab for refractory childhood autoimmune hemolytic anemia.  Isr Med Assoc J. 2002;  4 (11) 1006-1008
  • 287 Mukhtyar C, Guillevin L, Cid M C European Vasculitis Study Group et al. EULAR recommendations for the management of primary small and medium vessel vasculitis.  Ann Rheum Dis. 2009;  68 (3) 310-317
  • 288 Teichmann L L, Woenckhaus M, Vogel C, Salzberger B, Schölmerich J, Fleck M. Fatal pneumocystis pneumonia following rituximab administration for rheumatoid arthritis.  Rheumatology (Oxford). 2008;  47 (8) 1256-1257
  • 289 Alexandrescu D T, Dutcher J P, O'Boyle K, Albulak M, Oiseth S, Wiernik P H. Fatal intra-alveolar hemorrhage after rituximab in a patient with non-Hodgkin lymphoma.  Leuk Lymphoma. 2004;  45 (11) 2321-2325
  • 290 Hainsworth J D, Litchy S, Lamb M R, Rodriguez G I, Scroggin Jr C, Greco F A. First-line treatment with brief-duration chemotherapy plus rituximab in elderly patients with intermediate-grade non-Hodgkin's lymphoma: phase II trial.  Clin Lymphoma. 2003;  4 (1) 36-42
  • 291 Heresi G A, Farver C F, Stoller J K. Interstitial pneumonitis and alveolar hemorrhage complicating use of rituximab: case report and review of the literature.  Respiration. 2008;  76 (4) 449-453
  • 292 Leon R J, Gonsalvo A, Salas R, Hidalgo N C. Rituximab-induced acute pulmonary fibrosis.  Mayo Clin Proc. 2004;  79 (7) 949-953, 953
  • 293 Schlesinger C, Koss M N. The organizing pneumonias: an update and review.  Curr Opin Pulm Med. 2005;  11 (5) 422-430
  • 294 Wagner S A, Mehta A C, Laber D A. Rituximab-induced interstitial lung disease.  Am J Hematol. 2007;  82 (10) 916-919
  • 295 Chaiwatanatorn K, Lee N, Grigg A, Filshie R, Firkin F. Delayed-onset neutropenia associated with rituximab therapy.  Br J Haematol. 2003;  121 (6) 913-918
  • 296 Yi J H, Kim S J, Ahn H K, Lee S J, Chang M H, Kim W S. Rituximab-induced acute thrombocytopenia: a case report and review of the literature.  Med Oncol. 2009;  26 (1) 45-48
  • 297 Klink D T, van Elburg R M, Schreurs M W, van Well G T. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development.  Clin Dev Immunol. 2008;  2008 271363
  • 298 Ojeda-Uribe M, Gilliot C, Jung G, Drenou B, Brunot A. Administration of rituximab during the first trimester of pregnancy without consequences for the newborn.  J Perinatol. 2006;  26 (4) 252-255
  • 299 Østensen M, Lockshin M, Doria A et al.. Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs.  Rheumatology (Oxford). 2008;  47 (suppl 3) iii28-iii31
  • 300 Kazatchkine M D, Kaveri S V. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin.  N Engl J Med. 2001;  345 (10) 747-755
  • 301 Ito-Ihara T, Ono T, Nogaki F et al.. Clinical efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis.  Nephron Clin Pract. 2006;  102 (1) c35-c42
  • 302 Jayne D R, Chapel H, Adu D et al.. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity.  QJM. 2000;  93 (7) 433-439
  • 303 Chung S A, Seo P. Advances in the use of biologic agents for the treatment of systemic vasculitis.  Curr Opin Rheumatol. 2009;  21 (1) 3-9
  • 304 Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration.  Clin Rev Allergy Immunol. 2005;  29 (3) 173-184

Joseph P LynchIII M.D. 

Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Medicine, The David Geffen School of Medicine at UCLA

10833 Le Conte Ave., Rm. 37-131 CHS, Los Angeles, CA 90095-1690

Email: jplynch@mednet.ucla.edu

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