BioDrugs

, Volume 10, Issue 5, pp 397–422 | Cite as

Infliximab

A Review of its Use in Crohn’s Disease and Rheumatoid Arthritis
Adis Drug Evaluation

Summary

Abstract

Infliximab is a chimaeric monoclonal antibody which binds to and inhibits the activity of tumour necrosis factor-α (TNFα), a cytokine which is involved in the development of both Crohn’s disease and rheumatoid arthritis. In patients with treatment-resistant Crohn’s disease, infliximab was significantly more effective than placebo in the relief of symptoms. 50 to 89% of patients responded to infliximab and most of them also achieved remission. Patients showed signs of relapse 8 to 12 weeks after a single infusion but responded to additional infusions of the drug. Infliximab was also effective in closing the fistulae in 68% of patients with fistulising Crohn’s disease; the response rate with placebo was 26%.

Infliximab achieved a clinical response in 44 to 81% of patients with refractory rheumatoid arthritis. Following a single infusion, symptom recurrence was evident after 6 to 12 weeks, but subsequent infusions re-established a clinical response. Concurrent methotrexate appeared to prolong the effects of infliximab in this patient group.

Anti-infliximab and anti-double-stranded DNA antibodies developed in some patients, particularly those who received multiple infusions of infliximab. Acute adverse events consistent with hypersensitivity occurred in some patients who received multiple infusions of infliximab. Infection occurred slightly more frequently with infliximab than with placebo.

Conclusions: Infliximab appears to be an effective therapy for patients with treatment-resistant or fistulising Crohn’s disease or refractory rheumatoid arthritis. The tolerability, long term efficacy and optimal dosage regimen need to be further defined in comparative trials before the full potential of infliximab is realised in these patients.

Pharmacodynamic Properties

Tumour necrosis factor-α (TNFα) is present at elevated levels in inflamed tissues and is thought to play a central role in the pathogenesis of Crohn’s disease and rheumatoid arthritis. Infliximab is a mouse-human chimaeric monoclonal antibody which binds to and blocks the function of human TNFα. Consistent with blockade of TNFα, intravenous infliximab resulted in reduced expression of TNFα-regulated chemokines, endothelial adhesion molecules and interleukins in patients with Crohn’s disease or rheumatoid arthritis. A 25 to 50% decrease in peripheral monocyte counts was observed in some patients who received infliximab, but resolved within a few weeks.

Patients who received multiple infusions of infliximab were more likely to develop anti-infliximab antibodies than those who received single infusions, but concurrent methotrexate or higher doses of infliximab markedly reduced the antiinfliximab response. Anti-double-stranded DNA (anti-dsDNA) antibodies also developed in patients more frequently after multiple than after single infusions of infliximab.

Pharmacokinetic Properties

Serum infliximab concentrations increased in proportion with higher doses, and the median volume of distribution was 3.0 L with infliximab 5 mg/kg. Eight weeks after patients received infusions of infliximab 1 to 20 mg/kg, serum infliximab was detectable only in patients who received ≥10 mg/kg. Concurrent methotrexate tended to increase serum concentrations of infliximab.

The elimination half-life of infliximab was 9 to 10 days in patients with either Crohn’s disease or rheumatoid arthritis. This is longer than that reported for intact mouse monoclonal antibodies, but shorter than that reported for native human antibodies.

Clinical Use in Crohn’s Disease

In 8- to 48-week clinical trials involving 9 to 107 patients with treatment-resistant Crohn’s disease, infliximab 5 to 20 mg/kg achieved a clinical response [defined as a reduction in Crohn’s disease activity index (CDAI) score of ≥70 points] in 50 to 89% of patients. In the only fully reported, placebo-controlled trial, single infusions of infliximab 5, 10 or 20 mg/kg achieved a clinical response in 50 to 81% of patients with Crohn’s disease compared with 17% of patients with placebo. Remission (defined as a CDAI score <150) was achieved in 27 to 50% of patients who received infliximab compared with 4% of patients who received placebo in this study. There was no dose-response pattern with infliximab 5, 10 and 20 mg/kg, although the 1 mg/kg dose was associated with a lower clinical response rate.

Patients with treatment-resistant Crohn’s disease generally responded to a single infusion of infliximab by week 2, the earliest time-point reported, and exhibited maximum improvement by week 4 to 6. Disease activity started to return after approximately 8 to 12 weeks. A longer overall duration of response was achieved with multiple infusions of infliximab. To date, a maximum of 5 infusions have been administered with an associated duration of effect of at least 44 weeks.

In patients with fistulising Crohn’s disease, infliximab was significantly more effective than placebo on the basis of closure of fistulae. At least 50% of fistulae were closed during ≥2 consecutive visits in 68% of patients who received infliximab 5 mg/kg compared with 26% of placebo recipients. In 55% of infliximab recipients, all fistulae were closed.

Clinical Potential in Rheumatoid Arthritis

In 4- to 26-week trials, single doses of infliximab 1 to 20 mg/kg achieved a clinical response in 44 to 81% of patients with rheumatoid arthritis refractory to ≥1 disease-modifying antirheumatic drug (DMARD), based on the Paulus 20% or American College of Rheumatology criteria (range 7 to 81 evaluable patients). In 1 trial, pain score, swollen joint count and C-reactive protein (CRP) levels were improved by 63, 61 and 45%, respectively, 4 weeks after patients received a single infusion of infliximab 10 mg/kg.

The response to infliximab was apparent 1 week after infusion and reached a maximum after approximately 3 weeks. The median duration of the Paulus 20% response after a single infusion of infliximab 10 mg/kg was 8 weeks in 1 trial. Patients who were re-infused with infliximab after responding to an initial infusion and subsequently relapsing continued to respond similarly. However, the duration of the response was reduced with each successive infusion administered after relapse in a noncomparative trial in 7 patients; after 1, 2, 3 or 4 infusions, the median response duration was 12, 9.1, 8.3 and 7.7 weeks, respectively. Concurrent methotrexate therapy improved the duration of the response to multiple infusions of infliximab.

Tolerability

Adverse events associated with infliximab were usually mild and resolved spontaneously. Acute, infusion-related adverse events suggestive of hypersensitivity (urticaria, somnolence, pruritus, chills, fever, headache, facial flushing, chest pain, dyspnoea and/or nausea) occurred in 6 to 38% of patients who received multiple infusions of infliximab and were more common in patients with anti-infliximab antibodies. Such events were not reported in recipients of a single infusion of infliximab. The incidence of infection was slightly higher in patients who received infliximab than in placebo recipients. Other adverse events, at least possibly related to treatment, included hypertension, rigors, rash, headache and eczema. Two patients developed symptoms of systemic lupus erythematosus after multiple infusions of infliximab, and in 1 patient this was correlated with the development of anti-dsDNA antibodies. Five patients developed lympho-proliferative disorders after receiving infliximab, but the data did not establish a relationship between this adverse event and treatment.

Dosage and Administration

Infliximab is indicated for the management of moderate to severe, active Crohn’s disease which does not respond to conventional therapies, and for fistulising Crohn’s disease. The recommended dose in patients with treatment-resistant Crohn’s disease is a single, 2-hour intravenous infusion of infliximab 5 mg/kg. In patients with fistulising Crohn’s disease, intravenous infusions of infliximab 5 mg/kg administered at 0, 2 and 6 weeks are recommended. Currently, no formal dosage recommendations are available for the administration of infliximab in patients with rheumatoid arthritis. In clinical trials in patients with refractory rheumatoid arthritis, the most effective doses of infliximab were 3 and 10 mg/kg, and clinical responses were maintained when infusions of infliximab were administered every 4 or 8 weeks.

Because some infliximab recipients with Crohn’s disease or rheumatoid arthritis have developed anti-dsDNA antibodies, hypersensitivity-type reactions or anti-infliximab antibodies, infliximab should be used with caution in patients with pre-existing anti-dsDNA antibody titres and in those who have previously received mouse or mouse-human monoclonal antibodies.

Keywords

Rheumatoid Arthritis Infliximab Adis International Limited Single Infusion Multiple Infusion 

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References

  1. 1.
    Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993; 30(16): 1443–53PubMedCrossRefGoogle Scholar
  2. 2.
    Siegel SA, Shealy DJ, Nakada MT. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 1995 Jan; 7(1): 15–25PubMedCrossRefGoogle Scholar
  3. 3.
    Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNFα monoclonal antibody cA2 binds recombinant transmembrane TNFα and activates immune effector functions. Cytokine 1995 Apr; 7(3): 251–9PubMedCrossRefGoogle Scholar
  4. 4.
    Donaldson Jr RM. Crohn’s disease. In: Sleisenger MH, Fordtran JS, editors. Gastrointestinal disease: pathophysiology, diagnosis, management. 4th ed. v. 2. Philadelphia: W.B. Saunders Company, 1989: 1327–58Google Scholar
  5. 5.
    Lipsky PE. Rheumatoid arthritis. In: Wilson JE, Braunwald E, Isselbacher, editors. Harrison’s principles of internal medicine. 12th ed. v. 2. New York: McGraw-Hill, Inc., 1991: 1437–43Google Scholar
  6. 6.
    Starkebaum G. Role of cytokines in rheumatoid arthritis. Sci Med 1998 Mar–Apr; 5: 6–15Google Scholar
  7. 7.
    van Deventer SJH, Camoglio L. Monoclonal antibody therapy of inflammatory bowel disease. Aliment Pharmacol Ther 1996; 10Suppl. 2: 107–11PubMedGoogle Scholar
  8. 8.
    Weckmann AL, Alcocer-Varela J. Cytokine inhibitors in autoimmune disease. Semin Arthritis Rheum 1996 Oct; 26: 539–57PubMedCrossRefGoogle Scholar
  9. 9.
    Eigler A, Sinha B, Hartmann G, et al. Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol Today 1997 Oct; 18: 487–92PubMedCrossRefGoogle Scholar
  10. 10.
    Dinarello CA. Role of pro- and anti-inflammatory cytokines during inflammation: experimental and clinical findings. J Biol Regul Homeost Agents 1997 Jul–Sep; 11: 91–103PubMedGoogle Scholar
  11. 11.
    van Deventer SJH. Tumour necrosis factor and Crohn’s disease. Gut 1997; 40: 443–8PubMedGoogle Scholar
  12. 12.
    Sartor RB. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol 1997 Dec; 92(12) Suppl. 1: 5S–11SPubMedGoogle Scholar
  13. 13.
    Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397–440PubMedCrossRefGoogle Scholar
  14. 14.
    Radford-Smith G, Jewell DP. Cytokines and inflammatory bowel disease. Baillieres Clin Gastroenterol 1996 Mar; 10(1): 151–64PubMedCrossRefGoogle Scholar
  15. 15.
    Mantovani A. The interplay between primary and secondary cytokines: cytokines involved in the regulation of monocyte recruitment. Drugs 1997; 54Suppl. 1: 15–23PubMedCrossRefGoogle Scholar
  16. 16.
    Szekanecz Z, Koch AE, Kunkel SL, et al. Cytokines in rheumatoid arthritis: potential targets for pharmacological intervention. Drugs Aging 1998 May; 12(5): 377–90PubMedCrossRefGoogle Scholar
  17. 17.
    Feldmann M, Elliott MJ, Woody JN, et al. Anti-tumor necrosis factor-α therapy of rheumatoid arthritis. Advances in Immunology 1997; 64: 283–350PubMedCrossRefGoogle Scholar
  18. 18.
    Dalesandro MR, Kinney CS, Frederick B, et al. Potential clinical relevance of the mechanism of inhibition of immune function by the mouse/human chimeric anti-TNFα antibody, cA2 [abstract]. Arthritis Rheum 1995 Sep; 38 Suppl.: S401Google Scholar
  19. 19.
    Radema SA, van Dullemen JM, Tytgat GNJ, et al. Decreased production of chemokines in patients with Crohns disease after anti-TNF therapy [abstract]. Clin Immunol Immunopathol 1995 Jul; 76 (Pt 2): 45Google Scholar
  20. 20.
    Tak PP, Taylor C, Breedveld FC, et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor-α monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996 Jul; 39: 1077–81PubMedCrossRefGoogle Scholar
  21. 21.
    Paleolog EM, Hunt M, Elliot MJ, et al. Deactivation of vascular endothelium by monoclonal anti-tumour necrosis factor α antibody in rheumatoid arthritis. Arthritis Rheum 1996 Jul; 39: 1082–91PubMedCrossRefGoogle Scholar
  22. 22.
    Baert F, Peeters M, D’Haens G, et al. Impressive histologic improvement after TNF antibody (cA2) therapy in active Crohn’s disease [abstract]. Gut 1996; 39Suppl. 1: A17Google Scholar
  23. 23.
    Shealy D, Mace K, De Woody K. Reduction in serum VEGF and sICAM-1 are associated with clinical response to anti-TNF therapy in patients with severe Crohn’s disease [abstract]. Gastroenterology 1997; 112(4): A1090Google Scholar
  24. 24.
    Lorenz H–M, Antoni C, Valerius T, et al. In vivo blockade of TNFα by intravenous infusion of a chimeric monoclonal TNFα antibody in patients with rheumatoid arthritis: short tem cellular and molecular effects. J Immunol 1996 Feb 15; 156: 1646–53PubMedGoogle Scholar
  25. 25.
    van Dullemen HM, van Deventer SJH, Hommes DW, et al. Treatment of Crohn’s disease anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995 Jul; 109: 129–35PubMedCrossRefGoogle Scholar
  26. 26.
    Taylor PC, Chapman P, Elliott MJ, et al. Reduced granulocyte traffic and chemotactic gradients in rheumatoid joints following anti-TNFα therapy [abstract]. Arthritis Rheum 1997 Sep; 40 Suppl.: S80CrossRefGoogle Scholar
  27. 27.
    Plevy SE, Landers CJ, Prehn J, et al. A role for TNFα and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol 1997; 159: 6276–82PubMedGoogle Scholar
  28. 28.
    Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor-α. Arthritis Rheum 1993 Dec; 36: 1681–90PubMedCrossRefGoogle Scholar
  29. 29.
    Lorenz H–M, Hieronymus T, Griinke M, et al. In vivo blockade of TNFα patients with rheumatoid arthritis: indication for tachyphylaxis in long term ex vivo and in vitro effects after repeated infusion of chimeric monoclonal antibody cA2 [abstract]. Arthritis Rheum 1996 Sep; 39 Suppl.: S244Google Scholar
  30. 30.
    Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med 1997 Oct 9; 337: 1029–35PubMedCrossRefGoogle Scholar
  31. 31.
    Targan SR, Schaible TF. Chimeric monoclonal antibody cA2 to tumor necrosis factor-alpha for Crohn’s disease. Reply [letter]. N Engl J Med 1998 Jan 29; 338: 334CrossRefGoogle Scholar
  32. 32.
    Meenan J, Hommes DW, van Dullemen H, et al. The influence of TNFα mAb, cA2, on circulating lymphocyte populations [abstract]. Gastroenterology 1997 Apr; 112 Suppl.: A1039CrossRefGoogle Scholar
  33. 33.
    LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A 1989 Jun; 86: 4220–4PubMedCrossRefGoogle Scholar
  34. 34.
    Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor-α (cA2) versus placebo in rheumatoid arthritis. Lancet 1994 Oct 22; 344: 1105–10PubMedCrossRefGoogle Scholar
  35. 35.
    Charles PJ, Elliott MJ, Feldmann M, et al. Development of anti dsDNA antibodies in patients with rheumatoid arthritis treated with a chimeric monoclonal antibody to TNFα [abstract]. Rheumatol Eur 1995; 24Suppl. 3: 108Google Scholar
  36. 36.
    Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor-α (cA2) in patients with rheumatoid arthritis. Lancet 1994 Oct 22; 344: 1125–7PubMedCrossRefGoogle Scholar
  37. 37.
    Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998 Sep; 41(9): 1552–63PubMedCrossRefGoogle Scholar
  38. 38.
    Janeway Jr CA, Travers P, editors. Immunobiology: the immune system in health and disease. London: Current Biology, Ltd., 1994Google Scholar
  39. 39.
    Centocor Inc. Remicade (infliximab) for IV injection prescribing information for USA. 12 Aug 1998 (Data on file)Google Scholar
  40. 40.
    Hahn BH. Systemic lupus erythematosus. In: Wilson JD, Braunwald E, Isselbacher KJ, editors. Principles of internal medicine. 12th ed. v. 2. New York: McGraw-Hill, Inc., 1991: 1432–7Google Scholar
  41. 41.
    Barland P, Lipstein E. Selection and use of laboratory tests in the rheumatic diseases. Am J Med 1996 Feb 26; 100Suppl. 2A: 16S–23SPubMedCrossRefGoogle Scholar
  42. 42.
    Folwaczny C, Noehl N, Endres SP, et al. Antinuclear autoanti-bodies in patients with inflammatory bowel disease: high prevalence in first-degree relatives. Dig Dis Sci 1997 Aug; 42(8): 1593–7PubMedCrossRefGoogle Scholar
  43. 43.
    Maini RN, Elliott MJ, Long-Fox A, et al. Clinical response of rheumatoid arthritis (RA) to anti-TNFα (cA2) monoclonal antibody (mab) is related to administered dose and persistence of circulating antibody [abstract]. Arthritis Rheum 1995 Sep; 38 Suppl.: S186Google Scholar
  44. 44.
    Maini RN, Breedveld FC, Kalden JR, et al. Sustained therapeutic efficacy of multiple intravenous infusions of anti-TNFα monoclonal antibody combined with low dose weekly methotrexate in rheumatoid arthritis. 1998, Centocor Inc. (Data on file)Google Scholar
  45. 45.
    Rutgeerts P, D’Haens G, van Deventer SJH, et al. Retreatment with anti-TNFα chimeric antibody (cA2) effectively maintains cA2-induced remission in Crohn’s disease [abstract]. Gastroenterology 1997 Apr; 112 Suppl.: A1078CrossRefGoogle Scholar
  46. 46.
    Present D, Mayer L, van Deventer SJH, et al. Anti-TNF-alpha chimeric antibody (cA2) is effective in the treatment of the fistulae of Crohn’s disease: a multicenter, randomized, double-blind, placebo-controlled study [abstract]. Am J Gastroenterol 1997 Sep; 92: 1746Google Scholar
  47. 47.
    McCabe RP, Woody J, van Deventer S, et al. A multicenter trial of cA2 anti-TNF chimeric monoclonal antibody in patients with active Crohn’s disease [abstract]. Gastroenterology 1996 Apr; 110 Suppl.: A962Google Scholar
  48. 48.
    Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s Disease Activity Index: National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70: 439–44PubMedGoogle Scholar
  49. 49.
    Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Gastroenterology 1994; 106: 287–96PubMedGoogle Scholar
  50. 50.
    Guyatt GH, Mitchell A, Irvine EJ, et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology 1989; 96: 804–10PubMedGoogle Scholar
  51. 51.
    Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Gut 1989; 30: 983–9PubMedCrossRefGoogle Scholar
  52. 52.
    Kavanaugh AF, Cush JJ, St Clair EW, et al. Anti-TNFα monoclonal antibody (mAb) treatment of rheumatoid arthritis (RA) patients with active disease on methotrexate (MTX): results of a double-blind, placebo-controlled multicenter trial [abstract]. Arthritis Rheum 1996 Sep; 39 Suppl.: S123CrossRefGoogle Scholar
  53. 53.
    Kavanaugh AF, Cush JJ, St Clair EW, et al. Anti-TNFα monoclonal antibody (mAb) treatment of rheumatoid arthritis (RA) patients with active disease on methotrexate (MTX): results of open label, repeated dose administration following a single dose double-blind, placebo controlled trial [abstract]. Arthritis Rheum 1996 Sep; 39 Suppl.: S244CrossRefGoogle Scholar
  54. 54.
    Arnett FC, Edworthy SM, Bloch DA. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988 Mar; 31(3): 315–24PubMedCrossRefGoogle Scholar
  55. 55.
    Mallya RK, Mace BEW. The assessment of disease activity in rheumatoid arthritis using a multivariate analysis. Rheumatology and Rehabilitation 1981; 20: 14–7PubMedCrossRefGoogle Scholar
  56. 56.
    Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. JAMA 1949; 140: 659–62CrossRefGoogle Scholar
  57. 57.
    Paulus HE, Egger MJ, Ward JR, et al. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum 1990 Apr; 33(4): 477–84PubMedCrossRefGoogle Scholar
  58. 58.
    Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995 Jun; 38(6): 727–35PubMedCrossRefGoogle Scholar
  59. 59.
    Boers M. International consensus on which measures to use in rheumatoid arthritis clinical trials. Neth J Med 1993 Aug; 43: 55–8PubMedGoogle Scholar
  60. 60.
    Kalden-Nemeth D, Grebmeier J, Antoni C, et al. NMR monitoring of rheumatoid arthritis patients receiving anti-TNFα monoclonal antibody therapy. Rheumatol Int 1997 Mar; 16: 249–55PubMedCrossRefGoogle Scholar
  61. 61.
    St Clair EW, Gordon B, Turkington TG, et al. Quantitative assessment of the therapeutic response to chimeric anti-TNF in rheumatoid arthritis (RA) by positron emission tomography (PET) [abstract]. Arthritis Rheum 1996 Sep; 39 Suppl.: S243Google Scholar
  62. 62.
    Centocor Inc. Characteristics of infliximab treated patients with lymphoproliferative disorders. (Data on file)Google Scholar
  63. 63.
    Kvist N, Jacobsen O, Nørgaard P, et al. Malignancy in Crohn’s disease. Scand J Gastroenterol 1986 Jan; 21(1): 82–6PubMedCrossRefGoogle Scholar
  64. 64.
    Nakajima H, Munakata A, Yoshida Y, et al. Extraintestinal cancers in Crohn’s disease. Digestion 1990; 47(1): 1–7PubMedCrossRefGoogle Scholar
  65. 65.
    Geboes K. Cancer and its prevention. Eur J Gastroenterol Hepatol 1994; 6(2): 117–20CrossRefGoogle Scholar
  66. 66.
    Greenstein AT, Mullin GE, Strauchen JA, et al. Lymphoma in inflammatory bowel disease. Cancer 1992; 69: 1119–23PubMedCrossRefGoogle Scholar
  67. 67.
    Baecklund E, Ekbom A, Sparén P, et al. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 1998 Jul; 317: 180–1PubMedCrossRefGoogle Scholar
  68. 68.
    Jones M, Symmons D, Finn J, et al. Does exposure to immuno-suppressive therapy increase the 10 year malignancy and mortality risks in rheumatoid arthritis? A matched cohort study. Br J Rheumatol 1996; 35: 738–45PubMedCrossRefGoogle Scholar
  69. 69.
    Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997; 40(9): 1580–6PubMedCrossRefGoogle Scholar
  70. 70.
    Mellemkjaer L, Linet MS, Gridley G, et al. Rheumatoid arthritis and cancer risk. Eur J Cancer 1996; 32A(10): 1753–7PubMedCrossRefGoogle Scholar
  71. 71.
    Hanauer SB, Meyers S. Management of Crohn’s disease in adults. Am J Gastroenterol 1997 Apr; 92: 559–66PubMedGoogle Scholar
  72. 72.
    Pincus T. The underestimated long term medical and economic consequences of rheumatoid arthritis. Drugs 1995; 50Suppl. 1: 1–14PubMedCrossRefGoogle Scholar
  73. 73.
    Gremillion RB, van Vollenhoven RF. Rheumatoid arthritis: designing and implementing a treatment plan. Postgrad Med 1998 Feb; 103(2): 103–6PubMedCrossRefGoogle Scholar
  74. 74.
    American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 1996 May; 39(5): 713–22CrossRefGoogle Scholar
  75. 75.
    Sandborn WJ, Van Os EC, Zins BJ, et al. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn’s disease. Gastroenterology 1995; 109: 1808–17PubMedCrossRefGoogle Scholar
  76. 76.
    Modigliani R. Chronic active Crohn’s disease: an update on prevention and treatment. Res Clin Forum 1998; 20: 169–77Google Scholar
  77. 77.
    Borley NR, Mortensen NJ, Jewell DP. Preventing postoperative recurrence of Crohn’s disease. Br J Surg 1997 Nov; 84: 1493–502PubMedCrossRefGoogle Scholar
  78. 78.
    Blackburn WD. Management of osteoarthritis and rheumatoid arthritis: prospects and possibilities. Am J Med 1996 Feb 26; 100Suppl. 2A: 24A–30SCrossRefGoogle Scholar
  79. 79.
    Ahern MJ, Chandran G. Category III symptom-modifying antirheumatic drugs: a comparative review. Clin Immunother 1995 Mar; 3: 196–217Google Scholar
  80. 80.
    Firestein GS, Zvaifler NJ. Anticytokine therapy in rheumatoid arthritis. N Engl J Med 1997 Jul 17; 337(3): 195–7PubMedCrossRefGoogle Scholar
  81. 81.
    Delemarre JBVM. What is new in the treatment of perianal fistulae in Crohn’s disease? Neth J Med 1996; 48: 74–6PubMedCrossRefGoogle Scholar
  82. 82.
    Hinterleitner TA, Petritsch W, Aichbichler B, et al. Combination of cyclosporine, azathioprine and prednisolone for perianal fistulas in Crohn’s disease. Z Gastroenterol 1997; 35(8): 603–8PubMedGoogle Scholar
  83. 83.
    Elton E, Hanauer SB. The medical management of Crohn’s disease. Aliment Pharmacol Ther 1996 Feb; 10: 1–22PubMedCrossRefGoogle Scholar
  84. 84.
    Egan LJ, Sandborn WJ, Tremaine SJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn’s disease with intravenous cyclosporine. Am J Gastroenterol 1998 Mar; 93(3): 442–8PubMedCrossRefGoogle Scholar
  85. 85.
    Tremaine WJ. Refractory IBD: medical management. Neth J Med 1997 Feb; 50: S12–4PubMedCrossRefGoogle Scholar
  86. 86.
    Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn’s disease. Dig Dis Sci 1985 Jan; 30(1): 58–64PubMedCrossRefGoogle Scholar
  87. 87.
    Stack WA, Mann SD, Roy AJ. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn’s disease. Lancet 1997 Feb 22; 349: 521–4PubMedCrossRefGoogle Scholar
  88. 88.
    Camussi G, Lupia E. The future role of anti-tumour necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs 1998 May; 55(5): 613–20PubMedCrossRefGoogle Scholar
  89. 89.
    Murray KM, Dahl SL. Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR: Fc) in rheumatoid arthritis. Ann Pharmacother 1997 Nov; 31: 1335–8PubMedGoogle Scholar
  90. 90.
    Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)- Fc fusion protein. N Engl J Med 1997 Jul 17; 337(3): 141–7PubMedCrossRefGoogle Scholar
  91. 91.
    Robinson M. Optimizing therapy for inflammatory bowel disease. Am J Gastroenterol 1997 Dec; 92 Suppl.: 12S–7SPubMedGoogle Scholar
  92. 92.
    Hawkey CJ, Stack WA. Chimeric monoclonal antibody cA2 to tumor necrosis factor-α for Crohn’s disease [letter]. N Engl J Med 1998 Jan 29; 338: 333–4PubMedCrossRefGoogle Scholar
  93. 93.
    Rutgeerts PJ. Prevention of early recurrence of Crohn’s disease after ileal resection with ileocolonic anastomosis. Eur J Gastroenterol Hepatol 1994; 6(2): 113–6CrossRefGoogle Scholar
  94. 94.
    Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci 1994 Feb; 39(2): 374–80PubMedCrossRefGoogle Scholar
  95. 95.
    Hanauer SB, Smith MB. Rapid closure of Crohn’s disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993; 88(5): 646–9PubMedGoogle Scholar
  96. 96.
    Feagan BG, Rochon J, Fedorak RN. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995 Feb 2; 332: 292–7PubMedCrossRefGoogle Scholar

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© Adis International Limited 1998

Authors and Affiliations

  1. 1.Adis International LimitedMairangi BayNew Zealand

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