An open study of pentoxyfylline and thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis (original) (raw)

Abstract

OBJECTIVE: Dysregulation of tumour necrosis factor alpha (TNF alpha) production is thought to be important in rheumatoid arthritis. Since pentoxifylline and thalidomide inhibit endotoxin induced TNF production in vitro, these drugs were tested in an open study in rheumatoid arthritis patients to assess toxicity, the effect on TNF production, and the antiarthritic effects. METHODS: 12 patients with active rheumatoid arthritis were treated with 1200 mg pentoxifylline and 100 mg thalidomide a day during 12 weeks. In addition, TNF production was assessed by ex vivo whole blood cultures stimulated with endotoxin. RESULTS: Adverse events such as xerostomia, drowsiness, and constipation occurred in almost all patients, which led to discontinuation in three. The drugs halved the TNF production capacity during treatment (ANOVA, P < 0.03) whereas production capacity of interleukin (IL) 6, IL-10, and IL-12 was not affected. Of the nine patients who completed the study, five fulfilled the ACR-20% response criteria after 12 weeks of treatment. CONCLUSIONS: Although pentoxifylline/thalidomide reduced the production capacity of TNF, the benefit/side effects ratio was poor due to multiple adverse effects, while clinical observation suggests limited efficacy.

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Selected References

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  1. Bianco J. A., Appelbaum F. R., Nemunaitis J., Almgren J., Andrews F., Kettner P., Shields A., Singer J. W. Phase I-II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantation. Blood. 1991 Sep 1;78(5):1205–1211. [PubMed] [Google Scholar]
  2. Chrousos G. P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995 May 18;332(20):1351–1362. doi: 10.1056/NEJM199505183322008. [DOI] [PubMed] [Google Scholar]
  3. Cid M. C., Kleinman H. K., Grant D. S., Schnaper H. W., Fauci A. S., Hoffman G. S. Estradiol enhances leukocyte binding to tumor necrosis factor (TNF)-stimulated endothelial cells via an increase in TNF-induced adhesion molecules E-selectin, intercellular adhesion molecule type 1, and vascular cell adhesion molecule type 1. J Clin Invest. 1994 Jan;93(1):17–25. doi: 10.1172/JCI116941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Di Perri G., Di Perri I. G., Monteiro G. B., Bonora S., Hennig C., Cassatella M., Micciolo R., Vento S., Dusi S., Bassetti D. Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J Infect Dis. 1995 May;171(5):1317–1322. doi: 10.1093/infdis/171.5.1317. [DOI] [PubMed] [Google Scholar]
  5. Han J., Thompson P., Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med. 1990 Jul 1;172(1):391–394. doi: 10.1084/jem.172.1.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Maksymowych W. P., Avina-Zubieta A., Luong M. H., Russell A. S. An open study of pentoxifylline in the treatment of severe refractory rheumatoid arthritis. J Rheumatol. 1995 Apr;22(4):625–629. [PubMed] [Google Scholar]
  7. Moreira A. L., Sampaio E. P., Zmuidzinas A., Frindt P., Smith K. A., Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med. 1993 Jun 1;177(6):1675–1680. doi: 10.1084/jem.177.6.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. No need for a dry run. Lancet. 1994 Jul 2;344(8914):1–2. [PubMed] [Google Scholar]
  9. Parker P. M., Chao N., Nademanee A., O'Donnell M. R., Schmidt G. M., Snyder D. S., Stein A. S., Smith E. P., Molina A., Stepan D. E. Thalidomide as salvage therapy for chronic graft-versus-host disease. Blood. 1995 Nov 1;86(9):3604–3609. [PubMed] [Google Scholar]
  10. Rankin E. C., Choy E. H., Kassimos D., Kingsley G. H., Sopwith A. M., Isenberg D. A., Panayi G. S. The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br J Rheumatol. 1995 Apr;34(4):334–342. doi: 10.1093/rheumatology/34.4.334. [DOI] [PubMed] [Google Scholar]
  11. Revuz J., Guillaume J. C., Janier M., Hans P., Marchand C., Souteyrand P., Bonnetblanc J. M., Claudy A., Dallac S., Klene C. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol. 1990 Jul;126(7):923–927. [PubMed] [Google Scholar]
  12. Sampaio E. P., Sarno E. N., Galilly R., Cohn Z. A., Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med. 1991 Mar 1;173(3):699–703. doi: 10.1084/jem.173.3.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Tramontana J. M., Utaipat U., Molloy A., Akarasewi P., Burroughs M., Makonkawkeyoon S., Johnson B., Klausner J. D., Rom W., Kaplan G. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med. 1995 May;1(4):384–397. [PMC free article] [PubMed] [Google Scholar]