Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 1996 Oct;55(10):761–768. doi: 10.1136/ard.55.10.761

Safety and efficacy of recombinant gamma interferon in the treatment of systemic sclerosis.

P G Vlachoyiannopoulos 1, N Tsifetaki 1, I Dimitriou 1, D Galaris 1, S A Papiris 1, H M Moutsopoulos 1
PMCID: PMC1010296  PMID: 8984943

Abstract

OBJECTIVE: To evaluate the safety and efficacy of recombinant gamma interferon (rIFN gamma) in the treatment of patients with systemic sclerosis. METHODS: Sixteen patients with systemic sclerosis were treated with r-IFN gamma, 60 micrograms m-2 (low dose, n = 10) and 150 micrograms m-2 (high dose, n = 6), three times weekly in an open phase I/II trial of eight months duration. The patients were stratified in low and high dose according to the severity and the extent of scleroderma; the two groups were comparable. RESULTS: The treatment was well tolerated. The most common side effects, almost certainly related to r-IFN gamma, were fever, chills, dizziness, headache, and severe flu-like syndrome with decreasing intensity with the time of treatment. Severe aphthous stomatitis (n = 1), ventricular tachycardia (n = 1), severe oesophageal ulcers due to gastro-oesophageal reflux (n = 1), disease exacerbation alone with frank arthritis and slight pericardial effusion (n = 1), and inability to conform to the requirements of the study (n = 1) were the reasons for discontinuing treatment. Side effects and degree of response were evident during the first five months of treatment. A significant decrease in mean skin thickness score was observed and was higher in the high dose group. Reactive oxygen species of peripheral neutrophils and soluble interleukin-2 receptor serum concentrations were higher than those of normal individuals at study entry and decreased in parallel with clinical improvement. CONCLUSIONS: Treatment of systemic sclerosis patients with r-IFN gamma was relatively safe and well tolerated for doses as high as 150 micrograms m-2 three times weekly. Side effects and the degree of response can be seen during the first months of therapy and can be used as predictors of ultimate toxicity or response. The drug seems to be effective in treating cutaneous scleroderma.

Full text

PDF
761

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bass D. A., Gerard C., Olbrantz P., Wilson J., McCall C. E., McPhail L. C. Priming of the respiratory burst of neutrophils by diacylglycerol. Independence from activation or translocation of protein kinase C. J Biol Chem. 1987 May 15;262(14):6643–6649. [PubMed] [Google Scholar]
  2. Berliner J. A., Territo M. C., Sevanian A., Ramin S., Kim J. A., Bamshad B., Esterson M., Fogelman A. M. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990 Apr;85(4):1260–1266. doi: 10.1172/JCI114562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bruckdorfer K. R., Hillary J. B., Bunce T., Vancheeswaran R., Black C. M. Increased susceptibility to oxidation of low-density lipoproteins isolated from patients with systemic sclerosis. Arthritis Rheum. 1995 Aug;38(8):1060–1067. doi: 10.1002/art.1780380807. [DOI] [PubMed] [Google Scholar]
  4. Carpentier P. H., Maricq H. R. Microvasculature in systemic sclerosis. Rheum Dis Clin North Am. 1990 Feb;16(1):75–91. [PubMed] [Google Scholar]
  5. Cassatella M. A., Della Bianca V., Berton G., Rossi F. Activation by gamma interferon of human macrophage capability to produce toxic oxygen molecules is accompanied by decreased Km of the superoxide-generating NADPH oxidase. Biochem Biophys Res Commun. 1985 Nov 15;132(3):908–914. doi: 10.1016/0006-291x(85)91893-5. [DOI] [PubMed] [Google Scholar]
  6. Czaja M. J., Weiner F. R., Eghbali M., Giambrone M. A., Eghbali M., Zern M. A. Differential effects of gamma-interferon on collagen and fibronectin gene expression. J Biol Chem. 1987 Sep 25;262(27):13348–13351. [PubMed] [Google Scholar]
  7. Duncan M. R., Berman B. Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation. J Exp Med. 1985 Aug 1;162(2):516–527. doi: 10.1084/jem.162.2.516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Emerit I. Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis. Free Radic Biol Med. 1994 Jan;16(1):99–109. doi: 10.1016/0891-5849(94)90246-1. [DOI] [PubMed] [Google Scholar]
  9. Fleischmajer R., Perlish J. S., Reeves J. R. Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977 May;20(4):975–984. doi: 10.1002/art.1780200410. [DOI] [PubMed] [Google Scholar]
  10. Freundlich B., Jimenez S. A., Steen V. D., Medsger T. A., Jr, Szkolnicki M., Jaffe H. S. Treatment of systemic sclerosis with recombinant interferon-gamma. A phase I/II clinical trial. Arthritis Rheum. 1992 Oct;35(10):1134–1142. doi: 10.1002/art.1780351005. [DOI] [PubMed] [Google Scholar]
  11. Frostegård J., Wu R., Giscombe R., Holm G., Lefvert A. K., Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein. Arterioscler Thromb. 1992 Apr;12(4):461–467. doi: 10.1161/01.atv.12.4.461. [DOI] [PubMed] [Google Scholar]
  12. Hein R., Behr J., Hündgen M., Hunzelmann N., Meurer M., Braun-Falco O., Urbanski A., Krieg T. Treatment of systemic sclerosis with gamma-interferon. Br J Dermatol. 1992 May;126(5):496–501. doi: 10.1111/j.1365-2133.1992.tb11824.x. [DOI] [PubMed] [Google Scholar]
  13. Jimenez S. A., Freundlich B., Rosenbloom J. Selective inhibition of human diploid fibroblast collagen synthesis by interferons. J Clin Invest. 1984 Sep;74(3):1112–1116. doi: 10.1172/JCI111480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kahaleh M. B., Leroy E. C. Endothelial injury in scleroderma. A protease mechanism. J Lab Clin Med. 1983 Apr;101(4):553–560. [PubMed] [Google Scholar]
  15. Kahaleh M. B., Osborn I., LeRoy E. C. Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in scleroderma and in Raynaud's phenomenon. Ann Intern Med. 1981 Apr;94(4 Pt 1):482–484. doi: 10.7326/0003-4819-94-4-482. [DOI] [PubMed] [Google Scholar]
  16. Kahaleh M. B., Sherer G. K., LeRoy E. C. Endothelial injury in scleroderma. J Exp Med. 1979 Jun 1;149(6):1326–1335. doi: 10.1084/jem.149.6.1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kahaleh M. B. Soluble immunologic products in scleroderma sera. Clin Immunol Immunopathol. 1991 Jan;58(1):139–144. doi: 10.1016/0090-1229(91)90155-4. [DOI] [PubMed] [Google Scholar]
  18. Kahaleh M. B., Sultany G. L., Smith E. A., Huffstutter J. E., Loadholt C. B., LeRoy E. C. A modified scleroderma skin scoring method. Clin Exp Rheumatol. 1986 Oct-Dec;4(4):367–369. [PubMed] [Google Scholar]
  19. Kahan A., Amor B., Menkes C. J., Strauch G. Recombinant interferon-gamma in the treatment of systemic sclerosis. Am J Med. 1989 Sep;87(3):273–277. doi: 10.1016/s0002-9343(89)80150-0. [DOI] [PubMed] [Google Scholar]
  20. Ku G., Thomas C. E., Akeson A. L., Jackson R. L. Induction of interleukin 1 beta expression from human peripheral blood monocyte-derived macrophages by 9-hydroxyoctadecadienoic acid. J Biol Chem. 1992 Jul 15;267(20):14183–14188. [PubMed] [Google Scholar]
  21. Lau C. S., Bridges A. B., Muir A., Scott N., Bancroft A., Belch J. J. Further evidence of increased polymorphonuclear cell activity in patients with Raynaud's phenomenon. Br J Rheumatol. 1992 Jun;31(6):375–380. doi: 10.1093/rheumatology/31.6.375. [DOI] [PubMed] [Google Scholar]
  22. LeRoy E. C., Black C., Fleischmajer R., Jablonska S., Krieg T., Medsger T. A., Jr, Rowell N., Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202–205. [PubMed] [Google Scholar]
  23. Leroy E. C. Connective tissue synthesis by scleroderma skin fibroblasts in cell culture. J Exp Med. 1972 Jun 1;135(6):1351–1362. doi: 10.1084/jem.135.6.1351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Leroy E. C., Smith E. A., Kahaleh M. B., Trojanowska M., Silver R. M. A strategy for determining the pathogenesis of systemic sclerosis. Is transforming growth factor beta the answer? Arthritis Rheum. 1989 Jul;32(7):817–825. [PubMed] [Google Scholar]
  25. Markert M., Andrews P. C., Babior B. M. Measurement of O2- production by human neutrophils. The preparation and assay of NADPH oxidase-containing particles from human neutrophils. Methods Enzymol. 1984;105:358–365. doi: 10.1016/s0076-6879(84)05048-5. [DOI] [PubMed] [Google Scholar]
  26. Maslen C. L., Hall N. D., Woolf A. D., Maddison P. J. Enhanced oxidative metabolism of neutrophils from patients with systemic sclerosis. Br J Rheumatol. 1987 Apr;26(2):113–117. doi: 10.1093/rheumatology/26.2.113. [DOI] [PubMed] [Google Scholar]
  27. Murrell D. F. A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol. 1993 Jan;28(1):78–85. doi: 10.1016/0190-9622(93)70014-k. [DOI] [PubMed] [Google Scholar]
  28. Norton W. L., Nardo J. M. Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med. 1970 Aug;73(2):317–324. doi: 10.7326/0003-4819-73-2-317. [DOI] [PubMed] [Google Scholar]
  29. Polisson R. P., Gilkeson G. S., Pyun E. H., Pisetsky D. S., Smith E. A., Simon L. S. A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels. J Rheumatol. 1996 Apr;23(4):654–658. [PubMed] [Google Scholar]
  30. Roberts A. B., Sporn M. B., Assoian R. K., Smith J. M., Roche N. S., Wakefield L. M., Heine U. I., Liotta L. A., Falanga V., Kehrl J. H. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. doi: 10.1073/pnas.83.12.4167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Roumm A. D., Whiteside T. L., Medsger T. A., Jr, Rodnan G. P. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984 Jun;27(6):645–653. doi: 10.1002/art.1780270607. [DOI] [PubMed] [Google Scholar]
  32. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  33. Sherer G. K., Jackson B. B., Leroy E. C. Chromosome breakage and sister chromatid exchange frequencies in scleroderma. Arthritis Rheum. 1981 Nov;24(11):1409–1413. doi: 10.1002/art.1780241112. [DOI] [PubMed] [Google Scholar]
  34. Uitto J., Bauer E. A., Eisen A. Z. Scleroderma: increased biosynthesis of triple-helical type I and type III procollagens associated with unaltered expression of collagenase by skin fibroblasts in culture. J Clin Invest. 1979 Oct;64(4):921–930. doi: 10.1172/JCI109558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Watters L. C., King T. E., Schwarz M. I., Waldron J. A., Stanford R. E., Cherniack R. M. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1986 Jan;133(1):97–103. doi: 10.1164/arrd.1986.133.1.97. [DOI] [PubMed] [Google Scholar]
  36. White B., Bauer E. A., Goldsmith L. A., Hochberg M. C., Katz L. M., Korn J. H., Lachenbruch P. A., LeRoy E. C., Mitrane M. P., Paulus H. E. Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis. Arthritis Rheum. 1995 Mar;38(3):351–360. doi: 10.1002/art.1780380309. [DOI] [PubMed] [Google Scholar]
  37. Zwijsen R. M., Japenga S. C., Heijen A. M., van den Bos R. C., Koeman J. H. Induction of platelet-derived growth factor chain A gene expression in human smooth muscle cells by oxidized low density lipoproteins. Biochem Biophys Res Commun. 1992 Aug 14;186(3):1410–1416. doi: 10.1016/s0006-291x(05)81563-3. [DOI] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES