Aktuelle Rheumatologie 2001; 26(1): 15-21
DOI: 10.1055/s-2001-11367
ORIGINALARBEIT

© Georg Thieme Verlag Stuttgart · New York

Humanes rekombinantes Erythropoietin in der Therapie der Anämie bei rheumatoider Arthritis

U. Kessler, J. P. Kaltwasser
  • Abteilung Rheumatologie, Medizinische Klinik III (Leiter: Prof. Dr. med. D. Hoelzer), J. W. Goethe-Universität, Frankfurt am Main
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Zusammenfassung

Die Anämie ist die häufigste extraartikuläre Manifestation der rheumatoiden Arthritis (RA) und trägt zur Reduktion der gesundheitsbezogenen Lebensqualität der betroffenen Patienten bei. Unter den vielfältigen möglichen Ursachen für die Entstehung einer Anämie im Rahmen der RA stehen die chronische Entzündungsanämie und die Eisenmangelanämie - meist als Folge chronisch-okkulter Blutungen - ganz im Vordergrund. Während die Blutungsanämie möglicherweise durch den Einsatz der neuen COX-2-Hemmer als Ersatz der klassischen nichtsteroidalen Antirheumatika (NSAR) in ihrer Häufigkeit reduziert werden kann, wird die chronische Entzündungsanämie, deren Pathogenese eng mit der RA als zugrundeliegender Krankheit verknüpft ist, auch in Zukunft ihre klinische Bedeutung beibehalten. Mit humanem rekombinanten Erythropoietin (rHu-Epo) steht heute ein Medikament zur Verfügung, das auch die Therapie dieser Anämieform ermöglicht, die lange als reines Epiphänomen der RA betrachtet wurde und nicht gezielt therapiert werden konnte. Die vorliegende Übersichtsarbeit fasst die klinische Bedeutung und Diagnose der chronischen Entzündungsanämie bei RA zusammen und diskutiert die Möglichkeiten eines optimierten therapeutischen Einsatzes von rHu-Epo als sinnvoller Erweiterung der bereits etablierten medikamentösen Therapiekonzepte bei Patienten mit RA.

Therapy of Anaemia in Rheumatoid Arthritis with Recombinant Human Erythropoietin

Anaemia is the most frequent extraarticular manifestation of rheumatoid arthritis (RA). Anaemia significantly reduces health-related quality of life of RA patients. The most commonly occurring among the various forms of anaemia associated with RA are anaemia of chronic disease (ACD) and iron deficiency anaemia, the latter being mostly caused by occult gastrointestinal blood losses due to NSAR treatment. In the near future NSAR-induced iron deficiency anaemia may be reduced by an increasing use of the new COX-2 selective NSAR. In contrast ACD, which is closely related to the pathogenesis of RA itself, will remain clinically important. ACD was formerly regarded as an epiphenomenon of RA without direct therapeutic option. Since recombinant human erythropoietin (rHu-Epo) has now been introduced in the treatment of anaemia, this may be successfully treated by direct stimulation of erythropoiesis by rHu-Epo. This paper reviews the clinical and diagnostic aspects of ACD in RA patients and summarises the therapeutic options for an optimised use of rHu-Epo in combination with current treatment modalities in RA patients.

Literatur

  • 1 Allen D A, Breen C, Yaqoob M M, Macdougall I C. Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of IFN-γ and TNF-α.  J Invest Med. 1999;  47 204-211
  • 2 Arnett F C, Edworthy S M, Bloch D A, McShane D J, Fries J F, Cooper N S, Healey L A, Kaplan S R, Liang M H, Luthra H S, Medsger T A, Mitchell D M, Neustadt D H, Pinals R S, Schaller J G, Sharp J T, Wilder R L, Hunder G G. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.  Arthritis Rheum. 1988;  31 315-324
  • 3 Atkins M B, Kappler K, Mier J W, Isaacs R E, Berkmann E M. Interleukin-6-associated anemia: determination of the underlying mechanism.  Blood. 1995;  86 1288-1291
  • 4 Baer A N, Dessypris E N, Goldwasser E, Krantz S B. Blunted erythropoietin response to anaemia in rheumatoid arthritis.  Br J Haematol. 1987;  66 559-564
  • 5 Belza B. The impact of fatigue on exercise performance.  Arthritis Care Res. 1994;  7 176-180
  • 6 Bennett R M. Haematological changes in rheumatoid disease.  Clin Rheum Dis. 1977;  3 433-465
  • 7 Besareb A, Flaharty K K, Erslev A J, McCrea J B, Vlasses P H, Medina F. Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: the case for subcutaneous administration.  J Am Soc Nephrol. 1992;  2 1405-1416
  • 8 Blake D R, Lunec J, Ahern M, Ring E FJ, Bradfield J, Gutteridge J MC. Effect of intravenous iron dextran on rheumatoid synovitis.  Ann Rheum Dis. 1985;  44 183-188
  • 9 Bommer J, Ritz E, Weinreich T, Bommer G, Ziegler T. Subcutaneous erythropoietin. Lancet II 1988: 406
  • 10 Bunn H F, Poyton R O. Oxygen sensing and molecular adaption to hypoxia.  Physiol Rev. 1996;  76 839-845
  • 11 Canadian Erythropoietin Study G roup. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis.  BMJ. 1990;  300 573-578
  • 12 Davis D, Charles P J, Potter A, Feldmann M, Maini N, Elliott M J. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumor necrosis α blockade.  Br J Rheumatol. 1997;  36 50-56
  • 13 Eckhardt K U, Bauer C. Erythropoietin in health and disease.  Eur J Clin Invest. 1989;  19 117-127
  • 14 Eschbach J W, Egrie J C, Downing M R, Browne J K, Adamson J W. Correction of the anaemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial.  N Eng J Med. 1987;  316 73-78
  • 15 Faquin W C, Schneider T J, Goldberg M A. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production.  Blood. 1992;  79 1987-1994
  • 16 Feelders R A, Vreugdenhil G, Eggermont A M, Kuiper-Kramer P A, van Eijk H G, Swaak A JG. Regulation of iron metabolism in the acute-phase response: interferon gamma and tumor necrosis factor alpha induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients.  Eur J Clin Invest. 1998;  28 520-527
  • 17 Giordano N, Sancasciani S, Borghi C, Fioravanti A, Marcolongo R. Antianemic and potential anti-inflammatory activity of desferrioxamine: Possible usefulness in rheumatoid arthritis.  Clin Exp Rheumatol. 1986;  4 25-29
  • 18 Gudbjoernsson B, Hallgren R, Wide L, Birgegard G. Response of anaemia in rheumatoid arthritis to treatment with subcutaneous recombinant human erythropoietin.  Ann Rheum Dis. 1992;  51 747-752
  • 19 Huyser B A, Parker J C, Thoreson R, Smarr K L, Johnson J C, Hoffmann R. Predictors of subjective fatigue among individuals with rheumatoid arthritis.  Arthritis Rheum. 1998;  12 2230-2237
  • 20 Jelkmann W, Metzen E. Erythropoietin in the control of red cell production.  Anat Anz. 1996;  178 391-403
  • 21 Kaltwasser J P, Gottschalk R. Erythropoietin and iron.  Kidney Int. 1999;  55 49-56
  • 22 Kampf D, Kahl A, Passlick J, Pustelnik, Eckardt K U, Ehmer B, Jacobs C, Baumelou A, Grabensee B, Gahl G M. Single-dose kinetics of recombinant human erythropoietin after intravenous, subcutaneous and intraperitoneal administration.  Contrib Nephrol. 1989;  76 106-111
  • 23 Kato Y, Takagi C, Tanaka J, Masaki Y, Furuya H. Effect of daily subcutaneous administration of recombinant erythropoietin on chronic anemia in rheumatoid arthritis.  Int Med. 1994;  33 1993-197
  • 24 Kessler U, Gottschalk R, Moeller B, Stucki G, Kaltwasser J P. Erythropoietin and intravenous iron: a new combination for patients with rheumatoid arthritis and anaemia of chronic disease.  Arthritis Rheum. 1999;  42 Suppl. 9 239
  • 25 Kessler U, Moeller B, Gottschalk R, Stucki G, Kaltwasser J P. Correction of anaemia in patients with rheumatoid arthritis increases health related quality of life.  Ann Rheum Dis. 2000;  59 Suppl. 1 48
  • 26 MacDougall I C. Strategies for iron supplementation: Oral versus intravenous.  Kidney Int. 1999;  55 61-66
  • 27 Means R T, Dessypris E N, Krantz S B. Inhibition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon.  J Cell Physiol. 1992;  150 59-64
  • 28 Means R T, Krantz S B. Inhibition of human erythroid colony-forming units by gamma interferon can be corrected by recombinant human erythropoietin.  Blood. 1991;  78 2564-2567
  • 29 Means R T, Krantz S B. Progress in understanding the pathogenesis of the anemia of chronic disease.  Blood. 1992;  80 1639-1647
  • 30 Means R T, Olsen N J, Krantz S B, Dessypris E N, Graber S E, Stone W J, O’Neil V L, Pincus T. Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: Clinical and in vitro studies.  Arthritis Rheum. 1989;  32 638-642
  • 31 Mercuriali F, Gualtieri G, Singaglia L, Inghilleri G, Biffi E, Vinci A, Colotti M T, Barosi G, Lambertenghi Deliliers G. Use of recombinant human erythropoietin to assist autologous blood donation by anemic rheumatoid arthritis patients undergoing major orthopedic surgery.  Transfusion. 1994;  34 501-506
  • 32 Miyake T, Kung C KH, Goldwasser E. Purification of human erythropoietin.  J Biol Chem. 1977;  252 5558-5564
  • 33 Mowat A G. Haematologic abnormalities in rheumatoid arthritis.  Sem Arthritis Rheum. 1971;  1 195-219
  • 34 Murphy E A, Bell A L, Wojtulewski J, Brzeski M, Madhok R, Capell H A. Study of erythropoietin in treatment of anaemia in patients with rheumatoid arthritis.  BMJ. 1994;  309 1337-1338
  • 35 Nordstroem D, Lindroth Y, Marsal L, Hafstroem I, Henrich C, Rantapaa-Dahlqvist S, Engstroem-Laurent a, Fyhrquist F, Friman C. Availability of iron and degree of inflammation modifies the response to recombinant human erythropoietin when treating anaemia of chronic disease in patients with rheumatoid arthritis.  Rheumatol Int. 1997;  17 67-73
  • 36 Peeters H RM, Jongen-Lavrencic M, Bakker C H, Vreugdenhil G, Breedveld F C, Swaak A JG. Recombinant human erythropoietin improves health-related quality of life in patients with rheumatoid arthritis and anaemia of chronic disease; utility measures correlate strongly with disease activity measures.  Rheumatol Int. 1999;  18 201-206
  • 37 Peeters H RM, Jongen-Lavrencic M, Vreugdenhil G, Swaak A JG. Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomised placebo controlled double blind 52 weeks clinical trial.  Ann Rheum Dis. 1996;  55 739-744
  • 38 Petterson T, Rosenloef K, Friman C, Mickos A, Teppo A M, Fyhrquist F. Successful treatment of the anemia of rheumatoid arthritis with subcutaneously administered recombinant human erythropoietin. Slower response in patients with more severe inflammation.  Scand J Rheumatol. 1993;  22 188-193
  • 39 Pincus T, Olsen N J, Russell J, Wolfe F, Harris E R, Schnitzer T J, Boccagno J A, Krantz S B. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis.  Am J Med. 1990;  89 161-168
  • 40 Pinero D J, Hu J, Cook B M, Scaduto R C, Connor J R. Interleukin-1beta increases binding of the iron regulatory protein and the synthesis of ferritin by increasing the labile iron pool.  Am J Physiol. 1999;  277 257-263
  • 41 Rave O, Wienands K. Erythropoietin - therapeutische Option bei c. P.-bedingter Anaemie. Z.  Rheumatol. 1995;  1 50-55
  • 42 Reddy P S, Lewis M. The adverse effect of intravenous iron-dextran in rheumatoid arthritis.  Arthritis Rheum. 1969;  12 454-457
  • 43 Remacha A F, Rodriguez-De La Serna A, Garcia-Die F, Geli C, Diaz C, Gimferrer E. Erythroid abnormalities in rheumatoid arthritis: the role of erythropoietin.  J Rheumatol. 1992;  19 1687-1691
  • 44 Rusten L S, Jacobsen S EW. Tumor necrosis factor (TNF)-α directly inhibits human erythropoiesis in vitro: Role of p55 and p75 TNF receptors.  Blood. 1995;  85 989-996
  • 45 Salvarani C, Lasagni D, Casali B, Macchioni P, Boiardi L, Rossi F, Rivasi P, Portioli I. Recombinant human erythropoietin therapy in patients with the anemia of chronic disease.  J Rheumatol. 1991;  18 1168-1171
  • 46 Sasaki R, Masuda S, Nagao M. Erythropoietin: multiple physiological functions and regulation of biosynthesis.  Biosci Biotechnol Biochem. 2000;  64 1775-1793
  • 47 Silverberg D S, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E, Brosh D, Laniado S, Schwartz D, Yachnin T, Shapira I, Gavish D, Baruch R, Koifman B, Kaplan C, Steinbruch S, Iaina A. The use of subcutaneous erythropoietin and intravenous iron in the treatment of the anemia of severe, resistant congestive heart failure improves cardiac class, and markely reduces hospitalizations.  J Am Coll Cardiol. 2000;  35 1737-1744
  • 48 Sunder-Plassmann G, Hoerl W H. Importance of iron supply for erythropoietin therapy.  Nephrol Dial Transplant. 1995;  10 2070-2076
  • 49 Sunder-Plassmann G, Hoerl W H. Eisen und Erythropoietin.  Clin Lab. 1996;  42 269-277
  • 50 Takashina N, Kondo H, Kashiwaszaki S. Suppressed serum erythropoietin response to anemia and the efficacy of recombinant erythropoietin in the anemia of rheumatoid arthritis.  J Rheumatol. 1990;  17 885-887
  • 51 Thomas M L. Impact of anemia and fatigue on quality of life in cancer patients: a brief review.  Medical Oncology. 1998;  15 3-7
  • 52 Thomas M L. Anemia and quality of life in cancer patients: impact of transfusion and erythropoietin.  Medical Oncology. 1998;  15 13-18
  • 53 Vreugdenhil G, Wognum A W, van Eijk H G, Swaak A JG. Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness.  Ann Rheum Dis. 1990;  49 93-98
  • 54 Ware J E Jr, Sherbourne C D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.  Med Care. 1992;  30 473-483
  • 55 Weiss G. Iron and anaemia of chronic disease.  Kidney Int. 1999;  55 12-17
  • 56 Wieczorek L, Hirth P, Schöpe K B, Scigalla P, Krüger D. Molekulare Biologie von Erythropoietin.  In: Innovative Aspekte der klinischen Medizin. Heidelberg; Springer 1989: 55-70
  • 57 Zermati Y, Fichelson S, Valensi F, Freyssinier J M, Rouyer-Fessard P, Cramer E, Guichard J, Varet B, Hermine O. Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors.  Exp Hamatol. 2000;  28 885-894

Dr. med. Uta Kessler

Abteilung RheumatologieMedizinische Klinik IIIJ. W. Goethe-Universität

Theodor-Stern-Kai 760596 Frankfurt a. Main

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