Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2008, vol. 17, nr 4, July-August, p. 433–439

Publication type: review article

Language: English

Perspectives of Systemic Lupus Erythematosus Therapy

Perspektywy terapii tocznia układowego

Krzysztof Borysewicz1,

1 Department of Rheumatology and Internal Diseases Silesian Piasts University of Medicine in Wrocław, Poland

Abstract

Although systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown origin, recent advances in our understanding of its pathogenesis have suggested new, targeted approaches to therapy. In this review the underlying scientific rationale and results of clinical studies of new treatment approaches to SLE are discussed with a focus on cell−depleting therapies and cytokine blockade. It has become clear that B lymphocytes play a key role in the disease’s pathogenesis and aberrant interaction between B and T cells are critical to its emergence and progression. New agents that directly target immune cells which are abnormal in SLE include B−celldepleting (anti−CD20) and −modulating (anti−CD22) antibodies. Another promising approach is to block co−stimulatory interactions between T and B cell (CTLA−4Ig). Immune cells can also be manipulated indirectly through cytokine effects (anti−BAFF). Pro−inflammatory cytokines can be blocked in SLE (anti−TNF, anti−IL−10). Most of the available data on these new treatment approaches stem from open−label trials, but controlled trials are underway.

Streszczenie

Chociaż toczeń układowy jest schorzeniem autoimmunologicznym o nieznanej etiologii, to postępy w poznaniu zachodzących zjawisk patogenetycznych pozwoliły na wyznaczenie nowych celów terapeutycznych. W artykule omówiono podstawy naukowe oraz wyniki wstępnych badań klinicznych nad zastosowaniem nowych celów terapeutycznych, takich jak metoda usuwania aktywnych komórek i blokowanie aktywności cytokin. Limfocyty B odgrywają podstawową rolę w patogenezie tocznia układowego, a wzajemne oddziaływanie między komórkami B i T wydaje się, że jest zasadniczym mechanizmem powodującym progresję choroby. Nowymi substancjami ingerującymi w odpowiedź immunologiczną, zależną od komórek B, jest usuwanie tych komórek (anty−CD20) oraz stosowanie przeciwciał modulujących wzajemne oddziaływanie komórkowe (anty−CD22). Inną obiecującą metodą jest blokowanie czynników kostymulujących oddziaływanie komórek B i T (CTLA−4Ig). Cytokiny mogą również oddziaływać na komórki immunologiczne w sposób pośredni (anty−BAFF). Inną metodą hamowania odpowiedzi immunologicznej jest stosowanie substancji blokujących działanie cytokin prozapalnych (anty−TNF, anty−IL10). Wprowadzenie nowych metod terapeutycznych wymaga przeprowadzenia kontrolowanych badań klinicznych, dotychczas większość przedstawionych danych pochodzi z otwartych obserwacji klinicznych prowadzonych na niewielkiej liczbie chorych.

Key words

SLE, treatment, monoclonal antibodies, rituximab

Słowa kluczowe

toczeń układowy, leczenie, przeciwciała monoklonalne, rytuksymab

References (40)

  1. Lipsky PE: Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2001, 2, 764–766.
  2. Godfrey T, Khamashta MA, Huges GR: Therapeutic advances in systemic lupus erythematosus. Curr Opin Rheumatol 1998, 10, 435–441.
  3. Abu−Shakra M, Urowitz MB, Gladman DD, Chan OT, Roschke V: Mortality studies in systemic lupus erythematosus. Results from a single center. J Rheumatol 1995, 22, 1259–1264.
  4. Shlomchik MJ, Craft JE, Mamula MJ: From T to B and back again: positive feedback in systemic autoimmune disease. Nature Rev Immunol 2001, 1, 147–153.
  5. Mamula MJ, Fatenejad S, Craft J: B cells process and present lupus autoantigens that initiate autoimmune T cell response. J Immunol 1994, 152, 1453–1461.
  6. Linton PJ, Harbeston J, Bradley LM: A critical role for B cells in the development of memory CD4 cells. J Immunol 2000, 165, 5558–5565.
  7. Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ: A novel mouse with B cells but lacking serum antibody reveals as antibody−independent role for B cells in murine lupus. J Exp Med 1999, 189, 1639–1648.
  8. Cheema GS, Roschke V, Hilbert DM, Stohl W: Elevated serum B lymphocyte stimulator levels in patients with systemic immune−based rheumatic diseases. Arthritis Rheum 2001, 44, 1313–1319.
  9. Petri M, Stohl W, Chatmam W, Jones RJ, Karlson EW: BlyS plasma concentrations correlate with disease activity and levels of anti−dsDNA autoantibodies and immunoglobulins (IG) in a SLE observational study. Arthritis Rheum 2003, 48, 655.
  10. Browning JL: B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nature 2006, 5, 564–576.
  11. Grillo−Lopez AJ, White CA, Varns C, Hungtor NB, Brown G: Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999, 26, 66–73.
  12. Anolik JH, Barnard J, Cappione A, Pugh−Bernard AE, Felgar RE, Looney J, Sanz I: Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 2004, 50, 3580–3590.
  13. Levine TD: Apilot study of rituximab therapy for refractory dermatomyositis. Arthritis Rheum 2002, 46, Suppl. 9, 1299.
  14. Specks U, Fervenza FC, McDonald TJ, Hogan MC: Response of Wegener granulomatosus to anti−CD20 chimeric monoclonal antibody therapy. N Engl J Med 2001, 44, 2836–2840.
  15. Edwards JC, Szczepański L, Szechiński J, Filipowicz−Sosnowska A, Emery P, Close DR, Stevens RM, Shaw TS: Efficacy of B cell targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004, 350, 2572–2581.
  16. Anolik JH, Campbell D, Ritchlin C, Looney RJ, Young F, Arend LJ, Sloand JA: B lymphocyte depletion as a novel treatment for systemic lupus (SLE): Phase I/II trial of rituximab (Rituxan) in SLE. Arthritis Rheum 2001, 44, S387.
  17. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA: An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002, 46, 2673–2677.
  18. Lenardo MJ, Ehrenstein MR, Edwards JC, Ehrenstein MR, Isenberg DA: Treatment of refractory lupus nephritis with B lymphocyte depletion. Arthritis Rheum 2003, 48, Suppl. 9, 594.
  19. Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, Sloand JA, Rosenblatt J, Sanz I: B cell depletion as a novel treatment of systemic lupus erythematosus. Arthritis Rheum 2004, 50, 2580–2589.
  20. Boletis JN, Sfikakis PP, Lionaki SJ, Kostakis A, Viglis JV, Daphnis E: An open study of B cell depletion in patients with proliferative lupus nephritis: preliminary results. J Am Soc Nephrol 2003, 14, 379.
  21. Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA: B−cell depletion in the treatment for systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology 2005, 44, 1542–1545.
  22. Tahir H, Isenberg DA: Novel therapies in lupus nephritis. Lupus 2005, 14, 77–82.
  23. Albert D, Khan S, Stransbury J, Clarkin C, Brensinger CM: Aphase I trial of rituximab (anti−CD20) for treatment of systemic lupus erythematosus. Arthritis Rheum 2004, 50, 5446.
  24. Teeling JL, French RR, Cragg MS, Brakel J, Pluyter M, Huang H, Chan C, Parren PWH, Hack E, Dechant M, Valerius T, Winkel JGJ, Glennie MJ: Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non−Hodgkin lymphomas. Blood 2004, 104, 1793–1800.
  25. Kaufmann J, Wegener WA, Horak ID, Kvien TK, Hansen A: Initial clinical study of immunotherapy in SLE using epratuzumab (humanized anti−CD22 antibody). Arthritis Rheum 2004, 50, S447.
  26. Schneider M: Exploring new territory: Considering the future. Lupus 2007, 16, 221–226.
  27. Wnag X, Huang W, Schiffer LE, Mihara M, Akkerman A, Hiromatsu K, Davidson A: Effects of anti−CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum 2003, 48, 495–506.
  28. Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A: A short course of BG9588 (anti−CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003, 48, 719–727.
  29. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Naumah IF, Williams GR, Becker JC, Hagerty DT, Moreland LW: Treatment of rheumatoid arthritis by selective inhibition of T−cell activation with fusion protein CTLA4Ig. N Eng J Med 2003, 349, 1907–1915.
  30. Crow M: Costimulatory molecules and T−cell−B−cell interactions. Rheum Dis Clin North Am 2004, 30, 1225–1227.
  31. Petri M, Stohl W, Chatham W et al.: BLyS plasma concentrations correlate with disease activity and levels of anti−dsDNAautoantibodies and immunoglobulins (IG) in a SLE observational study. Arthritis Rheum 2003, 48, 655.
  32. Stohl W: A therapeutic role for BlyS antagonists. Lupus 2004, 13, 317–322.
  33. Aringer M, Graninger WB, Steiner G, Smolen J: Safety and efficacy of TNFα blockade in systemic lupus erythematosus–an open label study. Arthritis Rheum 2005, 50, 3161–3169.
  34. Aringer M, Smolen JS: TNF and other proinflammatory cytokines in SLE: A rationale for therapeutic intervention. Lupus 2004, 13, 344–347.
  35. Gonzalez CM, Lopez−Longo FJ, Monteagudo, Humintonn JG: Anti−TNF agents are effective and safe in the management of systemic lupus erythematosus. Arthritis Rheum 2005, 50, S412.
  36. Park YB, Lee SK, Kom DS, Withell BG, Boerg HM: Elevated interleukin−10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 1998, 16, 283–288. 438 K. BORYSEWICZ
  37. Llorente L, Richaud−Patin Y, Garcia−Padilla C et al.: Systemic and biological effects of anti−interleukin−10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 2000, 43, 1790–1800.
  38. Ostendorf B, Iking−Konert C, Kurz K, Jung G, Sander O, Schneider M: Preliminary results of safety and efficacy of the interleukin−1 receptor antagonist anakinra in patients with severe lupus arthritis. Ann Rheum Dis 2005, 64, 630–633.
  39. Aringer M, Steiner G, Ekhart H, Wegener JM, Porkot J: Interleukin−18 (IL−18) is increased in SLE and induced bt TNF. Arthritis Rheum 2004, 50, S201.
  40. Baechler EC, Gregersen PK, Behrens TW: The emerging role of interferon in systemic lupus erythematosus. Curr Opin Immunol 2004, 16, 801–807.
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