Cytokines As Therapeutic Targets in SLE

Overview

Journal Nat Rev Rheumatol

Specialty Rheumatology

Date 2010 May 5

PMID 20440285

Citations 73

Authors

Lars Ronnblom

Keith B Elkon

Affiliations

Soon will be listed here.

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease involving most immune cells. Studies in both experimental animal models of lupus and patients with SLE have revealed a number of cytokine pathways that are important in the disease process. Among these are B-cell activating factor, which promotes B-cell survival and autoantibody production, interferon-alpha, which acts as an immune adjuvant, and tumor necrosis factor, which contributes to organ inflammation. This knowledge, in combination with the successful use of anti-TNF treatment in rheumatoid arthritis, has spurred the development of several biologic agents targeting different cytokines or their receptors in SLE. Consequently, many trials of anticytokine therapies for SLE are underway. Although most of these trials are small or in early phases, the results of some large studies have also been reported. In this Review, we discuss the rationale for anticytokine therapies in SLE and review agents currently in use, and those being developed and tested experimentally. We present the results from published trials and discuss the tentative conclusions that can be drawn regarding the efficacy of the new agents. Finally, we provide suggestions for the future of treatment for SLE, including new therapeutic strategies.

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References

Hu N, Long H, Zhao M, Yin H, Lu Q . Aberrant expression pattern of histone acetylation modifiers and mitigation of lupus by SIRT1-siRNA in MRL/lpr mice. Scand J Rheumatol. 2009; 38(6):464-71. DOI: 10.3109/03009740902895750. View

Castigli E, Wilson S, Scott S, Dedeoglu F, Xu S, Lam K . TACI and BAFF-R mediate isotype switching in B cells. J Exp Med. 2005; 201(1):35-9. PMC: 2212754. DOI: 10.1084/jem.20032000. View

Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X . Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009; 60(5):1472-83. DOI: 10.1002/art.24499. View

Tak P, Thurlings R, Rossier C, Nestorov I, Dimic A, Mircetic V . Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study. Arthritis Rheum. 2008; 58(1):61-72. DOI: 10.1002/art.23178. View

Sturfelt G, Roux-Lombard P, Wollheim F, Dayer J . Low levels of interleukin-1 receptor antagonist coincide with kidney involvement in systemic lupus erythematosus. Br J Rheumatol. 1998; 36(12):1283-9. DOI: 10.1093/rheumatology/36.12.1283. View

Hu X, Ivashkiv L . Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity. 2009; 31(4):539-50. PMC: 2774226. DOI: 10.1016/j.immuni.2009.09.002. View

Vereecke L, Beyaert R, van Loo G . The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol. 2009; 30(8):383-91. DOI: 10.1016/j.it.2009.05.007. View

Baccala R, Hoebe K, Kono D, Beutler B, Theofilopoulos A . TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med. 2007; 13(5):543-51. DOI: 10.1038/nm1590. View

Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F . Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008; 58(1):251-62. DOI: 10.1002/art.23186. View

10.

Clarke A, Vyse T . Genetics of rheumatic disease. Arthritis Res Ther. 2009; 11(5):248. PMC: 2787281. DOI: 10.1186/ar2781. View

11.

Gordon C, Bertsias G, Ioannidis J, Boletis J, Bombardieri S, Cervera R . EULAR points to consider for conducting clinical trials in systemic lupus erythematosus. Ann Rheum Dis. 2008; 68(4):470-6. DOI: 10.1136/ard.2007.083022. View

12.

Bertsias G, Gordon C, Boumpas D . Clinical trials in systemic lupus erythematosus (SLE): lessons from the past as we proceed to the future--the EULAR recommendations for the management of SLE and the use of end-points in clinical trials. Lupus. 2008; 17(5):437-42. DOI: 10.1177/0961203308090031. View

13.

Braun D, Geraldes P, Demengeot J . Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice. J Autoimmun. 2003; 20(1):15-25. DOI: 10.1016/s0896-8411(02)00109-9. View

14.

Malide D, Russo P, Bendayan M . Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Hum Pathol. 1995; 26(5):558-64. DOI: 10.1016/0046-8177(95)90253-8. View

15.

Smolen J, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E . Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008; 371(9617):987-97. DOI: 10.1016/S0140-6736(08)60453-5. View

16.

Graham R, Hom G, Ortmann W, Behrens T . Review of recent genome-wide association scans in lupus. J Intern Med. 2009; 265(6):680-8. DOI: 10.1111/j.1365-2796.2009.02096.x. View

17.

Mosser D, Zhang X . Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 2009; 226:205-18. PMC: 2724982. DOI: 10.1111/j.1600-065X.2008.00706.x. View

18.

Strengell M, Julkunen I, Matikainen S . IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells. J Leukoc Biol. 2004; 76(2):416-22. DOI: 10.1189/jlb.1003488. View

19.

Baechler E, Batliwalla F, Karypis G, Gaffney P, Ortmann W, Espe K . Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003; 100(5):2610-5. PMC: 151388. DOI: 10.1073/pnas.0337679100. View

20.

Furie R, Petri M, Wallace D, Ginzler E, Merrill J, Stohl W . Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009; 61(9):1143-51. PMC: 2748175. DOI: 10.1002/art.24698. View