Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: A phase II dose-ranging randomised controlled trial

Annals of the Rheumatic Diseases

Volumn 76, Issue 3, 2017, Pages 534-542

  Wallace, Daniel J ^a   Strand, Vibeke ^b   Merrill, Joan T ^c   Popa, Serghei ^d   Spindler, Alberto J ^e   Eimon, Alicia ^f   Petri, Michelle ^g   Smolen, Josef S ^h   Wajdula, Joseph ⁱ   Christensen, Jared ⁱ   Li, Cheryl ⁱ   Diehl, Annette ⁱ   Vincent, Michael S ⁱ   Beebe, Jean ⁱ   Healey, Paul ⁱ   Sridharan, Sudhakar ^j  

^a CEDARS SINAI MEDICAL CENTER   (United States)

^b STANFORD UNIVERSITY   (United States)

^c OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

^d Republican Clinical Hospital   (Moldova)

^e Centro Medico Privado de Reumatologia   (Argentina)

^f CEMIC   (Argentina)

^g JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^h MEDICAL UNIVERSITY OF VIENNA   (Austria)

ⁱ PFIZER INC   (United States)

^j Pharmaceutical Product Development   (United States)

more..

Author keywords

Autoimmune Diseases; Cytokines; Systemic Lupus Erythematosus; Treatment

Indexed keywords

INTERLEUKIN 6 ANTIBODY; MONOCLONAL ANTIBODY; PF 04236921; PLACEBO; UNCLASSIFIED DRUG; INTERLEUKIN 6; PF-04236921;

ADULT; AGED; ARTHRALGIA; ARTICLE; BACKACHE; BRITISH ISLES LUPUS ASSESSMENT GROUP BASED COMPOSITE LUPUS ASSESSMENT; BRONCHITIS; BRONCHOPNEUMONIA; CELLULITIS; CLOSTRIDIUM DIFFICILE INFECTION; CONTROLLED STUDY; CONTUSION; COUGHING; CYSTITIS; DIARRHEA; DISEASE ACTIVITY; DISEASE ACTIVITY SCORE; DISEASE EXACERBATION; DIZZINESS; DRUG EFFICACY; DRUG SAFETY; DRUG WITHDRAWAL; FEMALE; FEVER; FOLLOW UP; HEADACHE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERTRIGLYCERIDEMIA; INJECTION SITE REACTION; INSOMNIA; LARYNGITIS; LIMB PAIN; MAJOR CLINICAL STUDY; MALE; NAUSEA; PHARYNGITIS; PHASE 2 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL; RASH; SEPSIS; SHORT FORM 36; SINUSITIS; SLEDAI; SYSTEMIC LUPUS ERYTHEMATOSUS; TUBERCULOSIS; UPPER ABDOMINAL PAIN; UPPER RESPIRATORY TRACT INFECTION; VAGINITIS; VOMITING; ANTAGONISTS AND INHIBITORS; CHEMICALLY INDUCED; CLINICAL TRIAL; LUNG EMBOLISM; LUPUS ERYTHEMATOSUS, SYSTEMIC; MIDDLE AGED; RECURRENT DISEASE; SEVERITY OF ILLNESS INDEX; SUBCUTANEOUS DRUG ADMINISTRATION;

ADULT; ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; DIARRHEA; FEMALE; HEADACHE; HUMANS; INJECTIONS, SUBCUTANEOUS; INTERLEUKIN-6; LUPUS ERYTHEMATOSUS, SYSTEMIC; MALE; MIDDLE AGED; NAUSEA; PULMONARY EMBOLISM; SEPSIS; SEVERITY OF ILLNESS INDEX; SYMPTOM FLARE UP;

EID: 85014603881     PISSN: 00034967     EISSN: 14682060     Source Type: Journal    
DOI: 10.1136/annrheumdis-2016-209668     Document Type: Article

References (35)

1. Gordon C, Isenberg D, Lerstrøm K, et al. The substantial burden of systemic lupus erythematosus on the productivity and careers of patients: a European patient-driven online survey. Rheumatology (Oxford) 2013;52:2292-301.
2. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002;4(Suppl 3):S233-42.
3. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol 1990;8:253-78.
4. Fauci AS, Moutsopoulos HM. Polyclonally triggered B cells in the peripheral blood and bone marrow of normal individuals and in patients with systemic lupus erythematosus and primary Sjögren's syndrome. Arthritis Rheum 1981;24:577-83.
5. Smith HR, Steinberg AD. Autoimmunity-a perspective. Annu Rev Immunol 1983;1:175-210.
6. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003;56:481-90.
7. Tackey E, Lipsky PE, Illei GG. Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 2004;13:339-43.
8. Castell JV, Gómez-Lechón MJ, David M, et al. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 1990;12:1179-86.
9. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8.
10. Chun HY, Chung JW, Kim HA, et al. Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol 2007;27:461-6.
11. Herrera-Esparza R, Barbosa-Cisneros O, Villalobos-Hurtado R, et al. Renal expression of IL-6 and TNFa genes in lupus nephritis. Lupus 1998;7:154-8.
12. Linker-Israeli M, Deans RJ, Wallace DJ, et al. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 1991;147:117-23.
13. Nürnberg W, Haas N, Schadendorf D, et al. Interleukin-6 expression in the skin of patients with lupus erythematosus. Exp Dermatol 1995;4:52-7.
14. Stuart RA, Littlewood AJ, Maddison PJ, et al. Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders. Clin Exp Rheumatol 1995;13:17-22.
15. Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010;62:542-52.
16. Fogel R, Sridharan S, Li C, et al. Safety, pharmacokinetics, and pharmacodynamics of a human anti-IL6 monoclonal antibody PF-04236921 in healthy subjects. Ann Rheum Dis 2013;71(Suppl 3):680.
17. Ware JE. User's manual for the SF-36v2 health survey. Lincoln, RI, USA: QualityMetric Incorporated, 1993.
18. Strand V, Crawford B. Improvement in health-related quality of life in patients with SLE following sustained reductions in anti-dsDNA antibodies. Expert Rev Pharmacoecon Outcomes Res 2005;5:317-26.
19. Lee J, Dhillon N, Pope J. All-cause hospitalizations in systemic lupus erythematosus from a large Canadian referral centre. Rheumatology (Oxford) 2013;52:905-9.
20. Furie RA, Leon G, Thomas M, et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis 2015;74:1667-75.
21. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 2012;71:1343-9.
22. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61:1168-78.
23. Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis 2014;73:183-90.
24. Isenberg DA, Petri M, Kalunian K, et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016;75:323-31.
25. Du Clos TW, Mold C. Pentraxins (CRP, SAP) in the process of complement activation and clearance of apoptotic bodies through Fcγ receptors. Curr Opin Organ Transplant 2011;16:15-20.
26. Croker BA, Krebs DL, Zhang JG, et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 2003;4:540-5.
27. Henriques A, Inês L, Couto M, et al. Frequency and functional activity of Th17, Tc17 and other T-cell subsets in Systemic Lupus Erythematosus. Cell Immunol 2010;264:97-103.
28. Kleczynska W, Jakiela B, Plutecka H, et al. Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus. Folia Histochem Cytobiol 2011;49:646-53.
29. Korn T, Mitsdoerffer M, Croxford AL, et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2008;105:18460-5.
30. Chung WS, Lin CL, Chang SN, et al. Systemic lupus erythematosus increases the risks of deep vein thrombosis and pulmonary embolism: a nationwide cohort study. J Thromb Haemost 2014;12:452-8.
31. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B Lymphocyte Stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918-30.
32. Isenberg D, Gordon C, Licu D, et al. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis 2015;74:2006-15.
33. Khamashta M, Merrill JT, Werth VP, et al. Sifalimumab, an anti-interferon-a monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016; Published Online First 23 March 2016. doi:10.1136/annrheumdis-2015-208562
34. Merrill JT, van Vollenhoven RF, Buyon JP, et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016;75:332-40.
35. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:721-31.