Hypocomplementemia during tocilizumab treatment: Long-term follow-up results.
Journal
Medicine
ISSN: 1536-5964
Titre abrégé: Medicine (Baltimore)
Pays: United States
ID NLM: 2985248R
Informations de publication
Date de publication:
17 Jun 2022
17 Jun 2022
Historique:
received:
23
10
2021
accepted:
09
05
2022
entrez:
17
6
2022
pubmed:
18
6
2022
medline:
22
6
2022
Statut:
epublish
Résumé
Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the long-term outcome of patients treated with TCZ who developed hypocomplementemia regarding serious bacterial infections or autoimmune diseases (AID).The charts of patients treated with TCZ at two rheumatology centers were reviewed retrospectively. Data regarding patients' age, gender, disease duration, autoantibodies status, previous or concomitant treatments, blood counts, liver enzymes, C3 and C4 levels at baseline and during TCZ treatment, episodes of infections, allergic reactions, and AID were analyzed. Univariate analysis was used to compare patients with low C3, C4 levels versus patients with normal C3, C4 levels. Variables that were statistically significant associated or tended to be associated with low C3 or C4 were included in multiple variable logistic regression.Of 132 patients treated with TCZ, 108 had serial measurements of serum complement concentration. Thirty-three (30%) patients developed low C4 levels and 23 (21%) had also low C3. Mean TCZ treatment period was 4.9 years (range, 1-14 years). All patients had normal complement levels at baseline. Leukopenia occurred in 18 (16.7%) patients, 14 of whom (77%) had low complement. Persistent leukopenia was observed in 8% and 5.3% of patients with normal C3 and C4 levels, respectively, as opposed to 47% and 42% of patients with low C3 or low C4, respectively. Low C3, C4 levels correlated with prolonged TCZ treatment retention time and effectiveness. There were no serious bacterial infections or new onset AID.Hypocomplementemia during TCZ treatment was accompanied by leukopenia that correlated with treatment duration. Hypocomplementemia was not associated with serious bacterial infections or new onset AID. Decreased complement levels were associated with treatment longevity. The role of monitoring complement level in predicting treatment response or assessing disease activity deserves further investigation.
Identifiants
pubmed: 35713462
doi: 10.1097/MD.0000000000029528
pii: 00005792-202206170-00041
pmc: PMC9276208
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Complement C3
0
tocilizumab
I031V2H011
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e29528Informations de copyright
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
Références
Garbers C, Hermanns HM, Schaper F, et al. Plasticity and cross-talk of Interleukin 6-type cytokines. Cytokine Growth Factor Rev 2012;23:85–97.
Scheller J, Rose-John S. Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol 2006;195:173–83.
Rose-John S. Il-6 trans-signaling via the soluble IL-6 receptor: importance for the proinflammatory activities of IL-6. Int J Biol Sci 2012;8:1237–47.
Jones SA, Scheller J, Rose-john S. Science in medicine therapeutic strategies for the clinical blockade of IL-6 /gp130 signaling. Cell 2011;121:3375–83.
Baumann H, Gauldie J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med 1990;7:147–59.
Volanakis JE. Transcriptional regulation of complement genes. Annual Rev Immunol 2003;13:277–305.
Castell JV, Gómez-Lechón MJ, David M, et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett 1989;242:237–9.
Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010;11:785–97.
Walport MJ. Complement. N Engl J Med 2001;344:1058–66.
Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371:987–97.
Spiera R, Unizony SH, Bao M, et al. Tocilizumab vs placebo for the treatment of giant cell arteritis with polymyalgia rheumatica symptoms, cranial symptoms or both in a randomized trial. Semin Arthritis Rheum 2021;51:469–76.
Mijušković Z, Rackov L, Pejović J, et al. Immune complexes and complement in serum and synovial fluid of rheumatoid arthritis patients. J Med Biochem 2009;28:166–71.
Gilliam BE, Reed MR, Chauhan AK, et al. Significance of complement components C1q and C4 bound to circulating immune complexes in juvenile idiopathic arthritis: support for classical complement pathway activation. Clin Exp Rheumatol 2011;29:1049–56.
Chen R, MA L, Wu S, et al. AB0491 Elevated complement 3 indicates disease activity in Takayasu Arteritis. Ann Rheum Dis 2020;79: (Suppl 1): 1543–1543.
Malmvall BE, Bengtsson BÅ, Kaijser B, et al. Serum levels of immunoglobulin and complement in giant-cell arteritis. JAMA 1976;236:1876–8.
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.
Braun-Moscovici Y, Braun M, Markovits D, et al. SAT0213 hypocomplementemia during Tocilizumab treatment for rheumatoid arthritis: long term follow-up results. Ann Rheum Dis 2015;74: (Suppl 2): 734.2–734.
Romano C, del Mastro A, Sellitto A, et al. Tocilizumab reduces complement C3 and C4 serum levels in rheumatoid arthritis patients. Clin Rheumatol 2018;37:1695–700.
Aletaha D, Neogi T, Silman AJ, et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569–81.
Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. Published 2004. https://pubmed.ncbi.nlm.nih.gov/14760812/ .
Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992;19:424–30.
Arend WP, Michel BA, Block DA. Criteria for the classification of Takayasu arteritis. Arthritis Rheumatol 1990;33:1129–34.
Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122–8.
Hoogen F, Van den, Baron M, et al. Classification criteria for systemic sclerosis: an ACR-EULAR Collaborative Initiative. Arthritis Rheumatol 2014;65:2737–47.
Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol 1989;16:328–34.
Sandri G, Lumetti F, Ferri C, et al. FRI0234 Complement depletion in rheumatoid arthritis patients treated with tocilizumab: a marker of clinical efficacy? Ann Rheum Dis 2013;72: (Suppl 3): A452.2–A453.
Lubbers R, van Essen MF, van Kooten C, et al. Production of complement components by cells of the immune system. Clin Exp Immunol 2017;188:183–94.
Barnum SR. Complement biosynthesis in the central nervous system. Crit Rev Oral Biol Med 1995;6:132–46.
Reis ES, Barbuto JAM, Isaac L. Human monocyte-derived dendritic cells are a source of several complement proteins. Inflam Res 2006;55:179–84.
Zhang M, Gu J, Zhang C. Hepatitis B virus X protein binding to hepsin promotes C3 production by inducing IL-6 secretion from hepatocytes. Oncotarget 2016;7:7780–800.
Okroj M, Heinegård D, Holmdahl R, et al. Rheumatoid arthritis and the complement system. Ann Med 2007;39:517–30.
Matsuo Y, Mizoguchi F, Kohsaka H, et al. Tocilizumab-induced immune complex glomerulonephritis in a patient with rheumatoid arthritis. Rheumatology (Oxford, England) 2013;52:1341–3.
Rubbert-Roth A, Sebba A, Brockwell L, et al. Malignancy rates in patients with rheumatoid arthritis treated with tocilizumab. RMD Open 2016;2:e000213.
Wright HL, Cross AL, Edwards SW, et al. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (United Kingdom) 2014;53:1321–31.
Lok LSC, Farahi N, Juss JK, et al. Effects of tocilizumab on neutrophil function and kinetics. Eur J Clin Invest 2017;47:736–45.
Moots RJ, Sebba A, Rigby W, et al. Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: Pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology (United Kingdom) 2017;56:541–9.