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Pediatric Rheumatology
Published in: Pediatric Rheumatology 1/2018

Open Access 01-12-2018 | Review

Off-label use of tocilizumab to treat non-juvenile idiopathic arthritis in pediatric rheumatic patients: a literature review

Authors: Ju-Yang Jung, Moon-Young Kim, Chang-Hee Suh, Hyoun-Ah Kim

Published in: Pediatric Rheumatology | Issue 1/2018

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Abstract

Tocilizumab, an anti-interleukin-6 (IL-6) agent, is indicated as a treatment for several autoimmune or inflammatory diseases, including rheumatoid arthritis and juvenile idiopathic arthritis (JIA). IL-6 plays roles in both immune system dysregulation and inflammation, and thus efforts to extend the utility of tocilizumab in patients with autoinflammatory conditions are ongoing. Here, we survey the literature on the off-label use of tocilizumab in patients with juvenile-onset rheumatic diseases including juvenile systemic lupus erythematosus (SLE), juvenile dermatomyositis (DM), vasculitis, juvenile scleroderma, and other autoinflammatory diseases. There is no real evidence that tocilizumab is useful for patients with SLE and juvenile DM, but several cases of childhood Takayasu arteritis have experienced promising outcomes. In juvenile-onset scleroderma, for which no therapy that can halt disease progression is available, tocilizumab may stop progression and the associated functional impairment. Tocilizumab prevents systemic inflammation in patients with Kawasaki’s disease, but may develop coronary aneurysms. Tocilizumab has been used to treat several pediatric autoinflammatory diseases, including JIA-associated uveitis and Castleman’s disease. Further work in larger populations is necessary to confirm the effects of tocilizumab in patients with pediatric rheumatic diseases.
Literature
1.
Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 2012;33:571–7.PubMedCrossRef
2.
Weyand CM, Fulbright JW, Hunder GG, et al. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum. 2000;43:1041–8.PubMedCrossRef
3.
4.
Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10:720–7.PubMedCrossRef
5.
Okada M, Kitahara M, Kishimoto S, et al. IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol. 1988;141:1543–9.PubMed
6.
Hibi M, Murakami M, Saito M, et al. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990;63:1149–57.PubMedCrossRef
7.
Kishimoto T, Akira S, Narazaki M, et al. Interleukin-6 family of cytokines and gp130. Blood. 1995;86:1243–54.PubMed
8.
Taga T, Hibi M, Hirata Y, et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989;58:573–81.PubMedCrossRef
9.
Kishimoto T, Akira S, Taga T. Interleukin-6 and its receptor: a paradigm for cytokines. Science. 1992;258:593–7.PubMedCrossRef
10.
Narazaki M, Yasukawa K, Saito T, et al. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood. 1993;82:1120–6.PubMed
11.
Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs. 2009;69:609–32.PubMedCrossRef
12.
Tanaka T, Narazaki M, Kishimoto T. Anti-interleukin-6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases. FEBS Lett. 2011;585:3699–709.PubMedCrossRef
13.
Lally L, Forbess L, Hatzis C, et al. Brief report: a prospective open-label phase IIa trial of tocilizumab in the treatment of polymyalgia Rheumatica. Arthritis Rheumatol. 2016;68:2550–4.PubMedPubMedCentralCrossRef
14.
Puechal X, DeBandt M, Berthelot JM, et al. Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken). 2011;63:155–9.CrossRef
15.
de Boysson H, Fevrier J, Nicolle A, et al. Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence. Clin Rheumatol. 2013;32:141–7.PubMedCrossRef
16.
Kamphuis S, Silverman ED. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat Rev Rheumatol. 2010;6:538–46.PubMedCrossRef
17.
Baqi N, Moazami S, Singh A, et al. Lupus nephritis in children: a longitudinal study of prognostic factors and therapy. J Am Soc Nephrol. 1996;7:924–9.PubMed
18.
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.PubMed
19.
Iwano M, Dohi K, Hirata E, et al. Urinary levels of IL-6 in patients with active lupus nephritis. Clin Nephrol. 1993;40:16–21.PubMed
20.
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.PubMedPubMedCentralCrossRef
21.
Maeshima K, Ishii K, Torigoe M, et al. Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus. Lupus. 2012;21:1003–6.PubMedCrossRef
22.
Garcia-Hernandez FJ, Gonzalez-Leon R, Castillo-Palma MJ, et al. Tocilizumab for treating refractory haemolytic anaemia in a patient with systemic lupus erythematosus. Rheumatology (Oxford). 2012;51:1918–9.CrossRef
23.
Makol A, Gibson LE, Michet CJ. Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutaneous lupus and urticarial vasculitis. J Clin Rheumatol. 2012;18:92–5.PubMedCrossRef
24.
Iwai A, Naniwa T, Tamechika S, et al. Short-term add-on tocilizumab and intravenous cyclophosphamide exhibited a remission-inducing effect in a patient with systemic lupus erythematosus with refractory multiorgan involvements including massive pericarditis and glomerulonephritis. Mod Rheumatol. 2017;27:529–32.PubMedCrossRef
25.
Kim MY, Park S, Suh CH, et al. Patient with systemic lupus erythematosus combined with erosive arthritis was treated successfully with tocilizumab: a case report. J Rheum Dis. 2018;25:144–7.CrossRef
26.
Feldman BM, Rider LG, Reed AM, et al. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008;371:2201–12.PubMedCrossRef
27.
Robinson AB, Reed AM. Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis. Nat Rev Rheumatol. 2011;7:664–75.PubMedCrossRef
28.
Gono T, Kaneko H, Kawaguchi Y, et al. Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease. Rheumatology (Oxford). 2014;53:2196–203.CrossRef
29.
Wakiguchi H, Hasegawa S, Hirano R, et al. Successful control of juvenile dermatomyositis-associated macrophage activation syndrome and interstitial pneumonia: distinct kinetics of interleukin-6 and -18 levels. Pediatr Rheumatol Online J. 2015;13:49.PubMedPubMedCentralCrossRef
30.
Reed AM, Peterson E, Bilgic H, et al. Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course. Arthritis Rheum. 2012;64:4078–86.PubMedPubMedCentralCrossRef
31.
Kondo M, Murakawa Y, Matsumura T, et al. A case of overlap syndrome successfully treated with tocilizumab: a hopeful treatment strategy for refractory dermatomyositis? Rheumatology (Oxford). 2014;53:1907–8.CrossRef
32.
Cabrera N, Duquesne A, Desjonqueres M, et al. Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children. RMD Open. 2016;2:e000271.PubMedPubMedCentralCrossRef
33.
Szugye HS, Zeft AS, Spalding SJ. Takayasu arteritis in the pediatric population: a contemporary United States-based single center cohort. Pediatr Rheumatol Online J. 2014;12:21.PubMedPubMedCentralCrossRef
34.
35.
Noris M, Daina E, Gamba S, et al. Interleukin-6 and RANTES in Takayasu arteritis: a guide for therapeutic decisions? Circulation. 1999;100:55–60.PubMedCrossRef
36.
Nishimoto N, Nakahara H, Yoshio-Hoshino N, et al. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum. 2008;58:1197–200.PubMedCrossRef
37.
Tombetti E, Franchini S, Papa M, et al. Treatment of refractory Takayasu arteritis with tocilizumab: 7 Italian patients from a single referral center. J Rheumatol. 2013;40:2047–51.PubMedCrossRef
38.
Bravo Mancheno B, Perin F, Guez Vazquez Del Rey Mdel M, et al. Successful tocilizumab treatment in a child with refractory Takayasu arteritis. Pediatrics. 2012;130:e1720–4.PubMedCrossRef
39.
Batu ED, Sonmez HE, Hazirolan T, et al. Tocilizumab treatment in childhood Takayasu arteritis: case series of four patients and systematic review of the literature. Semin Arthritis Rheum. 2017;46:529–35.PubMedCrossRef
40.
Decker P, Olivier P, Risse J, et al. Tocilizumab and refractory Takayasu disease: four case reports and systematic review. Autoimmun Rev. 2018;17:353–60.PubMedCrossRef
41.
Canas CA, Canas F, Izquierdo JH, et al. Efficacy and safety of anti-interleukin 6 receptor monoclonal antibody (tocilizumab) in Colombian patients with Takayasu arteritis. J Clin Rheumatol. 2014;20:125–9.PubMedCrossRef
42.
Goel R, Danda D, Kumar S, et al. Rapid control of disease activity by tocilizumab in 10 'difficult-to-treat' cases of Takayasu arteritis. Int J Rheum Dis. 2013;16:754–61.PubMedCrossRef
43.
Zulian F, Cuffaro G, Sperotto F. Scleroderma in children: an update. Curr Opin Rheumatol. 2013;25:643–50.PubMedCrossRef
44.
Dumoitier N, Chaigne B, Regent A, et al. Scleroderma peripheral B lymphocytes secrete Interleukin-6 and transforming growth factor beta and Activate fibroblasts. Arthritis Rheumatol. 2017;69:1078–89.PubMedCrossRef
45.
Abdel-Magied RA, Kamel SR, Said AF, et al. Serum interleukin-6 in systemic sclerosis and its correlation with disease parameters and cardiopulmonary involvement. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33:321–30.PubMed
46.
Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387:2630–40.PubMedCrossRef
47.
Martini G, Campus S, Raffeiner B, et al. Tocilizumab in two children with pansclerotic morphoea: a hopeful therapy for refractory cases? Clin Exp Rheumatol. 2017;35(Suppl 106):211–3.PubMed
48.
Lythgoe H, Baildam E, Beresford MW, et al. Tocilizumab as a potential therapeutic option for children with severe, refractory juvenile localized scleroderma. Rheumatology (Oxford). 2018;57:398–401.CrossRef
49.
Dale RC, Gorman MP, Lim M. Autoimmune encephalitis in children: clinical phenomenology, therapeutics, and emerging challenges. Curr Opin Neurol. 2017;30:334–44.PubMedCrossRef
50.
51.
Lee WJ, Lee ST, Moon J, et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics. 2016;13:824–32.PubMedPubMedCentralCrossRef
52.
Randell RL, Adams AV, Van Mater H. Tocilizumab in refractory autoimmune encephalitis: a series of pediatric cases. Pedatr Neurol. 2018;86:66–8.
53.
Migally K, Braunlin EA, Zhang L, et al. Duration of high-dose aspirin therapy does not affect long-term coronary artery outcomes in Kawasaki disease. Pediatr Res. 2018;83:1136–45.
54.
55.
Fujimaru T, Ito S, Masuda H, et al. Decreased levels of inflammatory cytokines in immunoglobulin-resistant Kawasaki disease after plasma exchange. Cytokine. 2014;70:156–60.PubMedCrossRef
56.
Nozawa T, Imagawa T, Ito S. Coronary-artery aneurysm in tocilizumab-treated children with Kawasaki's disease. N Engl J Med. 2017;377:1894–6.PubMedCrossRef
57.
Lopalco G, Fabiani C, Sota J, et al. IL-6 blockade in the management of non-infectious uveitis. Clin Rheumatol. 2017;36:1459–69.PubMedCrossRef
58.
Calvo-Rio V, Santos-Gomez M, Calvo I, et al. Anti-Interleukin-6 receptor tocilizumab for severe juvenile idiopathic arthritis-associated uveitis refractory to anti-tumor necrosis factor therapy: a multicenter study of twenty-five patients. Arthritis Rheumatol. 2017;69:668–75.PubMedCrossRef
59.
Tappeiner C, Mesquida M, Adan A, et al. Evidence for tocilizumab as a treatment option in refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2016;43:2183–8.PubMedCrossRef
60.
Hawkins MJ, Dick AD, Lee RJ, et al. Managing juvenile idiopathic arthritis-associated uveitis. Surv Ophthalmol. 2016;61:197–210.PubMedCrossRef
61.
Tsang AC, Roth J, Gottlieb C. Tocilizumab for severe chronic anterior uveitis associated with juvenile idiopathic arthritis in a pediatric patient. Ocul Immunol Inflamm. 2014;22:155–7.PubMedCrossRef
62.
Adan A, Mesquida M, Llorenc V, et al. Tocilizumab for retinal vasoproliferative tumor secondary to juvenile idiopathic arthritis-associated uveitis: a case report. Graefes Arch Clin Exp Ophthalmol. 2014;252:163–4.PubMedCrossRef
63.
Quesada-Masachs E, Caballero CM. Subcutaneous tocilizumab may be less effective than intravenous tocilizumab in the treatment of juvenile idiopathic arthritis-associated uveitis. J Rheumatol. 2017;44:260–1.PubMedCrossRef
64.
Kinney MC, Hummell DS, Villiger PM, et al. Increased interleukin-6 (IL-6) production in a young child with clinical and pathologic features of multicentric Castleman's disease. J Clin Immunol. 1994;14:382–90.PubMedCrossRef
65.
Galeotti C, Boucheron A, Guillaume S, et al. Sustained remission of multicentric Castleman disease in children treated with tocilizumab, an anti-interleukin-6 receptor antibody. Mol Cancer Ther. 2012;11:1623–6.PubMedCrossRef
66.
Smith C, Lee-Miller C, Dishop MK, et al. Multicentric Castleman disease presenting with fever. J Pediatr. 2014;165:1261–5.PubMedCrossRef
67.
Turcotte LM, Correll CK, Reed RC, et al. Sustained remission of severe multicentric Castleman disease following multiagent chemotherapy and tocilizumab maintenance. Pediatr Blood Cancer. 2014;61:737–9.PubMedCrossRef
68.
Chantarogh S, Vilaiyuk S, Tim-Aroon T, et al. Clinical improvement of renal amyloidosis in a patient with systemic-onset juvenile idiopathic arthritis who received tocilizumab treatment: a case report and literature review. BMC Nephrol. 2017;18:159.PubMedPubMedCentralCrossRef
69.
Okuda Y, Takasugi K. Successful use of a humanized anti-interleukin-6 receptor antibody, tocilizumab, to treat amyloid a amyloidosis complicating juvenile idiopathic arthritis. Arthritis Rheum. 2006;54:2997–3000.PubMedCrossRef
70.
Hakala M, Immonen K, Korpela M, et al. Good medium-term efficacy of tocilizumab in DMARD and anti-TNF-alpha therapy resistant reactive amyloidosis. Ann Rheum Dis. 2013;72:464–5.PubMedCrossRef
71.
72.
Frey N. Cytokine release syndrome: who is at risk and how to treat. Best Pract Res Clin Haematol. 2017;30:336–40.PubMedCrossRef
73.
Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121:5154–7.PubMedPubMedCentralCrossRef
74.
Fitzgerald JC, Weiss SL, Maude SL, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med. 2017;45:e124–e31.PubMedPubMedCentralCrossRef
75.
La Torre F, Muratore M, Vitale A, et al. Canakinumab efficacy and long-term tocilizumab administration in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Rheumatol Int. 2015;35:1943–7.PubMedCrossRef
76.
Senniappan S, Hughes M, Shah P, et al. Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome. J Pediatr Endocrinol Metab. 2013;26:877–82.PubMedCrossRef
77.
Bloom JL, Lin C, Imundo L, et al. H syndrome: 5 new cases from the United States with novel features and responses to therapy. Pediatr Rheumatol Online J. 2017;15:76.PubMedPubMedCentralCrossRef
78.
Rafiq NK, Hussain K, Brogan PA. Tocilizumab for the treatment of SLC29A3 mutation Positive PHID syndrome. Pediatrics. 2017;140:e20163148.
79.
Keidel SM, Hoyles RK, Wilkinson NM. Efficacy of tocilizumab for interstitial lung disease in an undifferentiated autoinflammatory disorder partially responsive to anakinra. Rheumatology (Oxford). 2014;53:573–4.CrossRef
80.
Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves' ophthalmopathy. Lancet Diabetes Endocrinol. 2017;5:134–42.PubMedCrossRef
81.
Sy A, Eliasieh K, Silkiss RZ. Clinical response to tocilizumab in severe thyroid eye disease. Ophthalmic Plast Reconstr Surg. 2017;33:e55–7.PubMedCrossRef
82.
Butnaru D, Perez-Moreiras JV, Sanchez-Ramon S. Anti-IL-6R therapy on Graves' ophthalmopathy. Clin Immunol. 2013;147:120–1.PubMedCrossRef
83.
Preez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, et al. Efficacy of tocilizumab in patients with moderate to severe corticosteroid resistant Graves orbitopathy: a randomized clinical trial. Am J Ophthalmol. 2018;195:181–90.
Metadata
Title
Off-label use of tocilizumab to treat non-juvenile idiopathic arthritis in pediatric rheumatic patients: a literature review
Authors
Ju-Yang Jung
Moon-Young Kim
Chang-Hee Suh
Hyoun-Ah Kim
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Pediatric Rheumatology / Issue 1/2018
Electronic ISSN: 1546-0096
DOI
https://doi.org/10.1186/s12969-018-0296-z

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