Generic placeholder image

Current Rheumatology Reviews


ISSN (Print): 1573-3971
ISSN (Online): 1875-6360

Review Article

Immune Checkpoint Inhibitors-related Rheumatic Diseases: What Rheumatologist Should Know?

Author(s): Fusun Gediz and Senol Kobak*

Volume 15 , Issue 3 , 2019

Page: [201 - 208] Pages: 8

DOI: 10.2174/1573397115666190119094736

Price: $65


Immune checkpoint inhibitors are revolutionized drugs for cancer immunotherapy in the last years. The mechanism of action of CPIs including the limitation of the activation of Tcells, and thus enhancing the self-immune response against tumour cells. Checkpointinhibitors( CPIs) may dysregulate the immune system, resulting in some toxicities. These toxicities or side effects are called Immune-related Adverse Events (IRAEs) that can potentially affect any organ and tissue. Rheumatic diseases due to checkpoint inhibitors are also reported in the literature. The spectrum of rheumatic manifestations are quite wide; the most common are arthralgia/arthritis, myalgia/myositis, polimyalgia rheumatica, lupus, rheumatoid arthritis, Sjögren’s syndrome. At the same time, these drugs can also cause an exacerbation of known rheumatologic disease. Treatment approaches for developing rheumatic findings due to checkpoint inhibitors should be multidisciplinary. There should be a close relationship between oncologists who follow-up these patients and rheumatologists. The rheumatic manifestations should be defined and treated early. In general, the musculoskeletal side effects are transient and may regress after stopping CPIs. The most commonly used medications are corticosteroids. Immunosuppressive drugs (HQ, MTX, anti-TNF-alpha, anti-IL-6) should be preferred when treatment is unresponsive or as steroid-sparing agents.

The aim of this review was to evaluate the checkpoint inhibitors-related rheumatologic findings and therapeutic strategies in light of recent literature data.

Keywords: Immune-checkpoint inhibitors, rheumatic diseases, features, treatment, approaches, therapeutic strategies.

Graphical Abstract
Davidson A. Autoimmune diseases. N Eng Med 2001; pp. 340-5.
Abbas AK, Lohr J, Knoechel B, Nagabhushanam V. T cell tolerance and autoimmunity. Autoimmun Rev 2004; 3(7-8): 471-5.
[] [PMID: 15546793]
Davies AJ. Immunological tolerance and the autoimmune response. Autoimmun Rev 2008; 7(7): 538-43.
[] [PMID: 18625442]
Ermann J, Fathman CG. Autoimmune diseases: genes, bugs and failed regulation. Nat Immunol 2001; 2(9): 759-61.
[] [PMID: 11526377]
Ravetch JV, Lanier LL. Immune inhibitory receptors. Science 2000; 290(5489): 84-9.
[] [PMID: 11021804]
Lleo A, Selmi C, Invernizzi P, Podda M, Gershwin ME. The consequences of apoptosis in autoimmunity. J Autoimmun 2008; 31(3): 257-62.
[] [PMID: 18513925]
Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016; 54: 139-48.
[] [PMID: 26765102]
van der Vlist M, Kuball J, Radstake TR, Meyaard L. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol 2016; 12(10): 593-604.
[] [PMID: 27539666]
Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013; 342(6165): 1432-3.
[] [PMID: 24357284]
Meffre E, Wardemann H. B-cell tolerance checkpoints in health and autoimmunity. Curr Opin Immunol 2008; 20(6): 632-8.
[] [PMID: 18848883]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252-64.
[] [PMID: 22437870]
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 19;363(8): 711-23.
Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384(9948): 1109-17.
[] [PMID: 25034862]
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4): 320-30.
[] [PMID: 25399552]
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016; 387(10030): 1837-46.
[] [PMID: 26970723]
van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J Immunol 2005; 175(9): 5575-80.
[] [PMID: 16237041]
Cooper GS, Miller FW, Pandey JP. The role of genetic factors in autoimmune disease: implications for environmental research. Environ Health Perspect 1999; 107(Suppl. 5): 693-700.
[PMID: 10502533]
Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50(2): 380-6.
[] [PMID: 14872479]
Koenig M, Joyal F, Fritzler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008; 58(12): 3902-12.
[] [PMID: 19035499]
Deane KD, El-Gabalawy H. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE. Nat Rev Rheumatol 2014; 10(4): 212-28.
[] [PMID: 24514912]
Tocut M, Brenner R, Zandman-Goddard G. Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev 2018; 17(6): 610-6.
[] [PMID: 29631064]
Guo Y, Walsh AM, Canavan M, Wechalekar MD, Cole S, Yin X, et al. Immune checkpoint inhibitor PD-1 pathway is downregulated in synovium at various stages of rheumatoid arthritis disease progression. PLoS One 2018; 28;13(2)e0192704
Liu C, Jiang J, Gao L, et al. Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways. Arthritis Res Ther 2015; 17: 340.
[] [PMID: 26608464]
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11(2): 141-51.
[] [PMID: 10485649]
Olde Nordkamp MJ, Koeleman BP, Meyaard L. Do inhibitory immune receptors play a role in the etiology of autoimmune disease? Clin Immunol 2014; 150(1): 31-42.
[] [PMID: 24333531]
Kuswanto WF, MacFarlane LA, Gedmintas L, Mulloy A, Choueiri TK, Bermas BL. Rheumatologic symptoms in oncologic patients on PD-1 inhibitors. Semin Arthritis Rheum 2018; 47(6): 907-10.
[] [PMID: 29191375]
Chan MM, Kefford RF, Carlino M, Clements A, Manolios N. Arthritis and tenosynovitis associated with the anti-PD1 antibody pembrolizumab in metastatic melanoma. J Immunother 2015; 38(1): 37-9.
[] [PMID: 25415286]
Shah M, Tayar JH, Abdel-Wahab N, Suarez-Almazor ME. Myositis as an adverse event of immune checkpoint blockadefor cancer therapy. Semin Arthritis Rheum 2018. Epub ahead of print
[PMID: 29909921]
Yoshioka M, Kambe N, Yamamoto Y, Suehiro K, Matsue H. Case of respiratory discomfort due to myositis after administration of nivolumab. J Dermatol 2015; 42(10): 1008-9.
[] [PMID: 26104017]
Sheik Ali S, Goddard AL, Luke JJ, et al. Drug-associated dermatomyositis following ipilimumab therapy: a novel immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4 blockade. JAMA Dermatol 2015; 151(2): 195-9.
[] [PMID: 25321335]
Khoja L, Maurice C, Chappell M, et al. Eosinophilic fasciitis and acute encephalopathy toxicity from pembrolizumab treatment of a patient with metastatic melanoma. Cancer Immunol Res 2016; 4(3): 175-8.
[] [PMID: 26822024]
Calabrese C, Kirchner E, Kontzias K, Velcheti V, Calabrese LH. Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity. RMD Open 2017; 3(1)e000412
[] [PMID: 28405474]
Naidoo J, Cappelli LC, Forde PM, et al. Inflammatory arthritis: A newly recognized adverse event of immune checkpoint blockade. Oncologist 2017; 22(6): 627-30.
[] [PMID: 28576858]
Jaberg-Bentele NF, Kunz M, Abuhammad S, Dummer R. Flare-up of rheumatoid rrthritis by anti-CTLA-4 antibody but not by anti-PD1 therapy in a patient with metastatic melanoma. Case Rep Dermatol 2017; 9(1): 65-8.
[] [PMID: 28611624]
Wells AF, Westhovens R, Reed DM, et al. Abatacept plus methotrexate provides incremental clinical benefits versus methotrexate alone in methotrexate-naive patients with early rheumatoid arthritis who achieve radiographic nonprogression. J Rheumatol 2011; 38(11): 2362-8.
[] [PMID: 21885491]
Aya F, Gaba L, Victoria I, et al. Life-threatening colitis and complete response with ipilimumab in a patient with metastatic BRAF-mutant melanoma and rheumatoid arthritis. ESMO Open 2016; 1(1)e000032
[] [PMID: 27843587]
de Velasco G, Bermas B, Choueiri TK. Autoimmune arthropathy and uveitis as complications of programmed death 1 inhibitor treatment. Arthritis Rheumatol 2016; 68(2): 556-7.
[] [PMID: 26314277]
Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017; 76(1): 43-50.
[] [PMID: 27307501]
Ngo L, Miller E, Valen P, Gertner E. Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema in a patient with melanoma: a case report. J Med Case Rep 2018; 26;12(1): 48.
Goldstein BL, Gedmintas L, Todd DJ. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4. Arthritis Rheumatol 2014; 66(3): 768-9.
[] [PMID: 24574239]
Hid Cadena R, Abdulahad WH, Hospers GAP, et al. Checks and balances in autoimmune vasculitis. Front Immunol 2018; 9: 315.
[] [PMID: 29520282]
Minor DR, Bunker SR, Doyle J. Lymphocytic vasculitis of the uterus in a patient with melanoma receiving ipilimumab. J Clin Oncol 2013; 31(20): e356-6.
[] [PMID: 23733772]
Manusow JS, Khoja L, Pesin N, Joshua AM, Mandelcorn ED. Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma. J Immunother Cancer 2014; 2(1): 41.
[] [PMID: 25516805]
Wilde B, Hua F, Dolff S, et al. Aberrant expression of the negative costimulator PD-1 on T cells in granulomatosis with polyangiitis. Rheumatology (Oxford) 2012; 51(7): 1188-97.
[] [PMID: 22447882]
Slot MC, Sokolowska MG, Savelkouls KG, Janssen RGJH, Damoiseaux JGMC, Tervaert JW. Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. Clin Immunol 2008; 128(1): 39-45.
[] [PMID: 18448390]
van den Brom RRH, Abdulahad WH, Rutgers A, et al. Rapid granulomatosis with polyangiitis induced by immune checkpoint inhibition. Rheumatology (Oxford) 2016; 55(6): 1143-5.
[] [PMID: 27069016]
Pedersen M, Andersen R, Nørgaard P, et al. Successful treatment with Ipilimumab and Interleukin-2 in two patients with metastatic melanoma and systemic autoimmune disease. Cancer Immunol Immunother 2014; 63(12): 1341-6.
[] [PMID: 25227926]
Ruiz-Bañobre J, García-González J. Anti-PD-1/PD-L1-induced psoriasis from an oncological perspective. J Eur Acad Dermatol Venereol 2017; 31(9): e407-8.
[] [PMID: 28295707]
Law-Ping-Man S, Martin A, Briens E, Tisseau L, Safa G. Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer. Rheumatology (Oxford) 2016; 55(11): 2087-9.
[] [PMID: 27436004]
Wofford J, Menter A. Ustekinumab for the treatment of psoriatic arthritis. Expert Rev Clin Immunol 2014; 10(2): 189-202.
[] [PMID: 24410536]
Barbosa NS, Wetter DA, Wieland CN, Shenoy NK, Markovic SN, Thanarajasingam U. Scleroderma induced by pembrolizumab: A case series. Mayo Clin Proc 2017; 92(7): 1158-63.
[] [PMID: 28599746]
Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med 2009; 361(2): 211-2.
[] [PMID: 19587352]
Lute KD, May KF Jr, Lu P, et al. Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood 2005; 106(9): 3127-33.
[] [PMID: 16037385]
Zimmer L, Goldinger SM, Hofmann L, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 2016; 60: 210-25.
[] [PMID: 27084345]
Gutzmer R, Koop A, Meier F, et al. Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer 2017; 75: 24-32.
[] [PMID: 28214654]
Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2016; 2(2): 234-40.
[] [PMID: 26633184]
Puzanov I, Diab A, Abdallah K, Bingham CO, Brogdon C, Dadu R. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 21; 5(1): 95.
van der Vlist M, Kuball J, Radstake TR, Meyaard L. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol 2016; 12(10): 593-604.
[] [PMID: 27539666]
Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 2016; 27(4): 559-74.
[] [PMID: 26715621]
Pagès C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res 2013; 23(3): 227-30.
[] [PMID: 23458760]
Merrill SP, Reynolds P, Kalra A, Biehl J, Vandivier RW, Mueller SW. Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient. Ann Pharmacother 2014; 48(6): 806-10.
[] [PMID: 24651165]
Kim ST, Tayar J, Trinh VA, Suarez-Almazor M, Garcia S, Hwu P, et al. Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann Rheum Dis 2017; 76(12): 2061-4.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy