The immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4, programmed cell death protein and programmed cell death protein ligand 1, were the normal self-regulatory pathways to control T-cell activities in human body. In tumor microenvironment, these molecules were overexpressed to inhibit the normal T-cell function and survival, leading to an escape from the destruction from immune system. The immune checkpoint inhibitors (ICPis) block this mechanism and restore the T-cell immunity to achieve tumor destructions. However, the loss of normal regulation leads to autoimmunity and various immune-related adverse events (irAEs).1
Ipilimumab, a CTLA-4 inhibitor, was first approved by the Food and Drug Administration in 2011 for the treatmentof late-stage melanoma. Since then, the development of immunotherapy has been thriving and became part of the standard oncology care. The indications of anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4), anti-programmed cell death protein (anti-PD1), and anti-programmed cell death protein ligand (anti-PDL1) now extend from melanoma to non-small-cell lung cancer, renal cell carcinoma, Hodgkin disease, urothelial carcinoma, head and neck squamous cell carcinoma, and so on.2 irAE, the adverse events caused by autoimmunity after the use of immunotherapy, has been increasingly recognized with increasing experience on immunotherapy.
Rheumatic manifestations were reported in case reports and case series. The treatment is mainly based on expert advice. The use of steroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), antitumor necrosis factor (anti-TNF), and anti-interleukin-6 (anti-IL6) were reported. Lately, the American Society of Clinical Oncology (ASCO) has published their guideline for the management of irAE after the use of immunotherapy.3
2 Immune checkpoint inhibitors and pathophysiology of irAE
Activation of T-cells requires costimulation signals from major histocompatibility complex (MHC) to T-cell receptor (TCR) and from CD80/86 to CD28 between T-cells and antigen presenting cells (APCs). CTLA-4 is normally expressed on T-cell as a competitor of CD28 for CD80/86. It blocks the costimulation signal leading to inhibitory response to T-cell proliferation and survival. T-regulatory cell controls T-cell activation by expressing CTLA-4 on its surface, binding CD80/86 to APC, and causing internalization of CD80/86. In tumor environment, the constant stimulation of T-cell upregulates CTLA-4 from intracellular to the cell surface, leading to the loss of T-cell response. Anti-CTLA-4 blocks the inhibitory signal and restores the T-cell immunity.4
PD-1 is another immune checkpoint that regulates the T-cell functions. Different from CTLA-4, it is also expressed in differentiated cells such as activated T-cells, B-cells, and myeloid cells. The binding between PD-1 on the immune cell with its ligand PD-L1 and PD-L2 leads to the inhibition of T-cell proliferation, interferon-gamma/ tumor necrosis factor (TNF) alpha/interleukin 2 (IL-2) release, and T-cell survival. Chronic stimulation in cancer will lead to PD-1 overexpression and exhausted T-cell response. On the other hand, PD-L1 was expressed in tumor cells and tumor-infiltrating lymphocytes to evade from the immune clearance. PD1 and PD L1 inhibitors reverse the inhibitions and achieve antitumor effect.4
The immune checkpoint is important for preventing autoimmunity. The loss of immune checkpoint causes loss of immune tolerance and irAEs. The unopposed T-cell function and loss of T-regulatory cell function will lead to enhanced type 1 T helper cell (Th1) and type 17 T helper cell (Th17), leading to increase in the IL-6 and IL-17 production. Altered T-cell and B-cell interaction will also lead to the production of autoantibodies. Because CTLA-4 acts at more upstream step of T-cell activation, while PD-1/
Common immune checkpoint inhibitors and FDA-approved indications
|Advanced renal cell carcinoma|
|Metastatic non-small-cell lung cancer|
|Metastatic renal cell carcinoma|
|Classical Hodgkin lymphoma|
|Metastatic squamous cell carcinoma of the head and neck Metastatic urothelial carcinoma|
|MSI-H or dMMR metastatic colorectal cancer a|
|Metastatic non-small-cell lung cancer|
|Metastatic squamous cell carcinoma of the head and neck Classical Hodgkin lymphoma|
|Primary mediastinal large B-cell lymphoma|
|MSI-H or dMMR cancer|
PD-L1 acts at the effector cells, irAEs are more common in CTLA-4 inhibitor and are different from irAE in PD-1/PD-L1 inhibitors.
3 Rheumatic manifestations of irAE
irAEs are common, reported in up to 60–85% of patients using ipilimumab, an anti-CTLA-4.5, 6 Rheumatic irAE were reported in up to 40% of clinical trials7. They were usually mild to moderate, and severe irAEs were rare.8Common rheumatic irAE includes arthralgia, inflammatory arthritis, myalgia, and sicca symptoms, with reported incidences of 1–43%, 1–7%, 2–21%, and 3–24%, respectively. Other rheumatic irAEs such as myositis, polymyalgia rheumatica, giant cell arteritis (GCA), systemic lupus erythematosus, vasculitis, and systemic sclerosis were reported in case series.7
The diagnosis of rheumatic irAE can be challenging. The irAE usually occurs early within weeks; however, delay in onset of up to 1 year was reported. The presentations can be highly variable. Patients usually have negative autoimmune markers comparing to the primary autoimmune diseases. Coexisting infections/metastases/paraneoplastic syndrome is the major differential diagnoses. Overall, the diagnosis relies on detailed assessment and the temporal relationship to immunotherapy.
4 Treatment guidelines and evidence of rheumatic irAE
There is no solid evidence, but only case reports are available, on the treatment of rheumatic irAE. The ASCO published their guideline in June 2018 to provide guidance on the management of irAE associated with immunotherapy, addressing on the management of inflammatory arthritis, myositis, and polymyalgia-like syndrome.3
The management of rheumatic irAE depends on the severity of the adverse events, which is classified from grade 1 to grade 5 using the Common Terminology Criteria for Adverse Events (CTCAE).9 Grade 1 is defined as asymptomatic or mild symptoms only. Grade 2 is defined as moderate symptoms limiting age appropriate instrumental activity of daily living (ADL). Grade 3 is defined by limitation of self-care ADL. Grade 4 is life-threatening consequences requiring urgent interventions, and Grade 5 is death.
|Inflammatory arthritis||Grade1||Mild pain with inflammation, erythema, or joint swelling|
|Grade 2||Moderate pain; limiting instrumental ADL|
|Myositis||Grade 3||Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage; disabling; limiting self-care ADL|
|Grade 1||Mild pain|
|Grade 2||Moderate pain associated with weakness; pain limiting instrumental ADL|
|Grade 3||Pain associated with severe weakness; limiting self-care ADL|
|Polymyalgia-like syndrome||Grade1||Mild stiffness and pain|
|Grade 2||Moderate stiffness and pain, limiting age-appropriate instrumental ADL|
|Grade 3||Severe stiffness and pain, limiting self-care ADL|
|Giant cell arteritis||Grading not available|
|Systemic lupus erythematosus-like syndrome|
While mild irAE can usually be managed with supportive treatments and continuing the immunotherapy at the same time, patients with severe irAE should stop the immunotherapy at least temporarily. ASCO guideline suggests withholding ICPi for patients experiencing grade 2 or above symptoms. Immunotherapy should only be resumed when symptoms are controlled at least back to grade 1. In patients with severe manifestation, for example, myocardial involvement in myositis, the immunotherapy should be stopped permanently.
Steroid is the mainstay of treatment for the rheumatic irAE with ICPi. While grade 1 toxicity can be managed conservatively, the ASCO suggested moderate to high-dose steroids for grade 2–4 irAE such as inflammatory arthritis, myositis, and polymyalgia-like syndrome.
While most of the cases can be managed by withholding the immunotherapy and short course of steroids, some patients require more intensive immunosuppression. The ASCO guideline recommends the use of csDMARDs or biologics for grade 3–4 adverse events not improved with steroids in 4 weeks.
Inflammatory arthritis is a commonly reported irAE. The use of csDMARDs including methotrexate, sulfasalazine, and hydroxychloroquine was reported in case reports but no high-level evidence is available.10,11. The use of biological including anti-TNF including etanercept, adalimumab, and infliximab were reported with successful outcome.11 A case series of three patients in 2017 showed that anti-IL6 is also useful in arthritis irAEs.12
The management of inflammatory myopathy in treating patients with cancer with immunotherapy can be tricky. It is difficult to differentiate between paraneoplastic myositis and irAE because of immunotherapy. The keys to management are steroid and withholding the ICPis. The ASCO guideline suggests plasmapheresis, Intravenous immunoglobulin, methotrexate, azathioprine, mycophenolate mofetil, or rituximab in selected cases. However, the efficacy of these therapeutic agents in immune-related inflammatory myopathy was not proven or documented.
Polymyalgia-like syndrome and GCA were reported as possible irAEs. However, caution should be taken as pain syndrome with elevated inflammatory markers can be common in patients with advanced malignancies. Further investigations including imaging and biopsy should be arranged in case of doubt. Steroid is the mainstay of treatment. The use of tocilizumab in general patients with GCA showed promising results, but its use in immunotherapy-related cases has not been validated.13
The ASCO guideline provided an insight on the management of both rheumatic and non-rheumatic irAEs. The management of other rarer rheumatic irAEs, for example, vasculitis and systemic sclerosis, were not mentioned in the ASCO guideline. The treatment plan for patients with rheumatic irAEs requires collaboration between rheumatologists and oncologists and should be made as case-by-case basis.
5 The use of immune checkpoint inhibitors in patient with preexisting autoimmune disease
Oncologists have been conservative on using immunotherapy in patients with preexisting autoimmune diseases, worrying about potential flare up of their existing disease or the development of new irAEs. Indeed, patients with preexisting autoimmune diseases were excluded from previous immunotherapy clinical trials. The latest evidence may provide us an insight in using immunotherapy in patients with autoimmune diseases.
A systematic review of 123 patients in 49 publications was released this year, reporting the immune-related adverse reaction in patients with preexisting autoimmune diseases receiving immunotherapy.14 irAE was common and occurred in 75% of the patients. Fifty percent of the patients experienced a flare of the preexisting disease and 34% of the patients experienced a de novo irAE. The mortality attributing to irAEs was alarmingly high, up to 2.4%. However, 90% of the cases responded after the treatment of irAE and 83% of the patients can resume on immunotherapy afterwards. This suggests that patients with autoimmune diseases may benefit from the use of immunotherapy, but careful patient selection and close monitoring are necessary.
ICPis revolutionized the cancer treatment but its associated irAEs are challenging. Rheumatologists in this age should be aware of rapid development of immunotherapy. At present, high-quality evidence on the management of rheumatic irAE is lacking. Careful surveillance and collaboration between oncologists and rheumatologists can improve the outcome in patients receiving immunotherapy, particularly in patients with preexisting autoimmune diseases who are at the risk of developing severe irAEs.
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Chan MM, Kefford RF, Carlino M, Clements A, Manolios N. Arthritis and tenosynovitis associated with the anti-PD1 antibody pembrolizumab in metastatic melanoma. Journal of Immunotherapy 2015:38(1):37-39.
Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, Lipson EJ, Bleich KB, Shah AA, Naidoo J, Brahmer JR. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis2017;76:43–50.
Kim ST, Tayar J, Suarez-Almazor M, Garcia S, Hwu P, Johnson DH, Uemura M, Diab A. Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann Rheum Dis 2017;0:1
Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C. Trial of tocilizumab in giant-cell arteritis. N Engl J Med 2017;377:317-28.
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