Management of immune-related adverse events in patients treated with immune checkpoint inhibitors– Rheumatology point of view

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Abstract

The development of immunotherapy has revolutionized the cancer treatment in the recent years. Immune checkpoint inhibitors (ICPis) such as anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death protein (anti-PD1) and its ligand (anti-PDL1) have become part of the standard treatment of various malignancies. Immune-related adverse events (irAEs) were common in patients treated with ICPis. Rheumatologists should be aware of the upcoming challenges in the management of irAEs in a patient receiving treatment with ICPis.

1 Introduction

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/

Table 1

Common immune checkpoint inhibitors and FDA-approved indications

DrugsIndications
IpilimumabMetastatic melanoma
Advanced renal cell carcinoma
NivolumabMetastatic melanoma
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
Hepatocellular carcinoma
PembrolizumabMetastatic melanoma
Metastatic non-small-cell lung cancer
Metastatic squamous cell carcinoma of the head and neck Classical Hodgkin lymphoma
Primary mediastinal large B-cell lymphoma
Urothelial carcinoma
MSI-H or dMMR cancer
aMSI-H, microsatellite instability-high; dMMR, mismatch repair deficient.

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.

Figure 1
Figure 1

(a) PD-1-mediated T-cell inhibitions and its blockade pathway. PD-1:PD-L2 binding inhibits the TCR-mediated signaling and, hence, T-cell proliferation and survival. Anti-PD1 and Anti-PDL1 reversed the T-cell inhibition signal. (b) CTLA-4-mediated T-cell inhibitions and its blockade pathway. CTLA-4 on T effector cells and T regulatory cells compete with CD-28 for CD80/86 preventing the stimulation of T effector cells proliferation and survival. CTLA-4 blockade reversed the T-cell inhibition signal. APC, Antigen presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; PD-1, programmed death 1; PD-L1, programmed death ligand 1

Citation: Hong Kong Bulletin on Rheumatic Diseases 18, 2; 10.2478/hkbrd-2018-0009

Table 2

Rheumatic manifestations of irAE and CTCAE grading 7, 9

ManifestationCTCAE grading
Inflammatory arthritisGrade1Mild pain with inflammation, erythema, or joint swelling
Grade 2Moderate pain; limiting instrumental ADL
MyositisGrade 3Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage; disabling; limiting self-care ADL
Grade 1Mild pain
Grade 2Moderate pain associated with weakness; pain limiting instrumental ADL
Grade 3Pain associated with severe weakness; limiting self-care ADL
Polymyalgia-like syndromeGrade1Mild stiffness and pain
Grade 2Moderate stiffness and pain, limiting age-appropriate instrumental ADL
Grade 3Severe stiffness and pain, limiting self-care ADL
Giant cell arteritisGrading not available
Sjogren syndrome
Vasculitis
Systemic lupus erythematosus-like syndrome
Systemic sclerosis
birAE, immune-related adverse event; CTCAE, Common Terminology Criteria for Adverse Events

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.

6 Conclusions

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.

References

  • [1]

    Calabrese L Velcheti V. Checkpoint immunotherapy: good for cancer therapy bad for rheumatic diseases. Ann Rheum Dis 2017;76:1–3

    • Crossref
    • PubMed
    • Export Citation
  • [2]

    Haanen JB Carbonnel F Robert C Kerr KM Peters S Larkin J Jordan K. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up. Annals of Oncology 2017;28:119-142

    • Crossref
    • Export Citation
  • [3]

    Brahmer JR Lacchetti C Thompson JA. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. Journal of oncology practice. 2018;14(4):247-9.

    • Crossref
    • Export Citation
  • [4]

    Buchbinder EI Desai A. CTLA-4 and PD-1 pathways: similarities differences and implications of their inhibition. American journal of clinical oncology. 2016;39:98–106.

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Hodi FS O’day SJ McDermott DF Weber RW Sosman JA Haanen JB Gonzalez R Robert C Schadendorf D Hassel JC Akerley W. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723.

    • Crossref
    • PubMed
    • Export Citation
  • [6]

    Larkin J Chiarion-Sileni V Gonzalez R Grob JJ Cowey CL Lao CD Schadendorf D Dummer R Smylie M Rutkowski P Ferrucci PF. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med2015; 373: 23–34.

  • [7]

    Cappelli LC Gutierrez AK Bingham III CO Shah AA. Rheumatic and Musculoskeletal Immune‐Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. Arthritis Care Res (Hoboken). 2017;69(11):1751-63.

    • Crossref
    • PubMed
    • Export Citation
  • [8]

    Michot JM Bigenwald C Champiat S Collins M Carbonnel F Postel-Vinay S Berdelou A Varga A Bahleda R Hollebecque A Massard C. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European Journal of Cancer 2016(54):139-148

    • Crossref
    • Export Citation
  • [9]

    US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0. National Institutes of Health National Cancer Institute. 2009;4(03).

  • [10]

    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.

    • Crossref
    • Export Citation
  • [11]

    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.

  • [12]

    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

  • [13]

    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.

    • Crossref
    • PubMed
    • Export Citation
  • [14]

    Abdel-Wahab N Shah M Lopez-Olivo MA Suarez-Almazor ME. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review. Ann Intern Med. 2018;168:121-130

    • Crossref
    • PubMed
    • Export Citation

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  • [1]

    Calabrese L Velcheti V. Checkpoint immunotherapy: good for cancer therapy bad for rheumatic diseases. Ann Rheum Dis 2017;76:1–3

    • Crossref
    • PubMed
    • Export Citation
  • [2]

    Haanen JB Carbonnel F Robert C Kerr KM Peters S Larkin J Jordan K. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up. Annals of Oncology 2017;28:119-142

    • Crossref
    • Export Citation
  • [3]

    Brahmer JR Lacchetti C Thompson JA. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. Journal of oncology practice. 2018;14(4):247-9.

    • Crossref
    • Export Citation
  • [4]

    Buchbinder EI Desai A. CTLA-4 and PD-1 pathways: similarities differences and implications of their inhibition. American journal of clinical oncology. 2016;39:98–106.

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Hodi FS O’day SJ McDermott DF Weber RW Sosman JA Haanen JB Gonzalez R Robert C Schadendorf D Hassel JC Akerley W. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723.

    • Crossref
    • PubMed
    • Export Citation
  • [6]

    Larkin J Chiarion-Sileni V Gonzalez R Grob JJ Cowey CL Lao CD Schadendorf D Dummer R Smylie M Rutkowski P Ferrucci PF. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med2015; 373: 23–34.

  • [7]

    Cappelli LC Gutierrez AK Bingham III CO Shah AA. Rheumatic and Musculoskeletal Immune‐Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. Arthritis Care Res (Hoboken). 2017;69(11):1751-63.

    • Crossref
    • PubMed
    • Export Citation
  • [8]

    Michot JM Bigenwald C Champiat S Collins M Carbonnel F Postel-Vinay S Berdelou A Varga A Bahleda R Hollebecque A Massard C. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European Journal of Cancer 2016(54):139-148

    • Crossref
    • Export Citation
  • [9]

    US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0. National Institutes of Health National Cancer Institute. 2009;4(03).

  • [10]

    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.

    • Crossref
    • Export Citation
  • [11]

    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.

  • [12]

    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

  • [13]

    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.

    • Crossref
    • PubMed
    • Export Citation
  • [14]

    Abdel-Wahab N Shah M Lopez-Olivo MA Suarez-Almazor ME. Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review. Ann Intern Med. 2018;168:121-130

    • Crossref
    • PubMed
    • Export Citation
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    (a) PD-1-mediated T-cell inhibitions and its blockade pathway. PD-1:PD-L2 binding inhibits the TCR-mediated signaling and, hence, T-cell proliferation and survival. Anti-PD1 and Anti-PDL1 reversed the T-cell inhibition signal. (b) CTLA-4-mediated T-cell inhibitions and its blockade pathway. CTLA-4 on T effector cells and T regulatory cells compete with CD-28 for CD80/86 preventing the stimulation of T effector cells proliferation and survival. CTLA-4 blockade reversed the T-cell inhibition signal. APC, Antigen presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; PD-1, programmed death 1; PD-L1, programmed death ligand 1

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