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Immune Checkpoint Inhibitor–Associated Myositis

Expanding the Spectrum of Cardiac Complications of the Immunotherapy Revolution
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.118.035898Circulation. 2018;138:743–745

    Immune checkpoint inhibitors (ICIs) provide frequent durable responses and improve patient overall survival in numerous cancers. Blocking immune checkpoints (Programmed cell Death 1 [PD-1]/PD-ligand 1 or Cytotoxic T Lymphocyte-Associated Protein 4 [CTLA-4]) to restore antitumor immune response may also break immune tolerance to self-antigens and induce specific immune-related adverse events (irAEs).1

    Most patients experience at least 1 irAE during therapy, but treatment-related mortality is <1% to 2%.2 irAEs most commonly affect the skin, gastrointestinal tract, and endocrine organs, but ICI-associated myocarditis is a major cause of ICI-associated mortality.3 It is interesting to note that the initial descriptions of ICI-associated myocarditis described 25% of concomitant myositis.

    To date, ≈10 cases of myositis, characterized by muscle weakness, high creatine kinase levels, and muscular inflammatory infiltrates, have been reported. It is intriguing that ICI-associated myositis may present with typical muscle inflammation symptoms, and ocular symptoms, as well, that are similar to those observed in autoimmune disorders of the neuromuscular junction (myasthenia gravis).4 With the increased rate of ICI use, improvement in recognition, description, and management of muscular irAEs is required.

    We used VigiBase (http://www.vigiaccess.org/), the World Health Organization database of individual safety case reports maintained by the Uppsala Monitoring Center in Sweden. Through March 25, 2018, we identified 180 cases of myositis by using the High Level Term “Muscle infections and inflammations” of the Medical Dictionary for Regulatory Activities terms and then refined the search with “Myositis” as Preferred Term. We included 7 approved ICIs in the search: nivolumab, pembrolizumab, ipilimumab, tremelimumab, avelumab, durvalumab, and atezolizumab. Myocarditis was defined by selection of myocarditis at preferred term level using Medical Dictionary for Regulatory Activities in the individual safety case reports. Institutional review board approval was not required (no intervention with human subjects or access to identifiable information).

    Affected patients had a median age of 71 years (range, 29–90 years, data available in 134/180 reports) and had most often been treated for melanoma or lung cancer. Eighty-five percent of patients were treated with ICI monotherapy (Table).

    Table. Description of Patients With Immune Checkpoint Inhibitor-Associated Myositis

    Characteristicsn/N (%)
    Age, y, median (IQR)71 (62.3–76)
    Male sex110/166 (62.3)
    Region reporting ICI-associated myositis/total number of ICI-associated adverse events
     America70/19 867 (0.35)
     Europe58/10 771 (0.54)
     Asia47/3469 (1.4)
     Oceania5/972 (5.1)
    Indication
     Melanoma56/180 (31.1)
     Pulmonary cancer55/180 (30.6)
     Renal cancer20/180 (11.1)
     Other cancers*25/180 (13.9)
     Unknown24/180 (13.3)
    Treatment
     Monotherapy anti-PD1/PD-L1149/180 (83)
      Nivolumab92
      Pembrolizumab34
      Durvalumab20
      Atezolizumab1
      Avelumab2
     Monotherapy anti-CTLA44/180 (2)
      Ipilimumab4
      Tremelimumab0
     Combination27/180 (15)
      Nivolumab+ipilimumab26
      Durvalumab+tremelimumab1
     Time to onsetN=61
      Median (IQR) days26 (18–39)
     Statin exposure25/180 (13.9)
    Associated irAEs
     Myasthenia-like disorder28/180 (15.6)
     Myocarditis29/180 (16.1)
     Other25/180 (13.9)
    Fatal outcome36/170 (21.2)
    Year of reportingN=180
     2012–201517
     201643
     2017§87
     2018, through March 2533

    ICI indicates immune checkpoint inhibitor; IQR, interquartile range; irAE, immune-related adverse event; n, number of cases; and N, number of total available data.

    *Other cancers: colorectal cancer (n=4), urothelial carcinoma (n=3), thymoma (n=3), bladder cancer (n=2), endometrial cancer (n=2), head and neck cancer (n=2), neuroendocrine carcinoma of the skin (n=2), hepatocellular carcinoma (n=1), mediastinal cancer (n=1), pancreas cancer (n=1), ovarian cancer (n=1), squamous cell carcinoma (n=1), Merkel cell carcinoma (n=1), and prostate cancer (n=1).

    †Other associated irAEs: hepatitis (n=14), colitis (n=3), thyroiditis (n=3), nephritis (n=3), and hypophysitis (n=2).

    ‡Fatal outcome: myositis (n=10), myositis and other irAEs (n=21 including cardiac disorders mostly myocarditis (n=17), hepatitis (n=3), and colitis (n=1)), cancer progression (n=3), and combined irAE and cancer progression (n=2).

    §In 2017, ICI-associated myositis/total number of reported ICI-associated adverse events 87/15 334 (0.57%), and ICI-associated myositis/total number of drug-induced reported myositis 87/405 (21.5%).

    Precise timing to myositis onset was available in 61 patients. In these patients, the median time of myositis onset was 26 days (range, 18–39 days) after the initial exposure to ICIs. Among all patients with myositis, 16.1% (n=29) also presented with myocarditis and 15.6% (n=28) presented with myasthenia gravis–like symptoms. Both myocarditis and myasthenia gravis–like symptoms occurred in 3.3% (n=6) of those with myositis. Other concurrent irAEs included hepatitis (n=14), colitis (n=3), thyroiditis (n=3), nephritis (n=3), and hypophysitis (n=2).

    We noted a dramatic increase in reporting of ICI-associated myositis in the past years in parallel with the increased rate of ICI use. In 2011, ipilimumab obtained the Food and Drug Administration approval, and 300 immunotherapies are currently in development. Before 2016, 0.5 cases/mo were reported, in comparison with 3.6 cases/mo in 2016, and 7.3 cases/mo in 2017.

    In this analysis, we found that ICI-associated myositis caused significant morbidity and mortality, with fatalities occurring in 21.2% of patients (detailed in Table). Moreover, 49.4% of patients with myositis had severe complications such as prolonged hospitalization, a life-threatening event, or a disabling effect. The mortality rate was significantly associated with combination therapy in comparison with monotherapy (38.5% versus 18.1%, P=0.02) and was higher in patients with concomitant myocarditis (51.7% versus 14.9% in patient without myocarditis, P<0.0001).

    Although a systematic, comprehensive clinical description of muscle (cardiac and skeletal tissues) irAEs remains an urgent need, we observed that they present as unique entities different from spontaneous myositis and myocarditis in the following ways. First, the mortality rate of spontaneous autoimmune myopathies remains <10% (n=66/716) within the first year after the diagnosis.5 In contrast, ICI-associated myositis has a poor prognosis with a higher mortality rate.

    Next, we noted that patients with ICI-associated myositis frequently had myasthenia-like symptoms such as ptosis and oculomotor disorders in addition to the classical phenotype of patients with myositis. This observation is in line with previous reports4 describing the occurrence of ocular symptoms in ICI-associated myositis that are quite unusual for spontaneous myositis, and may be related to either muscle inflammation or neuromuscular junction disorder. Most described cases of ICI-associated myasthenia gravis have been associated with antiacetylcholine receptor autoantibodies,4 but these data were not available in the VigiBase.

    In summary, in the largest study of its kind, our data show that ICI-associated myositis is a severe irAE with a high mortality rate and is associated with concomitant myocarditis and coexisting myasthenia gravis–type features. It occurs early during therapy and more frequently with combination regimens. The preliminary data on the nature of presentation suggest different mechanisms from those occurring in spontaneous autoimmune myopathies. Because symptoms of myositis can be overlooked, especially in patients who are ill, our observations suggest the need for a high index of suspicion among oncologists and a low threshold for skeletal muscle biopsy. The concomitant presence of myocarditis may require systematic cardiac screening.

    Acknowledgments

    The supplied data come from a variety of sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the World Health Organization.

    Footnotes

    https://www.ahajournals.org/journal/circ

    Data sharing: The sources of the data used to produce the results are available on Vigibase website (http://www.vigiaccess.org/). The methods used in the article, including the preferred terms and drug names are outlined in the research letter.

    Yves Allenbach, MD, PhD, Department of Internal Medicine and Clinical Immunology, Sorbonne Universités, Pitié-Salpêtrière University Hospital, 82 Boulevard de l’Hôpital, F-75013, Paris, France. Email

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