Immune Checkpoint Inhibitor–Associated Myositis
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).
|Age, y, median (IQR)||71 (62.3–76)|
|Male sex||110/166 (62.3)|
|Region reporting ICI-associated myositis/total number of ICI-associated adverse events|
|America||70/19 867 (0.35)|
|Europe||58/10 771 (0.54)|
|Pulmonary cancer||55/180 (30.6)|
|Renal cancer||20/180 (11.1)|
|Other cancers*||25/180 (13.9)|
|Monotherapy anti-PD1/PD-L1||149/180 (83)|
|Monotherapy anti-CTLA4||4/180 (2)|
|Time to onset||N=61|
|Median (IQR) days||26 (18–39)|
|Statin exposure||25/180 (13.9)|
|Myasthenia-like disorder||28/180 (15.6)|
|Fatal outcome‡||36/170 (21.2)|
|Year of reporting||N=180|
|2018, through March 25||33|
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.
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.
Sources of Funding
This work was supported by The Cancer Multi-Organisation Thematic Institute of the French National Alliance for Life and Health Sciences (AVIESAN): Plan Cancer 2014 to 2019.
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.Lancet. 2016; 387:1540–1550. doi: 10.1016/S0140-6736(15)01281-7CrossrefMedlineGoogle Scholar
Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis.BMC Med. 2015; 13:211. doi: 10.1186/s12916-015-0455-8CrossrefMedlineGoogle Scholar
Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.Lancet. 2018; 391:933. doi: 10.1016/S0140-6736(18)30533-6CrossrefMedlineGoogle Scholar
Gonzalez NL, Puwanant A, Lu A, Marks SM, Živković SA. Myasthenia triggered by immune checkpoint inhibitors: New case and literature review.Neuromuscul Disord. 2017; 27:266–268. doi: 10.1016/j.nmd.2017.01.002CrossrefMedlineGoogle Scholar
Dobloug GC, Svensson J, Lundberg IE, Holmqvist M. Mortality in idiopathic inflammatory myopathy: results from a Swedish nationwide population-based cohort study.Ann Rheum Dis. 2018; 77:40–47. doi: 10.1136/annrheumdis-2017-211402CrossrefMedlineGoogle Scholar