Immune checkpoint inhibitors (ICIs) have been revolutionary in cancer therapeutics. They block certain immune regulatory checkpoint proteins, allowing for the body’s immune system to target and attack the cancer cells. However, these powerful agents are also known to cause various adverse effects on organs, known as immune-related adverse events (irAEs). Myositis is a known rheumatic irAE. Although relatively rare, accounting for approximately 0.38-0.6% of irAEs, it is one of the most severe forms of rheumatic irAEs with a case fatality rate of 26.8% when associated with myasthenia gravis and 51.3% when associated with myocarditis (1). Studies have shown a significantly increased risk of developing myositis in patients treated with ICIs compared to those not treated with ICIs (2).

There is limited data on ICI-associated myositis in terms of clinical presentation and laboratory parameters required to establish a diagnosis. Typically, in ICI-myositis, creatine kinase (CK) is elevated (2). Here, we present 2 cases of ICI-myositis with a normal CK and elevated aldolase levels, both of which responded well to steroids.

These 2 cases highlight an atypical presentation of immunotherapy-related myositis with normal CK levels but elevated aldolase levels that responded to steroid treatment.

ICI-myositis typically occurs with CK elevation, which was not the case in this report; it is important to note that the aldolase level was elevated, suggesting that this may be a sensitive laboratory marker in the diagnosis of ICI-myositis.

Aldolase elevation suggests damage of early regenerating muscle cells, which is not well understood; however, there are a few descriptive cases in rheumatology (4). In a study, aldolase A mRNA that was isolated from cultured human myoblasts and protein expression was highest in early differentiating myoblasts and remained elevated throughout differentiation, in contrast to CK mRNA and protein levels which remained low initially but increased as differentiation progressed (4). There have been several clinical studies showing a similar pattern of normal CK and elevated aldolase levels. In one study of 66 patients with dermatomyositis, 17 (26%) of them had normal CK with elevated aldolase (5). In another study, there were 12 patients with polymyositis confirmed on muscle biopsy, all of whom had a normal CK level with an elevated aldolase similar to our cases (6). There was another study of 34 patients with various myopathies including dermatomyositis, overlap myositis, and nonspecific myopathy. All of these patients were also found to have normal CK with elevated aldolase levels (7). This suggests that an elevated aldolase is a sensitive marker for many of these autoimmune myopathies and potentially ICI-myositis.

There have been a few studies exploring aldolase levels in patients with myopathy related to ICI use. In one retrospective study with 36 patients who either had ICI-myositis alone or with overlap manifestations including myocarditis and myasthenia gravis, 94% of the cohort had elevated CK levels and 26/27 patients tested had an elevated aldolase level (8). Two patients had a normal CK level, one of whom had elevated aldolase similar to our cases (8). Another retrospective study comparing patients with ICI myopathy to those with immune-mediated necrotizing myopathy (not exposed to immunotherapy) showed modest elevation in both aldolase and CK levels among the ICI myopathy group, but the elevation was far more prominent in the immune-mediated necrotizing myopathy group (9). Similar to our cases, 7/22 patients in the ICI myopathy group had normal CK levels, of which 2 had elevated aldolase levels (9). In contrast to our case series findings, there was another case series, of 2 patients who developed ICI-myositis following treatment with pembrolizumab who had both elevated CK and aldolase levels (10).

The variation in presentation of CK and aldolase levels seen in the literature further emphasizes the need for additional studies to better understand the diagnostic pattern for ICI-myositis. There is limited evidence on the diagnostic criteria for ICI-myositis. Presentation of ICI-myositis with a normal CK and elevated aldolase levels is rare. It may be that myositis is missed due to the diagnosis being dependent on an elevated CK level, which can lead to a delay in the diagnosis and treatment of such patients. This raises the question of whether aldolase should become part of the initial testing of patients for whom ICI-myositis is suspected.

The exact mechanism for an isolated elevated aldolase is unclear. A possible reason for this may include the extent of muscle fiber splitting and vacuolization of muscle fibers. Studies have shown patients with elevated CK have more frequent fibrillation potentials on EMG which correlate to presence of necrotic fibers, fiber splitting or vacuolization (7). Another explanation may be whether there is involvement of the perimysium. A study showed that 11/12 patients (92%) with isolated aldolase elevation had perimysial pathology (11). There needs to be further investigations exploring this to better understand the underlying mechanisms.

It is also important to note that both of our cases had prior steroid exposure for another ICI-related event, and so it is unclear whether the CK level was elevated before and normalized immediately upon starting steroids, or whether it was normal to begin with. Conversely, aldolase not only was elevated, but remained elevated for several months after the completion of steroids.

Studies have shown that patients in the acute setting of glucocorticoid-induced myopathy can have high aldolase levels with improvement within 3-4 weeks of discontinuing or reducing the steroid dose (12–14). This is typically seen at doses exceeding 60mg prednisolone daily (or equivalent) (12–14). Chronic steroid myopathy, however, is typically seen with steroid use for more than 4 weeks and in doses exceeding 10mg prednisolone daily (or equivalent) (12–14). In the setting of chronic steroid myopathy, aldolase levels have been shown to be typically normal (13). In the setting of inflammatory myopathies, or in our case of ICI-myositis, and prior steroid exposure, it becomes challenging to distinguish whether the aldolase elevation is due to the underlying disease or muscle damage related to the steroid. Studies have shown that EMG or muscle biopsy findings can aid in distinguishing between the two pathologies, however, these additional tests were not completed among our patients (13). Therefore, our study findings suggest that aldolase elevation may be a sensitive marker for ICI-myositis in the setting of prior steroid exposure. It is important to note, however, that for Case 1, he was started on steroids (with budesonide) over 10 weeks in advance from when aldolase was measured and tapered ( Figure 2 , box A). In this setting of chronic steroid use, we would expect to see normal aldolase levels. Additionally, after the completion of the steroid course (Case 1) or taper down to the maintenance dose (for adrenal insufficiency in Case 2), the aldolase level remained elevated for over 20 weeks which is atypical for steroid-induced myopathy, although further tests such as EMGs and muscle biopsies are needed to confirm.

ICI-myositis typically presents with progressive upper and lower extremity weakness within 2-3 months of ICI initiation, along with myalgias and fatigue. However, there can be additional clinical manifestations including ocular, cardiac, and even neurologic involvement. Studies report that oculo-bulbar symptoms can present in up to 25% of patients with ICI-myositis, an uncommon presentation seen with idiopathic inflammatory myopathies, unrelated to ICI use (15). These symptoms present as ptosis, ophthalmoplegia, dysphagia, and potentially dyspnea from diaphragm involvement. Additionally, studies report that myocarditis can concurrently occur in patients with ICI-myositis (2, 16, 17). In a study of 9,088 patients, around 36 (0.40%) patients had ICI-myositis, among which 14 (39%) patients had concurrent myocarditis (8). Neither of our two patients developed myocarditis and all cardiac work-up including EKG, troponins, and echocardiograms have been normal. Given these broad clinical manifestations and organ involvement that can be fatal if left untreated, it is even more important to recognize ICI-myositis so that appropriate therapy can be initiated.

The strengths of this case series include the fact that both patients at baseline had relatively few co-morbidities and took few medications. Medications they took were not commonly associated with myositis, thus limiting the confounding bias. One of the limitations of this case series is the lack of muscle biopsies to confirm the diagnosis of myositis; our diagnosis was based on clinical presentation and elevated aldolase levels. The inflammation seen on right wrist imaging for Case 1, however, did support the diagnosis. Additionally, both patients had prior steroid exposure for an irAE other than myopathy. This may have contributed to the normalization of CK levels at the time of ICI-myositis diagnosis and may also potentially confound the aldolase elevation seen. Further testing including EMG, muscle biopsies are needed to confirm.

Both patients at follow up 2-3 weeks after diagnosis of ICI-myositis, and on steroid treatment, noted significant improvement in myalgias and ability to perform daily activities of living.

Myositis is a rare but potentially severe irAE. Early identification of the clinical symptoms and understanding the varied clinical manifestations is key in recognizing ICI-myositis and initiating appropriate treatment. This case series highlights that, along with clinical features, laboratory abnormalities, including aldolase elevation despite normal CK levels, may further aid in the early identification of ICI-myositis, especially in the setting of prior steroid exposure.