Encephalomyeloneuritis and arthritis after treatment with immune checkpoint inhibitors

Discussion

The manifestation of different organ systems of immune-related adverse events (irAEs) at different time points makes this case very instructive.

First, after the third ipilimumab infusion, an immune-mediated synovitis was diagnosed and exacerbated after BRAF/MEK inhibitor treatment. Because musculoskeletal irAEs may last up to 1 year,² these side effects may subside deferred to the initiation of rituximab treatment.

Two weeks afterward, our patient developed cranial neuritis, which responded very well to oral steroids, but was rapidly complicated by longitudinal extensive transverse myelitis (TM), encephalitis, and ON. In general, neurologic side effects following immune checkpoint inhibitor and BRAF/MEK inhibitor treatment are rare, occurring in <1% of patients in large clinical trials.³ However, a recent evaluation of 59 trials reported a higher incidence of 3.8% in patients receiving anticytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies, 6.1% in patients receiving antiprogrammed death 1 (PD-1) antibodies, and 12% in patients receiving combination therapies,⁴ questioning the possibility of a cumulative effect of consecutive immune checkpoint inhibitor treatments, followed by BRAF/MEK inhibitors in the pathophysiology of neurologic adverse effects. It has been suggested that BRAF/MEK inhibition might upregulate inflammatory genes in macrophages and T cells and synergize PD-1 blockade.⁵ Given that this new symptoms appeared 1 month after the most recently introduced BRAF/MEK treatment, the possibility of an additive neurotoxic ocular adverse effect⁶ and worsening of ankle and knee pain from these treatments has to be considered.^7,–,9 However, BRAF/MEK inhibitors were not stopped and recovery occurred during treatment with these agents.

Most neurologic complications involve the peripheral nervous system rather than the CNS. Central inflammation is rare and includes, in addition to typical demyelination, several antibody-mediated and paraneoplastic conditions such as anti-NMDA receptor encephalitis.¹⁰ A recent review¹¹ on irAEs and neurotoxicity including 29 articles encompassing 38 patients identified 11 patients with CNS toxicity. TM has only been reported in 5 cases so far (table e-1, links.lww.com/NXI/A268).

IrAEs occur when T-cell activation exceeds its normal range and induces inflammation.¹² The pathophysiologic pathway remains only partially understood, but immune checkpoints play an important role in immune homeostasis, preventing autoimmunity and promoting self-tolerance. Ipilimumab is directed against CTLA-4, whereas nivolumab and pembrolizumab are directed against PD-1.¹³ Inherent to the mechanism of action, these agents upregulate immunity by blocking inhibitory T-cell receptors enhancing antitumor immunity.¹⁴ It is known that both PD-1 and CTLA-4 inhibition can stimulate antibody production leading to antibody-mediated autoimmune diseases, especially in patients with pre-existing autoimmunity or autoimmune susceptibility.¹⁵

Rapid diagnosis and treatment initiation are crucial because severe neurologic sequelae can result from spinal neurotoxicity. A thorough and periodic neurologic examination, a spinal MRI, usually complemented by cerebral MRI, blood laboratory analysis (including HIV, rapid plasma regain test, vitamin B12, thyroid-stimulating hormone, antinuclear antibodies, Ro/La, and AQP4 antibodies), and CSF studies (including cytology and immunocytological studies) are the cornerstone of diagnostics. We furthermore want to underline that the severe neurologic manifestations (TM and ON) occurred under low doses of steroids (20 mg of MP) and were first detected by MRI. Therefore, a close monitoring, not only clinically but also with CSF analysis and MRI studies during irAEs, is suggested because MRI might show new abnormalities that might precede the appearance of severe clinical manifestations. Consequently, this might give the opportunity of an early therapeutic change, such as reincrease of steroids, slower tapering, or consideration of high-dose IV steroids that might have prevented or decrease the severity of CNS involvement.

The clinical manifestation of TM and ON in our patient may cast suspicion for neuromyelitis optica spectrum disease (NMOSD). The patient however does not meet the revised criteria for NMOSD without AQP4 antibodies because the required imaging findings were not met. Still, the number of reported cases of iatrogenic demyelination of the CNS is on the rise.¹¹

Oncologic societies have released guidelines on the treatment of these irAEs. The European Society of Medical Oncology⁴ and the American Society of Clinical Oncology guidelines¹⁶ recommend MP 2 mg/kg body weight for moderate toxicity; however, as soon as activities of daily living are affected, high-dose IV MP (1 g, 3–5 days) is recommended and treatment with immune checkpoint inhibitors should be stopped.

In our patient, we administered rituximab because anti-CD20 treatment proved to be particularly beneficial in NMOSD and symptoms occurred after ongoing MP and severe side effects had occurred.

In summary, we present a case with irAEs affecting the musculoskeletal system, the cranial nerves, and the brain and spinal cord in a metastatic melanoma patient treated with nivolumab followed by ipilimumab and BRAF/MEK inhibitors. The frequency of spinal cord involvement and neuronal toxicity in general in cancer immunotherapy is very low and requires an extensive diagnostic workup including MRI, a number of laboratory tests, and CSF analyses to exclude a broad spectrum of differential diagnoses such as meningeosis carcinomatosa. Differentiation between disease progression and side effects may be difficult and treatment decisions should be discussed in a multidisciplinary team. Immune checkpoint inhibitors should be discontinued and treatment with corticosteroids should be initiated early as the drug of first choice. Therapy may be escalated by other immune-modulating treatments, such as rituximab.