Management of myasthenia gravis without significant exacerbation during nivolumab therapy for metastatic melanoma: a case report and review of literature

A B S T R A C T

A 51-year-old man with myasthenia gravis (MG) and metastatic melanoma had progression of his melanoma with supratentorial metastases on dabrafenib-trametinib and was transitioned to anti-PD1 immunotherapy with nivolumab. He presented to the hospital soon after starting nivolumab with headache, mild diplopia, and right-sided dysdiadochokinesia and reduced proprioception. EMG showed a mildly increased percentage of fiber pairs with increased jitter without impulse blocking, and MG outcome measures were worse, consistent with mild exacerbation. He continued to receive pyridostigmine, and after discharge showed functional improvement and return of his MG outcome measures to baseline. Nivolumab was continued for three months without further MG exacerbations until disease progression in the liver, mesentery, and lung. Close monitoring of neurological autoimmune conditions by neurology in conjunction with oncology could help ensure greater patient safety during anti-PD1 immunotherapy treatment in MG patients. We recommend pursuit of larger trials to clarify immunotherapy safety profiles in such patients.

K E Y W O R D S

Myasthenia gravis, melanoma, neurology, neuromuscular disease, skin cancer, immunology, safety, immunotherapy, autoimmune disease, anti-PD-1

Background

The past decade has seen a revolution in the treatment of metastatic melanoma (MM). Since the FDA approval of the anti-CTLA-4 monoclonal antibody ipilimumab in 2011, single-agent and combination immunotherapies have become an integral component of the management of unresectable or metastatic melanoma. The anti-PD-1 agents nivolumab and pembrolizumab, developed soon after, demonstrated improved objective response rates and progression-free survival, in addition to lower incidence of treatment-related adverse events of grade 3 or higher in comparison to ipilimumab. These, along with combination nivolumab/ipilimumab therapy, have become first-line therapies for MM regardless of BRAF mutation status [1, 2]. As a treatment modality that promotes immune response enhancement, immunotherapy is associated with an adverse event profile including immune-related adverse events (irAEs) affecting a spectrum of organs and organ systems, notably the nervous system. Anti-CLTA-4 and anti-PD-1 therapies have even been reported to induce conditions such as acute inflammatory demyelinating polyneuropathy (AIDP), myositis, and myasthenia gravis (MG) [3-12]. Understandably, there is reluctance among physicians to prescribe immune checkpoint inhibitors to patients with preexisting autoimmune conditions such as MG out of concern for enhanced autoimmune reactivity triggering irAEs of increased frequency or severity, or even acute autoimmune crisis. In fact, the NCCN 2019 guidelines state that “Patients with underlying autoimmune disorders are generally excluded from treatment with checkpoint immunotherapies [13]”.

Here, we report a patient with MM and concomitant MG who was treated with the anti-PD-1 therapy nivolumab. The treatment was well-tolerated with no evidence of severe MG exacerbation observed during the course of treatment.

Case Presentation

In July 2008, a 44-year-old man was diagnosed with stage T3b invasive melanoma of his right lower back. No metastatic disease was found on wide excision and a sentinel lymph node biopsy, and the patient was treated with a month of high-dose adjuvant interferon alpha followed by 11 months of maintenance-dose interferon alpha. In late 2010, he developed bilateral lower extremity weakness which progressed to his upper extremities with muscle aches and a cold, burning sensation in his legs, followed by chronic cough and dyspnea, night sweats, stuttering speech, and blurred vision. Radiological studies showed no abnormalities. Single-fiber electromyography (SFEMG) in March 2011 was consistent with a mild defect of neuromuscular transmission, but repeat SFEMG was normal without decrement or facilitation, and a needle examination of his limb muscles was normal. On laboratory evaluation there was no evidence of Lyme’s disease or other infection, thyroid dysfunction, Lambert-Eaton syndrome, or myopathy, and no autoantibodies against acetylcholine receptor or striated muscle. However, his weakness improved on pyridostigmine, and a subsequent physical exam demonstrated mild limb weakness, proximal greater than distal, and asymmetrical ptosis. He was diagnosed with seronegative MG.

In February 2015, metastatic melanoma positive for BRAF V600E mutation was diagnosed in his liver and small bowel. He began treatment with dabrafenib and trametinib after jejunal resection. His treatment course was complicated by hepatitis requiring prednisone and one hospitalization. Numerous sub-centimeter brain metastases to both frontal and parietal lobes were discovered on PET/CT and MRI in September 2015, prompting the decision to discontinue dabrafenib-trametinib and begin whole-brain radiation therapy (WBRT). Therapeutic options and goals of treatment were discussed with the patient over several encounters with his oncologist and his neurologist. The patient verbalized understanding of the risks of immunotherapy given his underlying MG, and he accepted these risks. He began treatment with nivolumab in October. He continued to see his neurologist for MG management, which was monitored using four validated MG outcome measures at each office visit: MG-Activities of Daily Living score (MG-ADL), MG-Quality of Life score (MG-QOL15), MG-Manual Muscle Test score (MG-MMT), and MG-Composite score (MGC).

Later that month, the patient was admitted to the hospital with constipation, worsening nausea and vomiting, right arm and hand numbness and paresthesia, and a worsening occipital headache with neck stiffness. Neurological examination was notable for mild diplopia on sustained up-gaze without ptosis or other facial weakness, as well as decreased proprioception and slowed rapid alternating movements in the right hand. Initial treatment on admission consisted of SMOG (saline, mineral oil, and glycerin) enemas and a bowel regimen, prochlorperazine and acetaminophen.

Investigations

The differential diagnosis for the patient on admission included myasthenia gravis exacerbation and/or intracranial events cause by electrolyte imbalances, worsening brain metastases, intratumoral hemorrhage, or increasing metastatic disease burden. Serum electrolytes and chemistries measured on admission were normal other than a mildly elevated phosphate (4.9 mmol/L; normal:2.4-4.5 mmol/L) and though a serum LDH was not measured on admission, LDH from earlier that month had been elevated to 1728 U/L. Negative inspiratory force within normal limits. The patient was found to have normal oropharyngeal swallow function. EEG found mild diffuse slowing indicative of bihemispheric dysfunction. SFEMG at this time found increased mean consecutive difference (MCD) which was similar to one month before, but with a mildly increased shift in the percentage of fiber pairs with increased jitter without impulse blocking from the prior study. The patient’s MG outcome scores were minimally worse from baseline consistent with a mild myasthenic exacerbation.

Treatment

On admission he was initially given dexamethasone and discontinued on day 2. The patient continued to receive his pyridostigmine while hospitalized. Gabapentin was added to his medication regimen for his right-hand numbness.

Outcome and follow-up

The patient was discharged after a three-day hospital stay; diagnosed with a mild MG exacerbation. The patient’s neurological findings apart from diplopia, however, were attributed the patient’s brain metastases. Follow-up five days after discharge, the patient was stronger with returning right hand function. His myasthenia gravis scores returned to baseline. LDH at this time had reassuringly continued to trend downwards from prior to admission from 1728 to 1115 U/L. Brain MRI in December that year demonstrated interval increase from September in the conspicuity and number of bilateral supratentorial brain lesions, as well as increased intrinsic precontrast T1 signal in a left parietal metastasis consistent with intratumoral hemorrhage, with restricted diffusion consistent with infarct. The patient continued to receive nivolumab after discharge. Given the increase in brain metastases, Cyberknife treatment was given to his three parietal and three frontal lesions on days 81 and 83 of nivolumab treatment, respectively. His myasthenia gravis scores remained unchanged, indicating a stable MG course throughout most of the treatment period without indication of MG progression (Table 1). Three months into nivolumab treatment disease progressed in the liver, mesentery and lung. He was subsequently switched to vemurafenib and cobimetinib. He remained on this combination for over a year until February 2017, when he was transitioned to palliative care. He subsequently had no further exacerbations of his MG and deceased from complications of his metastatic disease.

Table 1: MG-ADL, MG-QOL15, MG-MMT, and MGC scores. MG-ADL -- Myasthenia Gravis Activities of Daily Living (0-24); MG-QOL15 -- Myasthenia Gravis Quality of Life (0-60); MG-MMT - Myasthenia Gravis Manual Muscle Test (0-120); MGC -- Myasthenia Gravis Composite (0-50). Lower scores correlate with fewer symptoms (MG-ADL), increased quality of life (MG-QOL), reduced disease severity (MG-MMT), and better clinical status (MGC).

Date of Visit	MG-ADL	MG-QOL15	MG-MMT	MGC
09/15/2015	3	4	2	5
10/08/2016 -- Nivolumab therapy initiated
10/08/2015	2	10	3	3
10/14/2015	7	44	11	15
10/20/2015	4	40	2	4
11/03/2015	5	15	3	3
11/17/2015	2	7	3	1
12/03/2015	0	15	2	1
01/14/2016	1	13	2	1
01/21/2016 -- Nivolumab therapy discontinued

Discussion

MG is a B-cell and complement mediated autoimmune disorder targeting the neuromuscular junction. Its cardinal feature is fatigable weakness typically affecting the ocular muscles – causing commonly-recognized symptoms of ptosis and diplopia – as well as proximal limb, bulbar, and respiratory muscle group weakness. This is most commonly due to an autoantibody against acetylcholine receptor (AChR) with induction of the complement membrane attack complex. Much less frequently patients will have antibody to muscle-specific tyrosine kinase (MuSK) protein or antigen targets of lipodensity receptor protein (LRP) 4 and agrin. The detection of these antibodies in patients is highly specific for diagnosis of MG [14, 15]. However, there is a subset of patients who, despite having the clinical features of MG, lack detectible autoantibodies. These patients are diagnosed by the clinical history, response to cholinesterase inhibitors and electrophysiological examination of synaptic transmission with the exclusion of alternative diagnoses. They are classified as seronegative MG patients. MG is often monitored through outcome measures such as an MG-Activities of Daily Living score (MG-ADL), an MG-Manual Muscle Test score (MG-MMT), an MG-Composite score (MGC), and an MG-Quality of Life score (MG-QOL), which help track symptom severity, disease severity, clinical status, and quality of life, respectively [16-19]. There is some evidence linking CTLA-4 to MG, with MG patients demonstrating reduced expression of CTLA-4 on T-cell membranes, as well as certain single nucleotide polymorphisms in the CTLA-4 promoter region affecting its expression in MG [20-22]. On the other hand, little biochemical evidence exists to show a connection between PD-1 and MG [23]. However, case reports have detailed the manifestation of MG in patients treated with ipilimumab-nivolumab combination therapy [3] as well as nivolumab or pembrolizumab alone, sometimes with fatal results [6-12]. Aggravation of autoimmune disease in the context of anti-PD-1 therapy has also been documented, in particular with MG and pembrolizumab, and in one instance a severe and highly refractory flare of MG in the context of nivolumab [24-28]. Guidelines exist for management of severe MG induced by immune checkpoint inhibitors including the use of methylprednisolone, and plasmapheresis or IVIG if there is no improvement [29]. Interestingly, there are also reports of MG being induced by interferon alpha for patients with chronic hepatitis C; there is a possibility that our patient’s MG was actually induced by his adjuvant interferon therapy [30].

Many cases of successful immunotherapy treatment in the context of preexisting autoimmune disease have also been published. Ipilimumab was administered to a patient with multiple sclerosis and another patient with rheumatoid arthritis in one report, with neither suffering from irAEs or autoimmune exacerbation during the course of treatment; the latter benefitted with respect to her melanoma [31]. Another patient receiving ipilimumab with preexisting ulcerative colitis (UC) experienced remission of his UC symptoms rather than exacerbation during treatment, in addition to deriving clinical benefit from ipilimumab [32]. In the realm of anti-PD-1 therapies as well, pembrolizumab was administered to a patient with Churg-Strauss vasculitis without autoimmune exacerbations and successfully reduced tumor burden [33]. Two subjects with MG also received nivolumab and, despite each experiencing an episode of symptom exacerbation consistent with an MG flare, too benefitted from treatment with regression of metastases and stable malignant disease burden, respectively, and resolution of MG symptoms [34, 35]. Our patient too was found to have mild MG exacerbation during nivolumab treatment; however, in the context of his major presenting neurological symptoms, due to progression of his brain metastases or, less likely, a nivolumab-induced flare of his brain metastases, his MG findings were merely incidental in nature and minimally contributed to his overall clinical status. He went on to successfully receive the following six doses of nivolumab, up until disease progression, with no indications of MG flare.

A retrospective study was published in February 2016 investigating irAE frequency and episodes of autoimmune flares in thirty metastatic melanoma patients with preexisting autoimmune conditions, including two with multiple sclerosis and one with transverse myelitis, who received ipilimumab therapy. The report found that irAE incidence among these patients was in fact no higher than the observed incidence in ipilimumab clinical trials, and for the majority of patients who did experience either an irAE or an autoimmune disease exacerbation, their events were well-managed with standard therapies, and ultimately they benefitted from having received ipilimumab [36]. Our paper differs from other reports because of the joint work between oncology and neurology to manage the patient’s MG for the duration of nivolumab therapy both in the inpatient and outpatient settings, and the use of EMG and MG outcome measures to monitor the patient’s MG status. Based on the single case we present, we cannot extrapolate that anti-PD-1 therapy can be used safely in patients with MG or other autoimmune conditions, and their application in such circumstances should continue to be treated with caution. However, it does suggest that preexisting MG need not necessarily preclude clinical benefit from anti-PD-1 therapy, especially when one considers the grim prognosis of MM. In these cases, a partnership between the medical oncologist and the neurologist is critical for close monitoring of MG through careful neuromuscular examination and outcome scores to detect signs of decline prior to onset of crisis. We urge that larger trials be conducted for the use of anti-PD1 therapy in such patients to better ascertain if they might safely be adopted into standard clinical practice.

Learning points

• Clinicians should maintain a low threshold of suspicion for autoimmune worsening in the care of MG patients on cancer immunotherapy who present with new-onset neurological symptoms.
• Close management and monitoring by the patient’s neurologist in conjunction with their oncologist can help ensure greater patient safety during the course of treatment for earlier detection of autoimmune exacerbations for oncology patients with preexisting neurological autoimmune disease starting immunotherapy.
• We recommend larger multi-center clinical trials or registries assessing the use of anti-PD1 therapies in patients with preexisting autoimmune disorders, and neurological autoimmune conditions in particular, to further clarify the magnitude of short-term and long-term risks of therapy and associated morbidity and mortality.

Abbreviations

MG – myasthenia gravis; MM – metastatic melanoma; irAEs – immune-related adverse events; SFEMG – single-fiber electromyography

Article Info

Article Type

Case Report & Review of Literature

Publication history

Received: Sun 28, Apr 2019
Accepted: Sat 11, May 2019
Published: Wed 22, May 2019

Copyright

© 2023 Yash Agrawal. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.ACO.2019.02.01

Author Info

Collichio Frances James F Jr Howard Yash Agrawal

Corresponding Author

Yash Agrawal
School of Medicine, The University of North Carolina, Chapel Hill, NC, USA 27514

Figures & Tables

Table 1: MG-ADL, MG-QOL15, MG-MMT, and MGC scores. MG-ADL -- Myasthenia Gravis Activities of Daily Living (0-24); MG-QOL15 -- Myasthenia Gravis Quality of Life (0-60); MG-MMT - Myasthenia Gravis Manual Muscle Test (0-120); MGC -- Myasthenia Gravis Composite (0-50). Lower scores correlate with fewer symptoms (MG-ADL), increased quality of life (MG-QOL), reduced disease severity (MG-MMT), and better clinical status (MGC).

Date of Visit	MG-ADL	MG-QOL15	MG-MMT	MGC
09/15/2015	3	4	2	5
10/08/2016 -- Nivolumab therapy initiated
10/08/2015	2	10	3	3
10/14/2015	7	44	11	15
10/20/2015	4	40	2	4
11/03/2015	5	15	3	3
11/17/2015	2	7	3	1
12/03/2015	0	15	2	1
01/14/2016	1	13	2	1
01/21/2016 -- Nivolumab therapy discontinued

References

1. Larkin J, Hodi FS, Wolchok JD (2015) Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 373: 1270-1271. [Crossref]
2. Robert C, Schachter J, Long GV, Arance A, Grob JJ et al. (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372: 2521-2532. [Crossref]
3. Loochtan AI, Nickolich MS, Hobson-Webb LD (2015) Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle Nerve 52: 307-308. [Crossref]
4. Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S et al. (2016) Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 60: 210-225. [Crossref]
5. Makarious D, Horwood K, Coward JIG (2017) Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors. Eur J Cancer 82: 128-136. [Crossref]
6. March KL, Samarin MJ, Sodhi A, Owens RE (2018) Pembrolizumab-induced myasthenia gravis: A fatal case report. J Oncol Pharm Pract 24: 146-149. [Crossref]
7. Chang E, Sabichi AL, Sada YH (2017) Myasthenia Gravis After Nivolumab Therapy for Squamous Cell Carcinoma of the Bladder. J Immunother 40: 114-116. [Crossref]
8. Nguyen BH, Kuo J, Budiman A, Christie H, Ali S (2017) Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients. Melanoma Res 27: 152-154. [Crossref]
9. Hibino M, Maeda K, Horiuchi S, Fukuda M, Kondo T (2018) Pembrolizumab‐induced myasthenia gravis with myositis in a patient with lung cancer. Respirol Case Rep 6: e00355. [Crossref]
10. Gonzalez NL, Puwanant A, Lu A, Marks SM, Živković SA (2017) Myasthenia triggered by immune checkpoint inhibitors: New case and literature review. Neuromuscul Disord 27: 266-268. [Crossref]
11. Shirai T, Sano T, Kamijo F, Saito N, Miyake T et al. (2016) Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol 46: 86-88. [Crossref]
12. Alnahhas I, Wong J (2017) A case of new-onset antibody-positive myasthenia gravis in a patient treated with pembrolizumab for melanoma. Muscle Nerve 55: E25-E26. [Crossref]
13. National Comprehensive Cancer Network. (2019) Cutaneous Melanoma, Version 1.2019. NCCN Clinical Practice Guidelines Oncol.
14. Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD (1976) Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 26: 1054-1059. [Crossref]
15. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A et al. (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7: 365-368. [Crossref]
16. Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW et al. (1999) Myasthenia gravis activities of daily living profile. Neurology 52: 1487-1489. [Crossref]
17. Sanders DB, Tucker-Lipscomb B, Massey JM (2003) A simple manual muscle test for myasthenia gravis: validation and comparison with the QMG score. Ann N Y Acad Sci 998: 440-444. [Crossref]
18. Burns TM, Conaway M, Sanders DB (2010) The MG Composite: A valid and reliable outcome measure for myasthenia gravis. Neurology 74: 1434-1440. [Crossref]
19. Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study Group (2008) Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis. Muscle Nerve 38: 957-963. [Crossref]
20. Wang X-B, Kakoulidou M, Giscombe R, Qiu Q, Huang D et al. (2002) Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence. J Neuroimmunol 130: 224-232. [Crossref]
21. Wang XB, Pirskanen R, Giscombe R, Lefvert AK (2008) Two SNPs in the promoter region of the CTLA-4 gene affect binding of transcription factors and are associated with human myasthenia gravis. J Intern Med 263: 61-69. [Crossref]
22. Renton AE, Pliner HA, Provenzano C, Evoli A, Ricciardi R et al. (2015) A genome-wide association study of myasthenia gravis. JAMA Neurol 72: 396-404. [Crossref]
23. Sakthivel P, Ramanujam R, Wang XB, Pirskanen R, Lefvert AK (2008) Programmed Death-1: from gene to protein in autoimmune human myasthenia gravis. J Neuroimmunol 193: 149-155. [Crossref]
24. Lau KH, Kumar A, Yang IH, Nowak RJ (2016) Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve 54: 157-161. [Crossref]
25. Phadke SD, Ghabour R, Swick BL, Swenson A, Milhem M et al. (2016) Pembrolizumab Therapy Triggering an Exacerbation of Preexisting Autoimmune Disease: A Report of 2 Patient Cases. J Investig Med High Impact Case Rep 4: 2324709616674316. [Crossref]
26. Zhu J, Li Y (2016) Myasthenia gravis exacerbation associated with pembrolizumab. Muscle Nerve 54: 506-507. [Crossref]
27. Earl DE, Loochtan AI, Bedlack RS (2018) Refractory myasthenia gravis exacerbation triggered By pembrolizumab. Muscle Nerve 57: E120-E121. [Crossref]
28. Cooper DS, Meriggioli MN, Bonomi PD, Malik R (2017) Severe Exacerbation of Myasthenia Gravis Associated with Checkpoint Inhibitor Immunotherapy. J Neuromuscul Dis 4: 169-173. [Crossref]
29. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P et al. (2019) Management of Immunotherapy-Related Toxicities, Version 1.2019. J Natl Compr Canc Netw 17: 255-289. [Crossref]
30. Borgia G, Reynaud L, Gentile I, Cerini R, Dello Russo M et al. (2001) Myasthenia gravis during low-dose IFN-α therapy for chronic hepatitis C. J Interferon Cytokine Res 21: 469-470. [Crossref]
31. Kyi C, Carvajal RD, Wolchok JD, Postow MA (2014) Ipilimumab in patients with melanoma and autoimmune disease. J Immunother Cancer 2: 35. [Crossref]
32. Pedersen M, Andersen R, Nørgaard P, Jacobsen S, Thielsen P et al. (2014) Successful treatment with Ipilimumab and Interleukin-2 in two patients with metastatic melanoma and systemic autoimmune disease. Cancer Immunol Immunother 63: 1341-1346. [Crossref]
33. Maul LV, Weichenthal M, Kähler KC, Hauschild A (2016) Successful Anti-PD-1 Antibody Treatment in a Metastatic Melanoma Patient With Known Severe Autoimmune Disease. J Immunother 39: 188-90. [Crossref]
34. Maeda O, Yokota K, Atsuta N, Katsuno M, Akiyama M et al. (2016) Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis. Nagoya J Med Sci 78: 119-122. [Crossref]
35. Mitsune A, Yanagisawa S, Fukuhara T, Miyauchi E, Morita M et al. (2018) Relapsed Myasthenia Gravis after Nivolumab Treatment. Intern Med 57: 1893-1897. [Crossref]
36. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI et al. (2016) Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncol 2: 234-240. [Crossref]