Polymyalgia rheumatica in a melanoma patient 11 months after completion of immunotherapy with nivolumab

Abstract

Background

Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of several cancers but can also lead to the development of immune‐related adverse effects including dermatologic, gastrointestinal, endocrine, hepatic, pulmonary and less commonly, rheumatic toxicities. Toxicities associated with ICI therapy can occur several months or even years after initiation. Case reports of polymyalgia rheumatica (PMR) associated with nivolumab use are rare. We herein describe, for the first time, a case of PMR in a melanoma patient after cessation of treatment with nivolumab.

Case

An 88‐year‐old man with a history of stage IV M1c BRAF wild‐type melanoma presented with a 1 month history of arthralgias and morning stiffness, predominantly affecting the shoulders and hips, associated with fatigue and weight loss. He had undergone wide local excision of a primary malignant melanoma in the left buttock region several years prior. Immunotherapy with nivolumab was initiated following disease relapse with multiple metastases. Nivolumab was discontinued due to demonstration of complete metabolic response on serial positron emission and computed tomography scans. Symptoms appeared 11 months after completion of treatment. A diagnosis of PMR was made and treatment with oral prednisone was initiated leading to complete resolution of symptoms within 1 week. We believe that the development of PMR in our patient was likely precipitated by nivolumab.

Conclusion

This case demonstrates that PMR, although rare, may occur as an adverse effect both during and after treatment with nivolumab, leading to disabling symptoms and poor quality of life. Prompt diagnosis is crucial to enable timely commencement of corticosteroid therapy in order to avoid further impact on morbidity and mortality for cancer patients. This case highlights the importance of prompt referral to rheumatology, as well as the need for close collaboration between oncologists and rheumatologists to accurately diagnose and successfully manage these patients.

1. INTRODUCTION

In recent years, immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of several cancers, in particular, melanoma, non‐small cell lung cancer (NSCLC), urothelial and renal cell cancers. Nivolumab is a fully human IgG4 anti‐programmed cell‐death‐1 (PD‐1) antibody that disrupts the interaction between PD‐1 receptor and its ligand PD‐L1, preventing T‐cell inactivation. Unrestrained T‐cell activation heightens the immune response which acts to suppress tumour growth and can also lead to the development of immune‐related adverse effects (irAEs) including dermatologic, gastrointestinal, endocrine, hepatic, pulmonary and less commonly, rheumatic toxicities. Case reports of polymyalgia rheumatica (PMR) associated with nivolumab use are rare. We herein describe, for the first time, a case of PMR in a melanoma patient after cessation of treatment with nivolumab.

2. CASE

An 88‐year‐old man presented in February 2019 with a 1 month history of arthralgias and morning stiffness, predominantly affecting the shoulders and hips, associated with difficulty mobilising, fatigue and a 3 kilogram weight loss. The patient had a history of stage IV M1c BRAF wild‐type melanoma. He had undergone wide local excision of a primary malignant melanoma in the left buttock region in 2015. In May 2016, immunotherapy with nivolumab was initiated following disease relapse with nodal, right adrenal, pulmonary and small bowel metastases. Nivolumab was discontinued in March 2018 due to demonstration of complete metabolic response on serial positron emission and computed tomography (CT) scans since October 2017.

Symptoms appeared 11 months after completion of treatment, leading to significant functional impairment with the inability to perform activities of daily living (ADL). Consequently, the patient reported that he was bed‐bound for majority of the day. He denied having symptoms of giant cell arteritis (GCA) including headaches, visual disturbances and jaw claudication. On examination, he was afebrile and demonstrated painful and restricted joint range of motion, particularly affecting the shoulder and hip joints. Erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP) levels were elevated at 61 mm/h and 96 mg/L, respectively. Creatine kinase level was normal (105 U/L; normal <200 U/L). Antinuclear antibodies, rheumatoid factor and anti‐cyclic citrullinated peptide antibodies were negative. A CT scan revealed a stable right pulmonary nodule with no evidence of metastatic disease. Bone scintigraphy showed no evidence of bony metastasis.

The patient was referred for rheumatologic evaluation. Our patient's presentation fulfilled the 2012 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for PMR using the screening algorithm without joint ultrasonography. ¹ Oral prednisone was initiated at 15 mg per day and 2 days later, a dramatic improvement in ESR and CRP levels was seen (26 mm/h and <5 mg/L respectively). Complete resolution of symptoms occurred after 1 week of corticosteroid use, enabling the patient to resume his usual ADL. He remained on 15 mg of prednisone for 2 weeks before a dose‐tapering regimen by 1 mg monthly was established. Our patient continues to remain symptom‐free and in disease remission from an oncologic standpoint.

3. DISCUSSION

Immune‐related adverse effects can occur in 39% of patients treated with anti‐PD‐1/PD‐L1 agents and are usually mild and appear within 3 to 6 months of treatment initiation; grade 3 to 4 toxic effects are reported in approximately 9% of patients. ² Most irAEs are corticosteroid‐responsive and resolve within 6 to 12 weeks. ³

To our knowledge, there have been 4 previously reported cases of PMR in melanoma patients secondary to nivolumab administration.4, 5, 6, 7 One patient was diagnosed with nivolumab‐associated PMR 3 months into treatment. ⁷ Nivolumab was discontinued and oral prednisone was commenced with resolution of symptoms after 3 weeks. A French retrospective study reported a case of PMR that developed within 4 weeks of nivolumab initiation for metastatic melanoma. ⁴ Nivolumab was continued and resolution of symptoms occurred with oral prednisone. The most recent case was a stage IV melanoma patient who was diagnosed with PMR and GCA after 30 cycles of nivolumab. ⁶ High‐dose prednisone was initiated with eventual resolution of symptoms.

Two cases of PMR have been diagnosed in NSCLC patients after 12 and 13 cycles of treatment with nivolumab, respectively.8, 9 In both cases, symptoms improved with corticosteroid use. In a case series from the Cleveland Clinic, 1 patient developed PMR after 4 years of being stable on nivolumab for renal cell carcinoma. ⁵ Similarly, 2 other corticosteroid‐responsive cases of PMR have been described in patients with metastatic renal carcinoma, between 9 and 16 months into treatment with nivolumab. ¹⁰ In all cases, clinical improvement was evident after corticosteroid therapy, which is consistent with our report.

Polymyalgia rheumatica presents with a wide range of non‐specific systemic features making the diagnosis challenging. As there is no single diagnostic test, a combination of findings is needed for diagnosis. There are a number of different diagnostic criteria for PMR with no international consensus. A diagnostic criteria was proposed by Bird et al. in 1979, which requires 3 of the following 7 features for the diagnosis of PMR: age more than 65 years; ESR greater than 40 mm/h; bilateral shoulder pain and/or stiffness; morning stiffness for more than 1 hour; onset of illness within 2 weeks; depression and/or weight loss; and bilateral upper arm tenderness. ¹¹ Our patient presented with 6 of the 7 features listed. The presence of just 3 features confirms a sensitivity of 92% and specificity of 80%. ¹¹ Our patient's symptoms also fulfilled the 2012 EULAR/ACR classification criteria for PMR. All essential criteria were met, including age over 50 years, bilateral shoulder aching and elevated ESR and CRP. In addition to these, using the screening algorithm without joint ultrasonography, a definitive diagnosis of PMR is reached with a score of 4 or more. Our patient scored the maximum of 6 points using this algorithm. Ultrasonography is a recommended investigation for PMR as it improves the specificity of diagnosis. ¹ Unfortunately, joint ultrasonography was not performed in our case.

Toxicities associated with ICI therapy can occur several months or even years after initiation, particularly rheumatic side effects. ¹² We describe, for the first time, the diagnosis of PMR in a melanoma patient almost 1 year after cessation of treatment with nivolumab. Although we cannot exclude age‐related PMR, given the absence of prior rheumatic disease and the temporal relationship between treatment cessation and the onset of rheumatologic symptoms, we believe that the development of PMR in our patient was likely precipitated by nivolumab.

4. CONCLUSION

This case demonstrates that PMR, although rare, may occur as an adverse effect both during and after treatment with nivolumab, leading to disabling symptoms and poor quality of life. Diagnosis may pose a challenge given the non‐specific nature of symptoms and lateness of onset. Nevertheless, prompt diagnosis is crucial to enable timely commencement of corticosteroid therapy in order to avoid further impact on morbidity and mortality for cancer patients. Since the use of ICIs in cancer treatment is increasing, knowledge of irAEs and their management is essential. This case highlights the importance of prompt referral to rheumatology, as well as the need for close collaboration between oncologists and rheumatologists to accurately diagnose and successfully manage these patients.

CONFLICT OF INTEREST

The authors report no conflicts of interest with respect to the research and/or authorship of this article. The authors received no financial support or sponsorship for the research and/or authorship of this article.

AUTHOR CONTRIBUTIONS

All authors had full access to the data used in this article and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualisation, Yolanka Lobo, Phillip Good, Felicity Murphy; Investigation, Yolanka Lobo, Phillip Good, Felicity Murphy; Writing ‐ Original draft, Yolanka Lobo, Phillip Good, Felicity Murphy; Writing ‐ Reviewing and editing, Yolanka Lobo, Phillip Good, Felicity Murphy; Visualisation, Yolanka Lobo, Phillip Good, Felicity Murphy.

ETHICAL STATEMENT

Written informed consent was obtained from our patient for the publication of this article.

Lobo Y, Good P, Murphy F. Polymyalgia rheumatica in a melanoma patient 11 months after completion of immunotherapy with nivolumab. Cancer Reports. 2020;3:e1244. 10.1002/cnr2.1244

DATA AVAILABILITY STATEMENT

The data that support the findings of this article are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.