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Year : 2018  |  Volume : 1  |  Issue : 4  |  Page : 142-144

Development of drug-induced arthritis in a glioblastoma patient treated with pembrolizumab

Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

Date of Web Publication30-Aug-2018

Correspondence Address:
Dr. Katherine B Peters
The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, PO Box 3624, Durham, NC 27710
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_28_18

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Glioblastoma (GBM, WHO Grade IV) is the most aggressive form of primary brain cancer in adults, and as with other cancers, clinical investigations to use immunotherapy as a possible therapeutic option for GBM are underway. One form of immunotherapy is immune checkpoint inhibition that targets the programmed cell death-1 (PD-1) receptor on lymphocytes. While PD-1 receptor inhibitors, such as pembrolizumab, are often tolerable, there can be dose-limiting immune-related adverse effects, which have the potential to result in impaired health-related quality of life. This case report discusses one patient with recurrent GBM who received pembrolizumab and developed refractory drug-induced arthritis.

Keywords: Arthritis, glioblastoma, immunotherapy, pembrolizumab

How to cite this article:
Brown CB, Peters KB. Development of drug-induced arthritis in a glioblastoma patient treated with pembrolizumab. Glioma 2018;1:142-4

How to cite this URL:
Brown CB, Peters KB. Development of drug-induced arthritis in a glioblastoma patient treated with pembrolizumab. Glioma [serial online] 2018 [cited 2023 Oct 2];1:142-4. Available from: http://www.jglioma.com/text.asp?2018/1/4/142/240232

  Introduction Top

Treatment of glioblastoma (GBM), the most common malignant brain tumor, continues to advance and immunotherapy represents one advancement. Similar to other cancers, neuro-oncology has adopted the use of checkpoint inhibitors, specifically programmed cell death-1 (PD-1) receptor blockade, in clinical trials and off-label use. Pembrolizumab, an antibody that inhibits PD-1, is Food and Drug Administration approved for the treatment of other cancers and is actively used in the clinical trials in GBM.[1] While patients can tolerate pembrolizumab, they can encounter immune-related adverse events (IrAEs) that can require treatment or discontinuation of therapy.[2] Common IrAEs include fatigue, rash, and colitis. We report a case of drug-induced arthritis, a rare IrAE, in a recurrent GBM patient treated with pembrolizumab. Consent from the patient was obtained.

  Case Report Top

A 44-year-old male with no significant past medical history presented to his ophthalmologist after seeing “floaters.” Later, he developed concentration difficulties, trouble reading, fatigue, headaches, and left homonymous hemianopia. This prompted brain magnetic resonance imaging (MRI) that showed a left occipital enhancing mass. He underwent a gross total resection and pathology revealed GBM (WHO Grade IV). Genetic analysis of the tumor showed that it was isocitrate dehydrogenase 1 wild type, telomerase reverse transcriptase promoter mutant, epidermal growth factor receptor overexpressed and amplified, and methyl-guanine methyltransferase promoter methylated. Initial treatment course included 6 weeks of concurrent radiation and temozolomide (TMZ) and enrollment in a clinical trial where he received two doses of basiliximab, CD25 monoclonal antibody, and adjuvant TMZ dosed at 200 mg/m 2 (5 days on and 23 days off in 28-day cycle). After the fifth cycle of adjuvant TMZ, he had tumor progression on MRI and underwent re-resection confirming recurrent GBM. He then enrolled in a clinical trial utilizing single-agent pembrolizumab dosed at 200 mg intravenously every 3 weeks. He was chosen for this trial as he was in his first progression of disease, had at least 4 weeks since surgical resection, had previously been treated with radiation and TMZ, and he did not have a diagnosis of immunodeficiency.

For 14 months, he tolerated pembrolizumab well. During month 15, the patient developed arthralgia at the left shoulder with associated decreased range of motion. He reported some mild knee pain and foot discomfort, although this was not interfering with his daily activities. He received a lidocaine injection to his left shoulder that relieved some discomfort, and he subsequently initiated in celecoxib 100 mg orally twice a day because of continued joint pain at his jaw, wrist, fingers, and ankles. This pain and arthralgia, although generalized, remained manageable for 3 months.

In early month 17, he reported worsening pain, particularly to the left shoulder, left knee, bilateral wrists, and ankles. Sports/rehabilitative medicine providers evaluated him and recommended prednisone 50 mg orally daily for 5 days. While this initially mitigated pain and arthralgia, these symptoms returned after therapy concluded. Despite these symptoms, he continued pembrolizumab.

After this initial course of prednisone, pain in the left knee worsened. MRI of the left knee showed evidence of synovial proliferation and thickening consistent with inflammatory arthritis. This prompted a cortisone injection to the knee and a short discontinuation of pembrolizumab. Despite these two interventions, pain and arthralgia persisted. Of note, prior to pembrolizumab therapy, the patient was an avid runner, running up to 10 miles at one time. After 17 months of pembrolizumab, he had challenges with running just 1 mile.

Because of continued joint pain, arthralgia, and decline in exercise ability, he discontinued pembrolizumab. Neuro-oncology providers consulted with the rheumatologist who initiated sulfasalazine, a common disease-modifying drug used in the treatment of rheumatoid arthritis, 500 mg orally twice daily. Unfortunately, the symptoms worsened. The patient attempted further courses of prednisone, nonsteroidal anti-inflammatory agents (NSAIDs), and narcotics, but pain continued and physical function declined. Pain and swelling now involved most joints including the jaw, bilateral knees, feet, ankles, hands, and wrists. He could no longer make a fist and could not type or write.

After laboratory and radiographic evaluation, the rheumatologist diagnosed him with inflammatory arthritis due to pembrolizumab. He started a prolonged prednisone taper, but unfortunately, his pain worsened. His providers stopped the tapering of prednisone and initiated methotrexate (MTX) 2.5 mg daily with folate 1 mg orally daily.

After 6 months on MTX and folate, he was able to make a fist with both hands and started swimming for exercise. Given that the pain had not completely resolved, his rheumatologist started adalimumab, a monoclonal antibody that blocks tumor necrosis factor-α and used for rheumatoid arthritis, approximately 5 months after MTX. He is currently in month 10 of MTX and has not required any additional prednisone after tapering off 8 months of daily use. [Table 1] elucidates the course of the patient's symptoms and relevant treatment.
Table 1: Time table of symptoms and interventions for the drug-induced arthritis

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It is important to note that despite not being on therapy for his GBM since discontinuation of pembrolizumab on month 15, he continues to have MRI brain with no evidence of tumor recurrence for over 24 months [Figure 1].
Figure 1: Magnetic resonance imaging brain of the patient during treatment course (T1 + gadolinium axial images). (A) At diagnosis, (B) after initial surgery, (C) at recurrence, (D) after second surgery, (E) at the start of pembrolizumab, (F) three years stable after the start of pembrolizumab

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  Discussion Top

Immunotherapy, in particular PD-1 checkpoint inhibitors, has revolutionized the treatment in many different types of cancer, and PD-1 inhibition via pembrolizumab is being explored in GBM patients.[3] Commonly seen IrAEs are fatigue, rash, and colitis.[2] Notably, the recent KEYNOTE-28 trial involving single-agent pembrolizumab in recurrent GBM reported common IrAEs that included fatigue, colitis, thyroiditis, and rash.[3]

Cancer patients receiving checkpoint inhibitors do report drug-induced arthralgia. The KEYNOTE-087 trial reported that 10% of non-Hodgkin's lymphoma patients receiving pembrolizumab had arthralgia.[4] The KEYNOTE-028 trial using pembrolizumab in mesothelioma noted that 20% had arthralgia.[5] While arthralgia can occur commonly, a systematic review of the literature by Abdel-Rahman et al.[6] revealed that arthritis and musculoskeletal IrAEs are very rare in cancer patients on checkpoint inhibitors.

In a retrospective study of 496 patients with melanoma who received pembrolizumab, eight patients (1.6%) reported arthralgia and noted one patient with synovitis of the wrist and one with exacerbation of psoriatic arthritis.[7] Treatment of these IrAEs included NSAIDs and systemic prednisolone (up to 0.5 mg/kg orally). Unique to our case presented, the patient required rheumatology referral and therapy with MTX and adalimumab.

This case shows the multiple interventions that one GBM patient underwent while managing drug-induced arthritis due to pembrolizumab. Although there is no definitive answer to the management of arthralgia and/or drug-induced arthritis due to pembrolizumab in GBM, this case offers suggestions that may be able to aid patients. In addition to the nonpharmacologic management of the pain including physical therapy, management including corticosteroids, rheumatology referral, and disease-modifying agents needs to be considered if pain and arthritis persist.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Peters S, Kerr KM, Stahel R. PD-1 blockade in advanced NSCLC: A focus on pembrolizumab. Cancer Treat Rev 2018;62:39-49.  Back to cited text no. 1
Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: Systematic review and meta-analysis. BMJ 2018;360:k793.  Back to cited text no. 2
Reardon DA, Kim TM, Frenel JS, Santoro A, Lopez J, Subramaniam DS, et al. Results of the phase 1B KEYNOTE-028 multi-cohort trial of pembrolizumab monotherapy in patients with recurrent PD-L1-positive glioblastoma multiforme (GBM). Neuro Oncol 2016;18:vi25-6.  Back to cited text no. 3
Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/Refractory classic Hodgkin lymphoma. J Clin Oncol 2017;35:2125-32.  Back to cited text no. 4
Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): Preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 2017;18:623-30.  Back to cited text no. 5
Abdel-Rahman O, Eltobgy M, Oweira H, Giryes A, Tekbas A, Decker M. Immune-related musculoskeletal toxicities among cancer patients treated with immune checkpoint inhibitors: A systematic review. Immunotherapy 2017;9:1175-83.  Back to cited text no. 6
Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60:210-25.  Back to cited text no. 7


  [Figure 1]

  [Table 1]


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