Giant cell arteritis associated with PD-1 inhibition

Abstract

A 50-year-old woman was referred to rheumatology for new onset polyarthralgia and headache. She had a history of metastatic lung adenocarcinoma and was started on treatment with the programmed death 1 receptor (PD-1) antagonist pembrolizumab 2 months prior. Examination revealed left temporal artery tenderness and hand synovitis. Investigations revealed enlarged temporal artery on ultrasound imaging. On steroid treatment, she had resolution of symptoms, but due to significant steroid side effects required methotrexate and her PD-1 antagonist therapy was continued in consultation with her oncologist. Her malignant disease has remained stable, and she has improved functional status.

Background

Giant cell arteritis (GCA) is a rare rheumatological immune-related adverse event (irAE). As the use of checkpoint inhibitors becomes more prevalent in cancer immunotherapy, it will be important for physicians to be aware of these adverse events. There have been two prior case reports of GCA with visual loss associated with pembrolizumab.^{1 2} Our patient is unique in that she did not have visual loss and developed concurrent inflammatory arthritis.

Case presentation

A 50-year-old woman with history of tobacco use disorder and metastatic lung adenocarcinoma who was on treatment with the programmed death 1 receptor (PD-1) antagonist pembrolizumab was referred to rheumatology for the evaluation of new onset polyarthralgia that first manifested 2 months after the initiation of anti-PD-1 therapy. At the initial visit the patient reported bilateral hand pain with associated swelling and stiffness lasting up to 3 hours. She also reported daily left sided temporal headaches, scalp tenderness and jaw claudication. She denied any visual symptoms. She reported improvement in these symptoms on the days leading up to her chemotherapy when she was taking prophylactic dexamethasone at a dose of 4 mg two times per day for 3 days. There was no family history of autoimmune disease. On examination, she was found to have tenderness over the left temporal artery with intact pulses. She had evidence of synovitis bilaterally in the metacarpophalangeal joints.

Investigations

Laboratory investigations revealed an erythrocyte sedimentation rate of 28 mm/hr (normal <30 mm/hr) and C reactive protein of 2.7 mg/L (normal <10 mg/L). These investigations were performed while she was on prophylactic dexamethasone. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Bilateral hand radiographs revealed no bony abnormalities. CT imaging of the brain showed no evidence of metastasis involving temporal or jaw region. She was referred for an urgent temporal artery biopsy to evaluate for GCA. As she had no visual symptoms, formal ophthalmological exam was deferred, and she was started on high dose prednisone at a dose of 1 mg/kg with significant improvement in symptoms. Ultrasound of the temporal arteries, performed after 7 days of glucocorticoid therapy, showed increased wall thickening of the left temporal artery (0.049 cm) compared with the right (0.035 cm) (figure 1), as well as increased vessel diameter on the left compared with the right (figure 2). She was not found to have halo sign or compression sign (figure 3). Based on the improvement in her symptoms and imaging findings, she was clinically diagnosed with GCA, thus temporal artery biopsy was deferred.

Figure 1.

Ultrasound of temporal artery wall thickness.

Figure 2.

Ultrasound of the temporal artery wall diameter.

Figure 3.

Left temporal artery: absence of halo or compression sign.

Treatment

In the interim, one dose of pembrolizumab was held, and she was continued on a steroid taper. On follow-up, she reported significant weight gain and had new hypertension and hyperglycaemia. Symptoms of hand pain and headaches remained under control. Due to these side effects, methotrexate was added in consultation with her oncologist. She was continued on PD-1 antagonist therapy, and last imaging studies showed stable disease in regards to her cancer.

Outcome and follow-up

At follow-up 6 months after onset of her symptoms, she is able to continue her activities of daily living and caring for her grandchildren. She has been able to taper steroids and is tolerating methotrexate. There are plans to continue her anti-PD-1 therapy for another year. She continues to have close follow-up with her oncologist and rheumatologist.

Discussion

GCA is a rare rheumatological irAE of immune checkpoint inhibitors. The incidence is difficult to calculate given its rarity.³ It is important to include GCA in the differential diagnosis of patients on PD-1 therapy who report new headache, visual symptoms or jaw claudication. The two previously described cases of GCA associated with pembrolizumab occurred in patients greater than 80 years old. Both presented with acute visual loss along with biopsy proven arteritis. One case was associated with concomitant immune-related colitis.^{1 2}

PD-1 and programmed death ligand-1 (PD-L1) may play important roles in the pathophysiology of large vessel vasculitis. Zhang et al showed that inhibition of the PD-1/PD-L1 checkpoint ex vivo led to increased T-cell-mediated inflammation and arterial wall damage.⁴ Checkpoint inhibitors iatrogenically produce a similar effect and can accelerate the autoimmune process in GCA.⁵ Jamal et al describe that rheumatological irAEs seem to be different from other irAEs in that they can occur early or have delayed onset (ranging from 1 week to 18 months after initial exposure) and may persist after checkpoint inhibitor therapy is discontinued. The median duration of checkpoint inhibitor therapy preceding symptom onset was 3 months.⁵

Due to rarity, there are no formal recommendations for management. The use of high dose steroids follows the American College of Rheumatology guidelines for the management of GCA.⁶ Delaying further PD-1 therapy can be considered. Discontinuation of the therapy should be considered in those with visual loss in consultation with the patient’s oncologist.³ As our patient had no visual symptoms but did have skeletal and brain metastasis, the decision was made to continue PD-1 therapy. Methotrexate was chosen as a steroid-sparing agent due to predominant inflammatory joint symptoms and significant steroid-induced side effects. The anti-inflammatory effect of methotrexate on interleukin 1 (IL-1) is thought to play a role in its effectiveness in vasculitis.⁷ Tocilizumab is another standard steroid-sparing agent used for GCA that acts by inhibiting IL-6, but its specific role in checkpoint inhibitor-related GCA is unclear.³

Some limitations of our report include that the patient’s inflammatory marker levels were obtained while she had already been receiving steroids. Despite this, her sedimentation rate remained near the upper limit of normal. She did not have a biopsy performed, but met American College of Rheumatology classification criteria for GCA based on her age, new headache and temporal artery tenderness. The European Alliance of Associations for Rheumatology (EULAR) guidelines consider a diagnosis of GCA without biopsy in whom there is high clinical suspicion and a positive imaging test.⁸ Her symptom onset, which occurred 2 months after starting pembrolizumab, fits previously described timelines for irAEs and makes a paraneoplastic aetiology less likely. In addition, she had improvement in symptoms with higher dose steroids.

The use of ultrasound (US) has become an important diagnostic tool in GCA. In a study investigating 451 patients with suspected GCA, among whom 256 patients had a final diagnosis of GCA, arrived at 91.6% sensitivity and 95.8% specificity for US compared with the final clinical diagnosis.⁹ The patient had temporal artery thickening on ultrasound after 1 week of treatment with steroids (figure 1). Reports suggest that there may be improvement, and even normalisation, of temporal artery thickness and disappearance of halo sign as early as 2–4 days after the initiation of therapy.¹⁰ Temporal artery US should be completed as soon as possible or within 48 hours of initial evaluation as steroids rapidly reduce imaging sensitivity. Normal temporal artery wall thickness ranges from 0.02 cm to 0.05 cm depending on the branch that is measured.⁹ The Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group has definitions of halo and compression signs of temporal and axillary arteries to help standardise examination for use in clinical trials.¹¹

As the use of immune checkpoint inhibitor therapies increase, it will be important for oncologists and rheumatologists to be aware of potential adverse events such as GCA. Though currently rare, it is possible that the incidence will increase as checkpoint inhibitors are used more frequently for a broader range of cancer immunotherapy. It is important to consider a diagnosis of GCA in patients reporting new headache as visual loss and jaw claudication may not always be present. Decisions should be made in collaboration with the oncologists with a goal to provide the patient with best quality of life and functional status.

Learning points.

• With increasing use of programmed death 1 receptor (PD-1)/programmed death ligand-1 (PD-L1) antagonists in cancer immunotherapy, physicians will see an increased incidence of immune-related adverse events including rare rheumatologic events such as giant cell arteritis (GCA).

• It is important to consider a diagnosis of GCA in patients reporting new headache as visual loss and jaw claudication may not always be present.

• Temporal artery ultrasound should be performed by an experienced ultra-sonographer within first 24–48 hours after initial evaluation.

• Decisions regarding treatment should be made as part of a collaborative team between the patient, rheumatologist and oncologist.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).