Sex: F
Vaccine: COVID19
Symptoms: Blood culture, Brain natriuretic peptide, C-reactive protein, Computerised tomogram head, Computerised tomogram thorax
Clinical narrative: Large-vessel vasculitis; This is a literature report.  Checkpoint inhibitors (CPIs) and pegfilgrastim, a long-acting growth factor agent, are vital components of current cancer treatments. Immune-related adverse events (irAEs) such as colitis and pneumonitis are well-established toxicities associated with CPI therapy. However, large-vessel vasculitis secondary to CPI utilization is reported only in rare case reports and case series. Interestingly, large-vessel vasculitis has also been reported as a rare complication of pegfilgrastim use. We present a 59- year-old female with left stage IIA (cT2N0M0) triple-negative breast cancer receiving neoadjuvant decitabine and pembrolizumab prior to neoadjuvant chemotherapy (NAC). NAC included standard-of-care dose dense doxorubicin and cyclophosphamide (ddAC) supported with pegfilgrastim use followed by weekly carboplatin and  paclitaxel. After receiving her second cycle of ddAC with pegfilgrastim, the patient reported five days of left shoulder and arm pain. Subsequent CT imaging demonstrated wall thickening and inflammatory changes surrounding the left ubclavian artery, aortic arch, left carotid artery, proximal innominate arteries, and the mid internal carotid arteries and its branching vessels. These findings were extremely concerning for large-vessel vasculitis. Excluding CPI therapy and pegfilgrastim use, no additional inciting event or medication  that the patient was exposed to was noted to be associated with large-vessel vasculitis. We present this case to report on this rare but severe complication from commonly utilized agents in cancer treatment. We also extend the possibility of large-vessel vasculitis development in relation to the COVID-19 vaccine due to shared ingredients found in both the vaccine and pegfilgrastim. It is important to outline the treatment used for such a complication as no standardized treatment has been established for large-vessel vasculitis caused by CPI therapy or pegfilgrastim use. A 59-year-old female with left stage IIA (cT2N0M0) triplenegative breast cancer was treated on a clinical trial with neoadjuvant chemoimmunotherapy. The investigational portion of treatment included decitabine (4 doses) administered on days 1-5 and pembrolizumab administered on days 8 and 22, prior to starting neoadjuvant chemotherapy (investigational use of an FDA approved agent). The patient then received standard-of-care chemotherapy with four cycles of ddAC and pegfilgrastim support followed by twelve weekly doses of carboplatin and paclitaxel. After receiving her second cycle of ddAC with pegfilgrastim, the patient reported 5 days of worsening left shoulder and arm pain. The pain started in the left scapula and radiated down the left arm to the back and under the left breast. It was pleuritic and severe in nature. The pain worsened with active but not passive range of motion. She denied chest pain, dyspnea, or fevers but also reported a pruritic, papular rash over her chest and back that started two weeks before the onset of arm pain. An X-ray of the left humerus showed no fracture. Given the pleuritic nature of her pain, the patient underwent a contrasted chest CT to assess for pulmonary embolism. This showed wall thickening and inflammatory changes surrounding the left subclavian artery extending into the aortic arch with involvement of the left carotid artery and proximal innominate arteries. These imaging findings were concerning for large-vessel vasculitis, and the patient was admitted to the hospital for work up and management. Vital signs were within normal limits. Basic labs revealed a neutrophilic predominant leukocytosis and mild normocytic anemia. Her kidney function was normal and urinalysis showed trace protein and blood; the urine protein-tocreatinine ratio was mildly elevated at 0.21. Liver function tests were within normal limits. Her troponin and BNP were in the normal ranges. ECG on admission was normal and a transthoracic echocardiogram showed a normal ejection fraction, cavity size, and wall thickness. Inflammatory markers revealed a normal sedimentation rate, but Creactive protein was elevated to 847 mmol/L (normal < 48mmol/L). Rheumatology was consulted to assist with the work up of her large-vessel vasculitis. Serologic testing demonstrated a negative antinuclear antibody, rheumatoid factor, yeloperoxidase antibody, proteinase 3 antibody, and normal C4 complement level. Hepatitis serologies revealed a nonreactive hepatitis C antibody and evidence of prior immunization to hepatitis B. Creatine kinase was ordered to rule out myositis and was normal. Blood cultures were obtained to assess for infection and no microbial growth was identified. Further vascular imaging was acquired to assess for involvement of other organs. CT of the head and neck with contrast revealed that the wall thickening of the common carotid arteries extended cranially to the level of the midinternal carotid arteries but there was no significant stenosis or involvement of the intracranial vessels. The vessels in the abdomen and pelvis were without inflammatory changes. After the above workup, the differential diagnosis for this patient's large-vessel vasculitis included CPI-induced vasculitis due to pembrolizumab- or pegfilgrastim-induced vasculitis. As part of the clinical trial for triple-negative breast cancer, she received two doses of pembrolizumab 45 and 31 days prior to onset of her left arm pain. Two doses of pegfilgrastim with ddAC were given 22 and 8 days prior to onset of her symptoms. Of note, she also received the two-dose Pfizer COVID-19 vaccine series prior to starting therapy for her breast cancer with doses administered two and three months prior to symptom onset. After being started on systemic steroids (prednisone 1 mg/kg) for treatment in the hospital, the patient demonstrated rapid improvement in her symptoms. The patient was discharged with plans to continue on a slow steroid taper. She had continued improvement in her left arm pain and reported only mild residual weakness at follow-up 2 weeks after discharge. She did note a change in the character of her vision and was referred to ophthalmology for further evaluation with no findings of ocular inflammation seen on eye exam. Repeat inflammatory markers two weeks after discharge were normal, and repeat imaging 8 weeks later showed marked improvement in vasculitis. She completed a slow steroid taper over 12 weeks with no recurrence of symptoms. The patient did not receive additional immunotherapy after onset of symptoms as she had already completed all doses per the clinical trial. The frequency of subsequent chemotherapy doses was decreased and carboplatin eventually discontinued to allow for avoidance of additional G-CSF doses and prevention of large-vessel vasculitis recurrence. The case of therapy-associated large-vessel vasculitis that we present is unique in that it contains several possible etiologies: CPI-induced vasculitis, pegfilgrastim/G-CSF induced vasculitis, or a combination with a potential immunostimulatory contribution of the PEG-containing mRNA COVID- 19 vaccine. Although large-vessel vasculitis is a rare adverse event in both of these lifesaving cancer therapies and should not preclude providers from utilizing them in the care of patients, oncologists should consider large-vessel vasculitis as a potential complication of immunotherapy and pegfilgrastim going forward with particular attention to when these medications are used in combination. They should be aware of such a complication when evaluating patients who have received the above agents and present with symptoms of unclear etiology.; Sender's Comments: Based on the information currently available, a possible contributory role of the suspect drugs in the reported events cannot be completely ruled out given the implied temporal association. The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regul atory Authorities, Ethics Committees and Investigators, as appropriate.