Digital ischemia triggered by coronavirus disease 2019 in a patient under cemiplimab treatment

Dear Editor,

Cutaneous manifestations of coronavirus disease 2019 (COVID‐19), including pseudo‐chilblain, vesicular, maculopapular, urticaria, and livedo/necrosis ¹ lesions, have been widely reported. Anti‐programmed cell death protein‐1 (PD‐1) immune checkpoint inhibitors have dramatically changed the treatment of locally advanced and metastatic squamous cell carcinoma (SCC). Likewise, Raynaud’s phenomenon and acral necrosis related to anti‐PD‐1 have been described. ² We present the case of a woman receiving cemiplimab who presented with digital ischemia and positive COVID‐19 serological tests.

A heavy‐smoker, 48‐year‐old woman with a history of hypertension and an unresectable facial basal cell carcinoma, receiving cemiplimab 350 mg intravenously every 3 weeks in a clinical trial (REGN‐1620), because of tumoral progression and side effects from treatment with vismodegib, presented in January 2020 (17 months after initiating cemiplimab) with de novo erythematous papulonodular lesions, pallor, and cyanosis on fingertips. She was diagnosed with idiopathic chilblains and Raynaud’s phenomenon, which resolved after cold avoidance strategies. In April 2020, she presented at the Emergency Department with painful digital distal ulcers. She denied having COVID‐19‐related respiratory symptoms. Physical examination showed white‐grayish coloration with a necrotic scar and bullae formation on the second, third, and fourth fingertips of the right hand, and erythema with a punctiform necrotic scar on the fifth fingertip of the left hand (Fig. 1).

Figure 1.

Digital ischemia triggered by COVID‐19 in a patient under cemiplimab treatment. (a) Necrotic distal digital ulcers affecting the second, third, and fourth fingers of the right hand with proximal white‐grayish discoloration as a sign of true ischemia. (b) Punctiform necrotic scar on the fifth fingertip of the left hand

RT‐PCR and serologic tests for COVID‐19 were performed, revealing negative PCR, positive IgG, and negative IgM antibodies. Blood tests showed high D‐Dimer levels (2,500 ng/ml, reference value <500) and low titer (1:40) antinuclear antibodies. Systemic sclerosis and antiphospholipid syndrome antibodies were negative. Angiotensin‐converting enzyme inhibitors and beta‐blockers were stopped, while amlodipine 10 mg b.i.d. and topical 0.2% nitroglycerin were prescribed for 3 weeks. The lesions worsened with progressive fingertip ischemia, cemiplimab treatment was stopped, amlodipine was changed for nifedipine 10 mg every 8 hours, which was tapered later on to 10 mg daily, aspirin 100 mg daily was started, and ciprofloxacin 500 mg b.i.d. and clindamycin 300 mg b.i.d. were prescribed for 2 weeks. Five days after, given the poor response, the patient was admitted to receive intravenous alprostadil 30 mg b.i.d. and wound care. Significant improvement of cutaneous lesions was observed within 1 week of this regimen (Fig. 2), prolonged for 10 days on an outpatient basis.

Figure 2.

Digital ischemia triggered by COVID‐19 in a patient under cemiplimab treatment. (a–b) Clinical resolution of the necrotic ulcers after treatment with intravenous alprostadil

Patients with COVID‐19 may present with altered coagulation parameters, such as elevated D‐Dimer and longer prothrombin time, which have been associated with poor prognosis. ³ Unilateral livedo reticularis, Raynaud’s phenomenon, retiform purpura, and acro‐ischemic skin lesions have previously been described. The latter have been associated with severe disease and poor prognosis. ¹ The exact pathophysiological pathways leading to this procoagulant state are still unclear. SARS‐CoV‐2 uses angiotensin‐converting enzyme‐2 receptor in pneumocytes to infect the hosts, which is widely expressed in endothelial cells, facilitating their infection and causing diffuse endotheliitis. Some reports suggest a generalized thrombotic microvascular injury mediated by complement activation. ⁴ An altered inflammatory immune response potentially leading to a cytokine storm syndrome with elevated interleukin‐6 levels and coagulation pathway activation has been described in genetically predisposed individuals with COVID‐19. Other patients with COVID‐19 and thrombotic events develop antiphospholipid antibodies, suggesting an antiphospholipid syndrome‐like condition. ⁵ Cemiplimab is a novel anti‐PD‐1 therapy recently approved for locally advanced or metastatic cutaneous SCC. Even though no ischemic or thrombotic adverse events have been reported with cemiplimab, other anti‐PD‐1 agents have been related to Raynaud’s phenomenon and acral vascular necrosis. ²

Asymptomatic COVID‐19 infection usually presents with chilblain‐like lesions, ¹ rarely progressing to digital recalcitrant ischemia. This well‐documented case describes the temporal process from chilblains and Raynaud’s phenomenon in early COVID‐19 to digital ischemia, in which the role of cemiplimab is unclear. We hypothesize that in a patient with several prothrombotic comorbidities and cemiplimab treatment, COVID‐19 immune alteration could have triggered severe ischemic lesions. Regardless that more cases of severe ischemia in patients with anti‐PD‐1 treatment and asymptomatic COVID‐19 must be collected to confirm this association, special care to prevent SARS‐CoV‐2 infection may be considered in these patients given the combination of prothrombotic factors.