Scleroderma-like syndrome associated with pembrolizumab

To the editor:

The monoclonal antibodies known as checkpoint inhibitors (CPIs) are used as immunotherapy in the treatment of several types of refractory cancer. Up to 80% of patients treated with CPIs experience immune-related adverse effects (irAEs), including systemic autoimmune diseases like rheumatoid arthritis, myositis, or granulomatosis with polyangiitis,^1,2 but only exceptionally, systemic sclerosis. ³

We report a case of scleroderma-like syndrome induced by pembrolizumab during therapy for bladder carcinoma. A 75-year-old man, former smoker, with hypertension and atrial fibrillation, was treated for a high-grade urothelial carcinoma since 2014. There was no history of preexisting autoimmune disease. After treatment with BCG and several transurethral resections, locoregional lymph node progression was observed in May 2017. He received cisplatin and gemcitabine, developing cyanosis in hands and necrotic lesions in the second and fourth fingers of the left hand. The patient reported previously self-limited episodes of painful discoloration in the hands caused by cold temperatures. It was attributed to cisplatin toxicity, improving with intravenous prostaglandins. In March 2018, pembrolizumab was started (200 mg/kg every 3 weeks). In the next month, a limited cutaneous thickening distal to metacarpophalangeal joints appeared with digital scars on the third and fourth fingers of both hands (Image 1). History was negative for gastroesophageal reflux, dysphagia, or shortness of breath. Laboratory test results showed anemia (Hb 5.7 g/dL) with normal red cell indexes, platelet, and white-cell differential counts. Indirect and direct antiglobulin tests (Coombs test) were negative. Examination of the peripheral blood smear revealed a 7% reticulocyte index, low schistocytes (1/1000), and normal morphologic features. Haptoglobin was undetectable. There were minimally elevated levels of serum lactate dehydrogenase and normal unconjugated bilirubin. The hormonal test revealed central hypothyroidism and low total testosterone. Immunology showed antinuclear antibodies 1/160 speckled pattern, with anti-Ro52 positive. Extractable nuclear antigen (ENA) and scleroderma-specific antibodies were negative. A nailfold capillaroscopy showed a non-specific pattern. Magnetic resonance imaging (MRI) neuroimaging revealed no enlargement of the pituitary. A computed tomography (CT) scan showed a significant decrease in the size of pelvic lymphadenopathies. Thus, a partial response to pembrolizumab with irAEs was considered, and CPI therapy was discontinued.

Image 1.

Digital scars on the fingers of both hands.

Our patient developed limited scleroderma-like syndrome induced by pembrolizumab. Furthermore, we postulate that autoimmune Coombs-negative hemolytic anemia and hypophysitis were the most likely additional diagnosis. However, Coombs test negativity and the absence of the characteristic findings of hypophysis on MRI challenged these diagnoses. The endocrine irAEs of CPIs include up to 9% reports of hypophysitis, although for pembrolizumab, it is less than 1%. ⁴ Neuroimaging findings in immune-related hypophysitis are mild enlargements of the pituitary but there are occasional reports of normal MRI. ⁴ Systemic corticosteroids are the treatment mainstay for irAEs ³ and were therefore initiated by the oncologist team before the diagnosis of scleroderma was suspected, with clinical improvement.

Nearly half of the patients with irAEs associated with CPIs are an exacerbation of the preexisting autoimmune diseases with recurrence or worsening of prior manifestations, ² but only a minority of patients with preexisting rheumatologic disease receiving these therapies experienced a flare of their preexisting rheumatologic disease or any other irAE. ⁵ Our patient had developed Raynaud’s phenomenon and digital ulcers under cisplatin treatment. Raynaud’s syndrome is a known side-effect of treatment of cisplatin-based chemotherapy. Although rare, serious complications like critical digital ischemia have been reported, with no temporal or accumulated dose relationship, and acute ischemia is rare in patients with scleroderma. ⁶ During therapy with other CPIs like nivolumab, there has been also reported cases of scleroderma and relapse of morphea.^7–9

CPI treatments are being used more often in cancer patients. So, we should be aware of the possibility of exacerbation or relapse of previous autoimmune diseases like scleroderma spectrum disorders, where early clinical diagnosis is always difficult.