To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis).We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2).Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059-16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement.irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.
BRAF inhibitors (BRAFi) improve progression-free survival and overall survival in patients with advanced melanoma (1,2), with 3 to 6% of patients experiencing complete remission (CR)(1,3). Nevertheless, this efficacy comes at a cost with 90% of patients experiencing at least one adverse event and 45% grade 3 or 4 adverse events (4).
Management of long-term responders is not yet well delineated: safety argues for treatment continuation, because evolution after discontinuation is unknown.
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Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein 1 (PD-1) antibodies have significantly improved prognosis in advanced melanoma with a low rate of adverse events.1Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5110) Google Scholar Hepatic sinusoidal obstruction syndrome (SOS) is a rare disease characterized by small hepatic vessels damage leading to partial or complete occlusion of small hepatic veins.2DeLeve L.D. Shulman H.M. McDonald G.B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).Semin Liver Dis. 2002; 22: 027-042Crossref PubMed Scopus (543) Google Scholar We here report the first case of hepatic SOS induced by an ICI. A 66-year-old woman was treated surgically for an ulcerated amelanotic vulvar melanoma of 3.5 mm Breslow thickness without any BRAF/NRAS/C-KIT mutations. Two years later, she presented with three pelvic lymph node and soft tissue metastases. Nivolumab was started, resulting in disease stability. Fourteen months after anti-PD-1 initiation, she presented with an 8% weight increase, diffuse edema of the face and lower limbs, and abdominal pain and swelling. Blood tests displayed a five-fold increase in alanine and aspartate aminotransferase levels, a two-fold increase in alkaline phosphatase and gamma-glutamyl transpeptidase levels, normal bilirubin, ferritin, prothrombin time, and platelet count. Laboratory values showed low albumin level (30 g/l), mild elevation of C-reactive protein (6.5 mg/l: normal <5). Serologic tests for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus were negative with undetectable hepatitis B virus DNA and hepatitis C virus RNA levels. Both anti-hepatitis E virus and anti-hepatitis A virus immunoglobulin G were positive. Serologic tests for parasites, the QuantiFERON assay, and liver autoantibodies were negative. Abdominal paracentesis diagnosed sterile chylous ascites with a protein level of 16 g/l, a triglyceride rate of 11 mmol/l, and no melanoma tumor cells (Figure 1A). The computed tomography scan revealed ascites, moderate pleural effusions and hepatomegaly with a heterogeneous enhancement of the liver at portal phase (mosaic appearance), and patency of portal and hepatic veins without any focal nodular lesions suggestive of liver metastases (Figure 1B). Cavography and hepatic and cardiac Doppler ultrasounds were normal. The hepatic pressure gradient was increased to 14 mmHg suggesting mild portal hypertension. The liver biopsy showed non-fibrous portal areas but moderate sinusoidal dilatation with perisinusoidal fibrosis and centrilobular veins partially occluded by fibrous tissue (Figure 1C–E). Such lesions were consistent with SOS. Immunotherapy was discontinued because of its possible causation; repeated paracenteses and diuretics resulted in a favorable outcome. The patient died of melanoma progression 6 months after nivolumab discontinuation. Hepatic SOS, also known as veno-occlusive disease, is an obliterative venulitis of the terminal hepatic venules histologically characterized by sinusoidal dilatation, hepatocyte necrosis, and obliterated hepatic venules. It may occur in the context of allograft bone marrow transplantation3Shulman H.M. McDonald G.B. Matthews D. et al.An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation.Gastroenterology. 1980; 79: 1178-1191Abstract Full Text PDF PubMed Scopus (254) Google Scholar or colorectal carcinoma with liver metastases following cytoreductive chemotherapy, or in patients taking pyrrolizidine alkaloid-containing herbal remedies. Cases of SOS induced by the immunotoxin gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody coupled to an antibiotic inducing the release of free radicals, have also been reported in allografted hematological malignancies.4Rajvanshi P. Shulman H.M. Sievers E.L. McDonald G.B. Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy.Blood. 2002; 99: 2310-2314Crossref PubMed Scopus (194) Google Scholar Our patient had no other known cause of hepatic SOS, no metastatic liver involvement, but had been treated with nivolumab for 14 months at the onset of SOS. The most frequent grade 3 and 4 adverse reactions reported with ICIs include rash, colitis, hepatitis, and endocrinopathy.5Weber J. Mandala M. Del Vecchio M. et al.Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.N Engl J Med. 2017; 377: 1824-1835Crossref PubMed Scopus (1346) Google Scholar This is the first reported case of SOS induced by an ICI. None declared
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