Systemic Capillary Leak Syndrome (Clarkson’s Disease) as a Complication of Anti–Programmed Death 1 Immunotherapy

Abstract

We report here the case of a 50-year-old woman treated for an advanced lung adenocarcinoma (thyroid transcription factor-1 negative, Cytokeratin 7 positive, KRAS+) with liver, bone, subcutaneous, and muscular metastases who suffered from rapidly progressing diffuse edema of unusual etiology. This patient received four cycles of cisplatin, pemetrexed, and bevacizumab as first-line therapy. Despite this first treatment strategy, tumor progression was observed. Considering her good general health, a treatment using nivolumab (anti–programmed death 1 [PD-1]) was initiated as second-line therapy. After eight cycles, body scan revealed tumor regression at all sites. At the ninth cycle, an asymptomatic hypothyroidism was observed (thyroid-stimulating hormone levels = 63 μU/mL versus 7 μU/mL, 15 days earlier; decreased free-T4 levels [3 pg/mL]) and levothyroxine (L-T4) was introduced (75 μg daily). On the 12th injection of nivolumab, an edema of the face was noticed followed by a rapidly occurring proximal swelling of both arms. Within the following 15 days, edema progressed with extension to the entire body. Computed tomographic scan revealed diffuse liver edema, the presence of ascites, and bilateral pleural effusions while the tumor was still regressing. Thyroid-stimulating hormone levels were still elevated and severe hypothyroidism was suspected. Levothyroxine dosage was increased (100 µg daily) and the patient was finally hospitalized. Clinical evaluation revealed hypotension and confirmed diffuse edema with a weight gain of 30 pounds in 3 weeks. Blood tests revealed severe hemoconcentration (hemoglobin concentration 191 g/L and hematocrit 55.7%), functional renal failure (creatinine level 144 μmol/L, urea 18 mmol/L) and decreased serum-albumin (18.8 g/L). Considering the severe generalized edema secondary to profound hypoalbuminemia with no proteinuria and without cardiac or liver failure, systemic capillary leak syndrome (SCLS) (or Clarkson’s disease) was suspected.1Atkinson J.P. Waldmann T.A. Stein S.F. et al.Systemic capillary leak syndrome and monoclonal IgG gammopathy; studies in a sixth patient and a review of the literature.Medicine. 1977; 56: 225-239Crossref PubMed Scopus (142) Google Scholar Known causes of secondary SCLS and hypoalbuminemia were eliminated including absence of exudative enteropathy, liver disease, or renal protein leak. There was no monoclonal gammopathy on serum electrophoresis. As hypothyroidism could not be responsible for such hypoalbuminemia, the diagnosis of idiopathic SCLS was established. Considering that only levothyroxine and nivolumab were recently introduced, and because levothyroxine had never been reported as a cause of SCLS, the hypothesis of an immunological adverse event of nivolumab was suspected. High doses of intravenous steroids were introduced but with no effect and the patient died 5 weeks after the beginning of this acute episode of edema. SCLS is a rare disorder of unknown cause and to date there is no report of SCLS induced by anti–PD-1 or anti–programmed death ligand 1 therapies in the literature or in the pharmacovigilance. Drug-induced SCLS has been described after pemetrexed, but in our case, the time between SCLS onset and pemetrexed discontinuation rules out this hypothesis.2Maroz N. Weiner I.D. Secondary capillary leak syndrome related to pemetrexed exposure.Am J Kidney Dis. 2012; 59: 582583Google Scholar Autoimmune processes are suspected in SCLS pathogenesis. The blockade of the PD-1/programmed death ligand 1 pathway by nivolumab restores an efficient antitumor cytotoxicity of T-CD8 lymphocytes but with possible overtargeted autoimmune manifestations. This first description of a nivolumab-induced SCLS strengthens that cell-mediated autocytotoxicity may play a role in SCLS pathophysiology. Beyond humoral mediators, T-CD8 cells may also be involved because these cells surround damaged endothelial cells in SCLS.3Cicardi M. Berti E. Caputo V. Radice F. Gardinali M. Agostoni A. Idiopathic capillary leak syndrome: evidence of CD8-positive lymphocytes surrounding damaged endothelial cells.J Allergy Clin Immunol. 1997; 99: 417-419Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar High doses of intravenous steroids might have a place in the management of immunotherapy-induced SCLS.4Voskens C.J. Goldinger S.M. Loquai C. et al.The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.PLoS One. 2013; 8: e53745Crossref PubMed Scopus (363) Google Scholar The relevance of intravenous immunoglobulin in this situation is still to be determined.5Pineton de Chambrun M. Gousseff M. Mauhin W. et al.intravenous immunoglobulins improve survival in monoclonal gammopathy-associated systemic capillary-leak syndrome.Am J Med. 2017; 130: 1219.e19-1219.e27Abstract Full Text Full Text PDF Scopus (43) Google Scholar