In patients with the classical acute form of SCLS, the rapid development of shock and edema due to plasma extravasation (up to 70% of total plasma volume) follows a typical prodrome of generalized weakness, fatigue, myalgias, and occasionally fevers, vomiting, abdominal pain, and diarrhea. This is called the leak phase of SCLS, and can progress to the characteristic triad of hypotension, hemoconcentration, and hypoalbuminemia in the absence of secondary causes of shock. The hypotension usually lasts for several days accompanied by extensive third-spacing of fluids. The symptoms reverse almost as quickly as they arise, with massive fluid mobilization from tissues into circulation and diuresis. This is the post-leak phase. It is during the post-capillary leak phase that most patients die, often from cardiovascular overload secondary to the after-effects of overzealous fluid resuscitation. The severity and frequency of episodes is often predictable in an individual patient but varies widely from patient to patient. The overall 10-year mortality of SCLS is approximately 25-34%. Secondary complications include compartment syndromes (due to increased pressure induced by leakage of fluid and proteins into muscles), renal failure from hypoperfusion-induced acute tubular necrosis or myoglobinuria secondary to muscle necrosis, and venous and arterial thrombosis including pulmonary embolism from hemoconcentration. Several lines of evidence suggest that immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. First, a monoclonal gammopathy of unknown significance (MGUS) is present in a majority of SCLS cases. MGUS is a premalignant precursor to multiple myeloma (MM), in which a clonal plasma cell population secretes large amounts of monoclonal immunoglobulin (Ig, also referred to as a paraprotein) detectable in patient sera. Likewise, increased numbers of circulating CD25+ T cells and peri-capillary infiltration of CD8+ lymphocytes in skin have been noted during acute SCLS attacks. Finally, several patients with SCLS in whom MGUS evolved into frank myeloma or plasma cell leukemia experienced fewer capillary leak episodes after chemotherapy for the hematopoietic disorder. Considered together, these findings suggest that the monoclonal paraprotein from the dysregulated plasma cell population may be the direct or indirect source of the pathophysiologic findings observed, possibly through activation of T lymphocytes. We are exploring the molecular mechanisms of SCLS by examining the function of the monoclonal Ig in the development of vascular pathology in vitro. Using monoclonal Ig from SCLS patients, we will determine whether it binds to a specific cell type, target antigen (if any), and resulting effect (direct or indirect) on endothelial cells. We are also characterizing the proteome of SCLS serum, both pre- and post-attack, to determine whether specific biomarkers of acute symptoms can be identified. During 2009-2010, we admitted 14 patients to the NIH clinical center under this protocol. A review describing the clinical symptoms and treatment of SCLS was published, and we presented our findings at the International Meeting of Vascular Biology and the Mayo Angiogenesis Symposium. We are now the primary worldwide referral center for research on SCLS. We found elevations in factors associated with vascular permeability (VEGF and Ang2) in the plasma of several SCLS patients, which correlated with disease symptoms. In contrast, plasma IL-2 and TNF-alpha were normal. RNA microarray analysis of peripheral blood mononuclear cells (PBMC) taken from 4 SCLS patients during an acute, severe leak episodes identified several log-fold changes in IL-8 expression compared to cells obtained from the patients at baseline. Although partially purified F(ab)2 fragments of monoclonal IgG from SCLS patients did not bind PBMC from healthy donors, incubation with autologous PBMC induced activation (CD154 expression) in a fraction of T cells. These results suggest that T lymphocyte activation, perhaps leading to secretion of pathogenic cytokines, might underlie the transient endothelial barrier dysfunction associated with SCLS.

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Druey, Kirk M; Arai, Andrew E; Parikh, Samir M (2018) Reply. J Allergy Clin Immunol 141:1540-1541
Bøe, Ole Wilhelm; Sveen, Kjell; Børset, Magne et al. (2018) Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson's Disease). Am J Case Rep 19:176-182
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Ertel, Andrew; Pratt, Drew; Kellman, Peter et al. (2015) Increased myocardial extracellular volume in active idiopathic systemic capillary leak syndrome. J Cardiovasc Magn Reson 17:76
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Xie, Zhihui; Chan, Eunice; Yin, Yuzhi et al. (2014) Inflammatory Markers of the Systemic Capillary Leak Syndrome (Clarkson Disease). J Clin Cell Immunol 5:1000213

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