Expert Perspective: Diagnosis and Treatment of Castleman Disease

Castleman disease (CD) is a major diagnostic challenge for rheumatologists. Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions. Both UCD and MCD may exhibit a wide range of symptoms that overlap with other immune-mediated conditions. MCD can be associated with excessive cytokine production due to a plasma cell neoplasm (MCD-polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes) or uncontrolled human herpesvirus-8 infection (HHV-8) (HHV-8-positive MCD), but more than half of cases are idiopathic. Although they are all driven by excessive cytokines such as interleukin-6 (IL-6), patients with idiopathic MCD (iMCD) often present as a diagnostic mystery with heterogeneous symptomatology that can be classified into three subtypes. The three subtypes are iMCD-thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD-idiopathic plasmacytic lymphadenopathy (IPL); and iMCD-not otherwise specified (NOS). Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD-TAFRO. Patients with iMCD-IPL present with subacute or chronic lymphadenopathy, anemia of inflammation, and polyclonal hypergammaglobulinemia, often with increased IgG4 in serum and lymph node tissue; these cases can be difficult to distinguish from IgG4-related disease and histiocyte disorders. Those who have iMCD not meeting criteria for TAFRO or IPL have iMCD-NOS, which often mimics indolent lymphoma or autoimmune conditions. Patients with autoimmune disease, lymphoma, and infections can experience Castleman-like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD. Broadly speaking, treatments for CD can be considered in three categories: immunomodulators such as glucocorticoids, cytokine inhibitors, and sirolimus; antilymphoma therapies such as rituximab, cytotoxic chemotherapy, and BTK inhibitors; and antimyeloma therapies such as thalidomide and bortezomib. The first-line therapy for all subtypes of iMCD is siltuximab, an IL-6 antagonist. Patients with refractory disease have numerous treatment options and consulting treatment guidelines as well as consultation with a center with expertise in CD are recommended.