iMCD: The spectrum of disease and clinical behaviour - Diagnosis
James Cavet, Consultant Haematologist discusses the different pathways to diagnose iMCD.
Castleman disease (CD) is a spectrum of lymphoproliferative disorders with a common histopathology.1-5
The idiopathic Multicentric Castleman Disease (iMCD) subtype is characterised by abnormal lymphoproliferation in multiple lymph node sites..1
iMCD is a rare and devasting disease that can cause multiple organ dysfunction which can lead to death - one in three patients die within 5 years of diagnosis.1,2
Cytokine storms, which often include elevated levels of IL-6, play a central role in the pathophysiology of iMCD and drive symptoms.5
Patients experience symptoms of systemic inflammation – such as fever and fatigue - that can significantly interfere with daily-life.1 Significant organ damage can also occur due to excessive and uncontrolled release of pro-inflammatory cytokines.
iMCD affects all populations, with diagnosis in patients in an age range of 2 – 80 years.1 There is limited epidemiological data on iMCD, however in the United States, approximately 540 – 960 new cases of iMCD are diagnosed each year.1
iMCD has a serious and significant impact on patient health and survival:
Patients with iMCD often present with a mix of symptoms which can look like an infection, and/or autoimmune/autoinflammatory disease and/or malignancy. Suspect iMCD if the patient presents with a combination of common signs and symptoms shown in Figure 1.
Figure 1: Common signs and symptoms of iMCD (note, not all iMCD patients will present all of these symptoms)
Patients with iMCD may also have a history of fatigue, abdominal pain, cough/shortness of breath, flu-like fever, fluid accumulation and night sweats.
Other symptoms and signs that are indicative of iMCD and can be helpful in leading towards a diagnosis include:1
Prompt and accurate diagnosis of iMCD is important to reduce treatment delays and ultimately improve clinical outcomes and survival.1 Many patients are initially misdiagnosed.
Correct diagnosis is often delayed due to a combination of factors including:
For an iMCD diagnosis the patient must have:1
Both criteria must be met.
For iMCD the patient must present with ≥2 signs, one of which must be a laboratory abnormality.1
Due to shared symptoms, a number of diseases must be excluded for an iMCD diagnosis.1
There is a more severe form of iMCD called the TAFRO subtype. Patients with this form of the disease have the following symptoms and signs:4
Patients can also have renal dysfunction and typically normal immunoglobulin levels.1
Other features of TAFRO-iMCD include:
Prompt diagnosis is especially important for these patients, as mortality in the first 6 months increases much more rapidly than in non-TAFRO patients.2
1. Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-57.2. Liu AY, Nabel CS, Finkelman BS, Ruth JR, Kurzrock R, van Rhee F, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-75.3. Sitenga J, Aird G, Ahmed A, Silberstein PT. Impact of siltuximab on patient-related outcomes in multicentric Castleman’s disease. Patient Relat Outcome Meas. 2018;9:35-41.4. Srkalovic G, Marijanovic, I., Srkalovic, M.B., Fjagenbaum, D.C.,. TAFRO syndrome: New subtype of idiopathic multicentric Castleman disease. Bosn J Basic Med Sci 2017 [Available from: http://www.bjbms.org/ojs/index.php/bjbms/article/view/1930].5. Nishimoto N, Kishimoto T, Yoshizaki K. Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis. 2000;59 Suppl 1:i21-7.
IL-6, Interleukin 6; sIL-2R, Soluble interleukin 2 receptor; VEGF, Vascular endothelial growth factor; IgA, Immunoglobulin A; IgE, Immunoglobulin E