Increased Comorbidities and Hospitalizations Associated with Idiopathic Multicentric Castleman Disease

Background:

Castleman disease (CD) describes a group of disorders that share characteristic lymph node histopathology with heterogeneous symptoms. Unicentric Castleman disease (UCD) involves a single region of enlarged lymph nodes, localized symptoms, and is typically curable with excision. In contrast, multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. MCD can be associated with human herpesvirus-8 infection or is idiopathic (iMCD). Presentation is heterogeneous, and multiple clinical phenotypes exist, including iMCD patients who meet criteria for the most severe form of the disease, the TAFRO subtype (thrombocytopenia, anasarca, fevers, reticulin fibrosis, organomegaly). Furthermore, iMCD is difficult to diagnose. Though there is an FDA-approved therapy (siltuximab) for iMCD, major unmet need exists as many patients do not receive this treatment and a subset of patients do not respond to siltuximab. To elucidate the burden of iMCD, we interrogated hospitalization and comorbidity data from patients with iMCD and UCD, as well as from a comparator group of patients who demonstrated iMCD-like features determined to result from a reactive process (‘Other’).

Methods:

The ACCELERATE Natural History registry was leveraged to identify a cohort of 193 patients with a pathology report suggestive of CD. All patients were reviewed by a panel of expert CD physicians to confirm or reject a CD diagnosis. Following review, 85 patients were categorized as having iMCD – including 49 (58%) iMCD-TAFRO, 65 were UCD, and 43 patients were consistent with an inflammatory or reactive processes not reflective of iMCD (Other).

Results:

The mean (SD) age of patients was 39 (16) with a range of 1-75. Prior to diagnosis, the top 10 comorbidities found among both iMCD and UCD patients included common chronic diseases observed in the general US population, such as diabetes, hypertension, GERD, obesity, asthma, anxiety, and depression. Among UCD patients, the top common comorbidities remained unchanged after diagnosis. Among iMCD patients, however, a number of other comorbidities emerged as top-most common, such as acute renal failure (20%), pneumonia (11%), sepsis (8%), chronic kidney disease (8%), thrombotic microangiopathy (7%), acute cholecystitis (7%), and diverticulitis (6%).

We also found that the iMCD patients spent a significantly longer time hospitalized in the 1^st year following diagnosis (mean 34.3 days) compared to UCD (mean 14 days) (p<0.05), but there was no significant difference from patients with an Other diagnosis (22 days). We saw a similar trend in days hospitalized per year since diagnosis, with iMCD patients hospitalized for a significantly greater time than UCD (24.2 vs. 10.5 average days hospitalized per year of diagnosis, p<0.001). There was no difference with the Other group (16.2 days). iMCD patients also spent an average of 12.1 days hospitalized before the first iMCD-treating drug and 44.7 days after the administration of the first iMCD-treating drug. Further, a large proportion of iMCD patients required supportive interventions, such as dialysis (23.6%, n=20) and mechanical ventilation (16.5%, n=14). This compares to 7% (n=3) of Other patients and no UCD patients who required dialysis and 9.3% (n=4) of Other patients and 4.6% (n=3) UCD patients who required mechanical ventilation.

Discussion:

Overall, these data demonstrate that iMCD patients face a significant disease burden, even years after a diagnosis is rendered and treatment is initiated. While siltuximab can effectively control symptoms in a subset of iMCD patients, not all patients receive siltuximab and not all patients treated respond to siltuximab. We found that patients require hospitalization and costly intervention such as dialysis and mechanical ventilation for extended periods of time. These findings have real implications for patient healthcare costs and hospital systems. iMCD patients demonstrate relatively common comorbidities prior to diagnosis and subsequently develop life-threatening conditions such as acute kidney failure and sepsis following diagnosis. These data highlight the importance of continuing research into iMCD etiology, subgroups, treatments, and outcomes, to control the burden of disease and improve outcomes and prognosis for this severely ill group of patients.