What is the recommended treatment for an adult with multicentric Castleman disease presenting with systemic symptoms and widespread lymphadenopathy?

Treatment of Multicentric Castleman Disease

Rituximab is the recommended first-line therapy for HIV-associated HHV-8-positive multicentric Castleman disease, while siltuximab (an anti-IL-6 monoclonal antibody) is the first-line treatment for idiopathic multicentric Castleman disease (iMCD). 1, 2

Treatment Algorithm by Disease Subtype

HHV-8-Positive MCD (HIV-Associated)

The 2024 EHA-ESMO guidelines provide clear direction for this subtype:

First-Line Therapy:

• Rituximab monotherapy is the cornerstone treatment (Level III, A evidence) 1
• Optimize or initiate antiretroviral therapy (ART) concurrently 1
• In severe cases (cytokine storm, hemophagocytic syndrome): Add etoposide to rituximab to control inflammatory consequences 1
• If Kaposi sarcoma is present: Combine rituximab with liposomal doxorubicin (minimum 4 cycles) or etoposide 1

Critical Caveat: Use rituximab cautiously if CD4 count <50 cells/mL—consider delaying until after initial etoposide cycles, though rituximab improves outcomes and reduces lymphoma risk 1

Relapsed/Refractory Disease:

• Multiple rituximab rechallenges are safe and effective 1
• For rituximab-refractory disease: escalate to aggressive chemotherapy regimens like CHOP 1

Important Warning: Rituximab's main serious adverse effect is reactivation or progression of concomitant Kaposi sarcoma—if this occurs, add liposomal doxorubicin 1

Idiopathic MCD (iMCD)

For HHV-8-negative disease, the approach differs fundamentally:

First-Line Therapy:

• Siltuximab (anti-IL-6 antibody) with or without corticosteroids is preferred 2, 3
• If siltuximab unavailable: Tocilizumab (anti-IL-6 receptor antibody) 2, 3
• Siltuximab achieved 52% response rate in real-world registry data 3

Severe/Life-Threatening Cases:

• Add combination chemotherapy to siltuximab upfront 2
• Cytotoxic chemotherapy showed 52% response and was particularly effective in TAFRO subtype (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) 3

Second-Line Options (for anti-IL-6 failures):

• Rituximab with or without corticosteroids 2, 3
• However, rituximab demonstrated inferior response and durability compared to anti-IL-6 therapy in iMCD 3
• Cytotoxic chemotherapy for refractory severe disease 2, 3
• Immunomodulators (sirolimus, thalidomide, bortezomib) 4, 2

What NOT to Do:

• Avoid corticosteroid monotherapy—associated with only 3% response rate in registry data 3
• IL-6-blocking agents, antivirals, and immunomodulators have limited value in HHV-8-positive disease 1

Disease Severity Stratification

Treatment intensity should match disease severity:

Mild-Moderate Disease:

• Single-agent anti-IL-6 therapy (iMCD) or rituximab (HHV-8+) 1, 2

Severe Disease Indicators:

• Cytokine storm/hemophagocytic syndrome
• Multi-organ dysfunction
• TAFRO features (thrombocytopenia, anasarca, renal failure)
• Concurrent Kaposi sarcoma

Severe Disease Management:

• Combination therapy from the start 1, 2
• Consider adjuvant chemotherapy 2

Monitoring and Follow-Up

• Monitor clinical, virological, and biochemical response during acute episodes 1
• Radiological assessment with CT or PET-CT after completing therapy 1
• Clinical follow-up every 3-6 months 1
• High-risk complication: NHL incidence remains elevated despite rituximab, especially HHV-8-associated NHL (primary effusion lymphoma, DLBCL)—maintain vigilance during follow-up 1

Key Divergence in Evidence

The fundamental distinction is HHV-8 status determines treatment choice: rituximab for HHV-8-positive disease based on 2024 high-quality guidelines 1, versus siltuximab for idiopathic disease based on international consensus and registry data 2, 3. This reflects different pathophysiology—HHV-8-driven B-cell proliferation responds to B-cell depletion, while iMCD's IL-6-mediated inflammation requires cytokine blockade.