Castleman Disease

The pathophysiology of Castleman disease (CD) varies between subtypes.

Unicentric CD (UCD) pathophysiology is poorly understood. The lymph node is characterized by abnormal features that include small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. Patients sometimes experience inflammatory symptoms, which are believed to be caused by elevated IL-6 levels in the blood. These symptoms typically resolve after lymph node excision.

HHV-8–associated MCD pathophysiology is well understood: Immunocompromise due to HIV or other causes enables the uncontrolled infection and replication of HHV-8 in lymph node plasmablasts and B cells, which signal for viral IL-6 and other proinflammatory cytokines. Depletion of B cells with rituximab typically results in resolution of symptoms.

POEMS-associated MCD pathophysiology is somewhat understood: monoclonal plasma cell populations responsible for causing POEMS syndrome also produce inflammatory cytokines that cause an MCD-like syndrome. Therapies targeted at plasma cells are generally effective.

HHV-8–negative/idiopathic MCD (iMCD) pathophysiology is poorly understood. Patients experience atypical CD-like lymphoproliferation, which occurs along with systemic inflammatory signs and symptoms (fevers, weight loss, fatigue, night sweats), abnormal blood cell counts, and multiple organ system dysfunction. The pathophysiology of the disease is caused by excess IL-6 in a portion of patients.[5, 6, 7]  Inhibition of IL-6 with siltuximab is effective in approximately 34-44% of patients. The pathophysiology in the remaining patients who do not improve with IL-6 inhibition is not known but is suspected to involve cytokines or mechanisms other than IL-6 excess.

Microscopic features

Patients with UCD, HHV-8–associated MCD, and iMCD can experience a spectrum of lymph node features that range from hyaline vascular (or hypervascular) to plasmacytic (or plasmablastic) with a mixed subtype in the middle.

The hyaline vascular histopathological subtype is used to describe lymph node features including atrophic germinal centers, onion-skinning mantle zones, hypervascularization, and FDC prominence. It is most commonly seen in UCD (approximately 90% in some studies)[8]  but can also be seen in iMCD. In iMCD, "hypervascular" is used to describe this constellation of features.

The plasmacytic histopathological subtype is used to describe lymph node features including hyperplastic germinal centers as well as occasional atrophic germinal centers and interfollicular plasmacytosis. It is most commonly seen in iMCD, but it can also be seen in UCD. In HHV-8–associated MCD, “plasmablastic” is used to describe this constellation of features, which also includes plasmablasts and positive staining for latency-associated nuclear antigen–1 (LANA-1) by immunohistochemistry.

The mixed histopathological subtype is used to describe cases in which lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes.

The etiologies differ between the four subtypes of Castleman disease.

The etiology of UCD is unknown, but a subset of UCD cases may be the result of somatic mutations in monoclonal cell populations, likely lymph node stromal cells. Alternatively, UCD may occur due to exaggerations of the types of reactive changes that can be seen in response to normal antigenic stimuli.

Active HHV-8 infection is the well-established etiology of HHV-8–associated MCD. HHV-8 is a gamma herpesvirus similar to Epstein-Barr virus (EBV) that has been found in both endemic and HIV-associated Kaposi sarcoma (KS). The HHV-8 virus is pathologically responsible for all symptoms and signs of the disease.[9]

Monoclonal plasma cell populations are responsible for causing POEMS-associated MCD.

The etiology of HHV-8–negative/idiopathic MCD (iMCD) is not known. The heterogeneity of clinical features and pathologic abnormalities, which overlap with a wide range of other immunologic disorders, suggests that multiple processes—each involving immune dysregulation and a common pathway of increased cytokine levels—may give rise to iMCD in different subsets of patients. Four candidate etiologic drivers of iMCD pathogenesis have been proposed: autoimmune, autoinflammatory, neoplastic, and/or infectious mechanisms.

There are at least three clinical subgroups of iMCD that may each arise from different etiologies than those proposed above:

• TAFRO syndrome, HHV-8–negative/idiopathic MCD (iMCD-TAFRO): Thrombocytopenia, anasarca, fever, myelofibrosis, renal dysfunction or reticulin fibrosis, and organomegaly (TAFRO) often occurs in HHV-8–negative MCD. These cases often have mixed or hypervascular (formerly called hyaline vascular) histopathological features and normal gamma globulin levels. The etiology and pathological cell types are unknown.
• iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL): These patients often have thrombocytosis, hypergammaglobulinemia, mixed or plasmacytic histopathological features, and a more chronic disease course. The etiology and pathological cell types are unknown.
• Not otherwise specified (NOS), HHV-8–negative/idiopathic MCD (iMCD-NOS): HHV-8–negative MCD patients who do not have iMCD-TAFRO or iMCD-IPL are considered to have iMCD-NOS. The etiology and pathological cell types are unknown.

Castleman disease is rare. An estimated 4300-5200 new cases are diagnosed each year in the United States; aproximately 1000 of those are HHV-8–associated multicentric Castleman disease (HHV-8–associated MCD) and 1000 are HHV-8–negative MCD.[10]  UCD, HHV-8–associated MCD, and HHV-8–negative MCD can affect individuals of all ages (including young children), genders, and ethnicities.

UCD is slightly more common in women and younger individuals.

HHV-8–associated MCD is more common in men and individuals with HIV infection.The incidence of HHV-8–associated MCD has increased with better antiretroviral therapy (ART) for the management of HIV infection. On multivariate analysis, risk factors for the development of HHV-8–associated MCD included the following[11] :

• Nadir CD4 count higher than 200/µL
• Older age
• No previous ART exposure
• Nonwhite ethnicity

HHV-8–negative/idiopathic MCD is similarly common in men and women. There are no known risk factors.

The prognosis of Castleman disease varies, depending on the subtype.

Unicentric Castleman disease (UCD) carries an excellent prognosis. The reported 10-year survival rate after complete resection is more than 95%.[12]  In unresectable cases, the reported survival at 20 months after radiotherapy is 82%.[12]  Overall, incomplete resection is associated with poorer outcomes.[12]  Development of lymphoma and/or paraneoplastic pemphigus (PNP) are two rare comorbidities that can be deadly for UCD patients. Though the risk of developing (PNP) is low (< 5%), it is the most deadly potential complication and should be evaluated in all UCD patients at the time of diagnosis and following diagnosis to ensure that treatment is rapidly initiated if it presents. Treatment of PNP often includes chemotherapy and immunosuppressive drugs. No cases of UCD have ever been reported to develop into HHV-8–negative MCD.

HHV-8–associated MCD was historically associated with a poor prognosis, with most patients dying within 2 years of diagnosis.[12] However, patients have a good prognosis when treated with rituximab, with greater than 94% 2-year survival.[12] In patients who do not respond to rituximab alone, chemotherapy agents such as doxorubicin and etoposide may be added to control the disease.

The prognosis for iMCD patients is worse than for patients with HHV-8–associated MCD. According to studies performed prior to the advent of anti–IL-6 therapy, approximately 65% of patients survive for 5 years after diagnosis. A study in 2021 found a 75% 5-year overall survival rate among iMCD patients. There is reasonable hope that the survival rates are currently greatly improved due to the new breakthroughs in treatment (such as anti-IL6 blockade). The Castleman Disease Collaborative Network is currently leading a global patient research study to collect data to update these numbers. Patients can enroll at www.CDCN.org/ACCELERATE 

Patient education information and a patient forum are available through the Castleman Disease Collaborative Network.

The four subtypes of Castleman disease can each cause a variety of signs and symptoms.

Unicentric Castleman disease (UCD) tends to have milder symptoms and rarely affects vital organs such as the liver, kidneys, and bone marrow but may present as follows:

• Enlargement of a single lymph node or single region of lymph nodes (eg, right cervical chain), possibly with resultant compressive symptoms ^[13]
• Systemic manifestations like those of human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD), such as flulike illness

The presentation of multicentric Castleman disease spans a wide spectrum of severity, from mild symptoms to life-threatening organ failure. The National Comprehensive Cancer Network (NCCN) criteria for active disease include fever, C-reactive protein > 20 mg/L in the absence of other causes, and 3 or more of the following[14] :

• Peripheral lymphadenopathy
• Splenomegaly
• Edema
• Pleural effusion
• Ascites
• Cough
• Nasal obstruction
• Xerostomia
• Rash
• Central nervous system symptoms
• Jaundice
• Autoimmune hemolytic anemia

HHV-8–associated multicentric Castleman disease (HHV-8–associated MCD) involves multicentric lymphadenopathy with characteristic "CD-like" lymph node histopathology and/or the following systemic manifestations, although some cases (< 10%) are asymptomatic:

• Flulike illness (fever, night sweats that soak the sheets, weight loss, loss of appetite, weakness, fatigue)
• Shortness of breath, cough
• Nausea and vomiting
• Numbness and weakness (neuropathy)
• Leg edema
• Skin rashes
• Hemangiomata
• Pemphigus
• Kaposi sarcoma

For idiopathic multicentric Castleman disease (iMCD), according to the Castleman Disease Collaborative Network (CDCN), at least 2 of following must be present for it to be classified as severe[15] :

• Eastern Cooperative Oncology Group (ECOG) performance status 2 or above
• Stage IV kidney dysfunction (estimated glomerular filtration rate < 30 mL/minute/1.73m ², creatinine > 3 mg/dL)
• Anasarca and/or ascites, pleural effusion, or pericardial effusion
• Hemoglobin ≤8 g/dL
• Pulmonary involvement/interstitial pneumonitis with dyspnea

IMCD involves multicentric lymphadenopathy with characteristic "CD-like" lymph node histopathology and a number of signs/symptoms and laboratory features, as defined by the 2017 International Consensus Diagnostic Criteria of iMCD, which may progress or remit/relapse over time:

• Elevated C-reactive protein (CRP) level and/or erythrocyte sedimentation rate (ESR)
• Anemia
• Thrombocytopenia or thrombocytosis
• Hypoalbuminemia
• Kidney dysfunction and/or proteinuria
• Polyclonal hypergammaglobulinemia
• Flulike illness (night sweats, fever, weight loss, fatigue)
• Large liver and/or spleen
• Fluid accumulation (edema, anasarca, ascites, pleural effusion)
• Eruptive cherry hemangiomatosis or violaceous papules
• Lymphocytic interstitial pneumonitis

There are at least three subtypes of iMCD that demonstrate varying clinical features:

• TAFRO syndrome, HHV-8–negative MCD (iMCD-TAFRO): Patients will sometimes present with thrombocytopenia, anasarca, myelofibrosis, kidney dysfunction, and organomegaly (TAFRO) without hypergammaglobulinemia. These cases often have mixed or hypervascular (formerly called hyaline vascular) histopathological features and normal gamma globulin levels.
• Not otherwise specified (NOS), HHV-8–negative/idiopathic MCD (iMCD-NOS): HHV-8–negative MCD patients, who do not have POEMS syndrome or the TAFRO subtype, are classified as having iMCD-NOS. These patients often have thrombocytosis, less severe fluid accumulation, hypergammaglobulinemia, and mixed or plasmacytic histopathological features.
• iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL): Thrombocytosis, hypergammaglobulinemia, and a more chronic disease course.The etiology and pathological cell types are completely unknown.

Other conditions that can co-occur with iMCD include the following:

• Amyloidosis, a condition in which abnormal proteins build up in tissues around the body, can occur in Castleman disease. This can lead to kidney damage; heart damage; nerve damage; and intestinal problems, mainly diarrhea. If the Castleman disease is treated successfully, the amyloidosis may improve or disappear.
• Autoimmune disease
• Autoimmune cytopenias such as hemolytic anemia and immune thrombocytopenia (ITP)
• Acquired factor VIII deficiency
• Paraneoplastic pemphigus
• Bronchiolitis obliterans organizing pneumonia (BOOP)
• Glomerular nephropathy
• Inflammatory myofibroblastic tumor
• Polyneuropathy (without POEMS)

The flulike signs and symptoms and acute-phase reaction, with elevation of the ESR and CRP level, elevated fibrinogen, thrombocytosis, and hypergammaglobinemia in HHV-8–associated MCD and iMCD, are believed to be driven by overproduction of interleukin-6 (IL-6).

The workup for Castleman disease (CD) varies among the subtypes.

Patients with unicentric CD (UCD) may have elevated inflammatory markers such as C-reactive protein (CRP). The diagnosis is made by histologic examination of an excised lymph node. Imaging should be performed to confirm that involvement is unicentric (ie, limited to a single lymph node or single region of enlarged lymph nodes) and to select the best lymph node for surgical excision.

Histopathologically, the lymph nodes demonstrate a constellation of "CD-like" features along a spectrum, including small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. Lymph node features of the different histopathological subtypes of UCD are as follows:

• Hyaline vascular –  Atrophic germinal centers, onion-skinning mantle zones, hypervascularization, and FDC prominence ^[8]
• Plasma cell – Hyperplastic germinal centers as well as occasional atrophic germinal centers and interfollicular plasmacytosis
• Mixed – Lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes

In human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (MCD), laboratory studies show elevation of inflammatory markers such as CRP, and evidence of organ dysfunction. The diagnosis is made by histologic examination of an excised lymph node. Imaging should be performed to confirm that the patient has multiple regions of enlarged lymph nodes (ie, multicentric involvement) and to select the best lymph node for surgical excision. 

Histopathologically, the lymph nodes in HHV-8–associated MCD demonstrate a contellation of "CD-like" features, including small or large germinal centers, hypervascularity, lambda-restricted polyclonal plasmacytosis, increased plasmablasts, and/or expansion of polyclonal B cells and T cells. IgH gene rearrangement studies should be performed on the lymph node specimen to rule out a clonal disorder (eg, occult lymphoma). Latency-associated nuclear antigen–1 (LANA-1) staining for HHV-8 by immunohistochemistry should be performed on all cases to confirm that HHV-8 is the pathological driver.

HHV-8–negative/idiopathic MCD (iMCD) also features elevated inflammatory markers such as CRP, and organ dysfunction. In 2017, an international panel published diagnostic criteria for iMCD.[10] For diagnosis, patients must meet both major criteria (characteristic lymph node histopathology and multicentric lymphadenopathy) and at least 2 of the 11 minor criteria, including at least 1 laboratory abnormality. Imaging should be performed to confirm that there are multiple regions of enlarged lymph nodes (multicentric) and to select the best lymph node for surgical excision. Histopathologically, the lymph nodes demonstrate a contellation of "CD-like" features along a spectrum, including small or large germinal centers, FDC prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. IgH gene rearrangement studies should be performed on the lymph node specimen to rule out a clonal disorder (eg, occult lymphoma).

LANA-1 staining for HHV-8 by IHC should be performed on all cases and should be negative, confirming that HHV-8 is NOT the pathological driver. In addition, diagnosis requires exclusion of infectious, malignant, and autoimmune disorders that can mimic idiopathic MCD (see DDx).

The clinical minor diagnostic criteria comprise the following:

• Constitutional symptoms
• Hepatosplenomegaly
• Anasarca, edema or effusions
• Eruptive cherry hemangiomatosis or violaceous papules
• Lymphocytic interstitial pneumonitis (LIP)

The laboratory minor criteria comprise the following:

• Elevated CRP and/or ESR level
• Anemia
• Thrombocytopenia or thrombocytosis
• Hypoalbuminemia
• Kidney dysfunction
• Polyclonal hypergammaglobulinemia

Imaging is primarily helpful in determining whether the patient has UCD or a form of MCD and in assessing response to therapy.

Whole-body imaging should be performed on all patients with suspected UCD or a form of MCD.

In UCD, a single persistently enlarged lymph node associated with moderate to intense post-contrast enhancement is often found on computed tomography (CT). In such cases, Fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered to establish that the disease is limited to a single site with a relatively lower standardized uptake value (SUV) in other nodes.

In HHV-8-associated MCD and HHV-8–negative MCD, multiple enlarged mediastinal and hilar lymph nodes (1 to 3 cm diameter) may be found along with peripheral lymphadenopathy. HHV-8-associated MCD and HHV-8-negative MCD are both PET avid usually with a relatively low standardized uptake value (SUV) of 2.5-5.[16] Imaging cannot be used to differentiate HHV-8-associated MCD from HHV-8-negative MCD.

In patients with HHV-8–associated MCD and HHV-8–negative MCD, a chest radiograph may show one or more of the following:

• Bilateral reticular or ground-glass opacities
• Mediastinal widening
• Bilateral pleural effusions

Lung parenchymal findings may be seen on CT, including subpleural nodules, interlobular septal thickening, peribronchovascular thickening, ground-glass opacities, and patchy rounded areas of consolidation. Small to moderate bilateral pleural effusions may also be present. CT scanning of the neck, abdomen, and pelvis, with and without contrast, may also be helpful.

Imaging may be used to determine the efficacy of therapy—in UCD, to assess whether resection was complete and no residual disease exists, and in MCD (HHV-8–associated or HHV-8-negative) to assess whether multicentric lymphadenopathy has improved after medical therapy.

Laboratory findings are quite variable across the subtypes of CD (UCD, HHV-8-associated MCD, HHV-8-negative/idiopathic iMCD) and even within the three clinical subtypes of HHV-8–negative/idiopathic iMCD (POEMS associated iMCD, TAFRO syndrome iMCD, iMCD-NOS). Characteristic findings include the following:

• Complete blood cell (CBC) count – Anemia (usually mild to moderate, occasionally, the hemoglobin level is < 8 g/dL), thrombocytosis or thrombocytopenia
• Liver function tests (LFT) – Hypoalbuminemia and elevated alkaline phosphatase
• Serum protein electrophoresis, with immunofixation and quantitative immunoglobulins – Polyclonal hypergammaglobulinemia
• C-Reactive Protein (CRP) - Usually elevated
• Erythrocyte sedimentation rate (ESR) – Usually elevated
• Fibrinogen – Usually elevated
• Creatinine and blood urea nitrogen – Usually elevated
• Serologies for hepatitis B, human herpesvius–8 (HHV-8), and HIV; with quantitative assays if initial results are positive
• Interleukin-6 (IL-6) and lactate dehydrogenase (LDH) – Usually elevated
• Vascular endothelial growth factor (VEGF) – May be elevated
• Autoantibodies, such as antinuclear antibody (ANA) – May be elevated

Excisional lymph node biopsy is the preferred method of lymph node biopsy and is used to establish diagnosis.[15]  The other methods of lymph node biopsy are not recommended. Fine needle aspiration is not typically suitable for initial diagnosis. Core needle biopsy has limited accuracy. 

Treatment varies depending on the subtype of Castleman disease.

Unicentric Castleman disease

For unicentric Castleman disease (UCD), surgical removal of the enlarged lymph node is considered the first-line treatment option and can be curative. Systemic manifestations and laboratory abnormalities, if present, tend to resolve with complete resection of the enlarged lymph node or solitary region of lymph nodes. Recurrences of UCD have been rarely reported and are usually related to incomplete initial resection or missed lymph nodes at the initial evaluation, though not all UCD recurrences are in the same anatomical location. In rare cases, patients with UCD may have persistent inflammatory symptoms (but not laboratory markers) even after complete surgical resection.

If surgical excision is not possible, treatment is recommended for symptomatic patients. If symptoms are due to compression, then rituximab is recommended. If symptoms are due to an inflammatory syndrome, then anti-interleukin-6 (IL-6) therapy is recommended. If these treatments are not effective, then radiation therapy may be needed.

Human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (MCD)

In HHV-8–associated MCD, treatment with rituximab is highly effective. For patients with concomitant HIV infection and a low CD4 count and/or higher HIV load, antiretroviral therapy (ART) should be included with the rituximab.[17] For HIV-negative patients, there may also be a role for concomitant antiviral therapy with ganciclovir. Treatment with rituximab should be repeated upon relapse. Rituximab may be administered or without corticosteroids and/or chemotherapy. However, rituximab therapy occasionally worsens Kaposi sarcoma, which must be carefully considered in HIV-positive patients with a high viral load, low CD4 count, and active Kaposi sarcoma.[18, 17] For HHV-8–associated MCD patients with evidence of life-threatening organ failure or poor performance status, liposomal doxorubicin or etoposide can be added.

HHV-8–negative MCD

Siltuximab (Sylvant) is the only drug approved by the US Food and Drug Administration (FDA) for HHV-8–negative MCD. Siltuximab is a monoclonal antibody that binds IL-6. Where available, siltuximab is the preferred therapy, based on its benefit in the only randomized trial[19] and its approval by the FDA; National Comprehensive Cancer Network (NCCN) and Castleman Disease Collaborative Network (CDCN) guidelines recommend siltuximab as the preferred primary treatment.[14] If siltuximab is not available, tocilizumab (anti–IL-6 receptor therapy) may be used in its place. Anti–IL-6 treatment is continued until progression of disease in order to maintain the response and prevent an early relapse.

Of note, after siltuximab is administered, laboratory tests for IL-6 levels become uninterpretable, because the assays detect complexed IL-6 and drug. Therefore, IL-6 levels should not be used to guide or contribute to treatment decisions for at least 18-24 months after the last dose of siltuximab.

Also, 66% of patients in the clinical trial did not respond to siltuximab treatment, approximately half of whom did not have elevated IL-6 levels. Optimal treatment for siltuximab non-responders is not known, but the following agents have been used:

• Other immunomodulatory therapies (eg, tocilizumab, sirolimus, corticosteroids, cyclosporine, anakinra, thalidomide, intravenous immunoglobulin [IVIg], bortezomib ^{[20, 21]} )
• Targeted B cell depletion with rituximab
• Cytotoxic chemotherapies (cyclophosphamide, etoposide, ^[22] doxorubicin, or vinblastine; or combinations such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or cyclophosphamide, vincristine, and prednisone [CVP]): Single-agent and combination chemotherapy yields symptomatic relief and a partial response in many patients. However, symptoms recur when treatment is stopped, necessitating intermittent maintenance therapy, often lifelong.

Surgery is usually curative. In patients whose lesions cannot be completely resected, outcomes remain favorable. Partially resected masses may remain stable and asymptomatic for many years.

Patients with unresectable disease with compressive symptoms can be treated as described for HIV-negative MCD.

Systemic corticosteroids can provide symptomatic relief but do not predictably reduce tumor size.

Radiation therapy with 30-45 Gy can result in complete and partial remission rates of 40% and 10%, respectively, but can cause radiation-induced fibrosis that makes subsequent surgical intervention more difficult.[23]

The National Comprehensive Cancer Network (NCCN) recommends siltuximab as a preferred primary treatment for patients with HIV-negative HHV-8-negative/idiopathic multicentric Castleman disease (iMCD).[14]

Disease response is assessed by evaluating lymph node size via imaging, as well as biochemical values. The following markers of inflammatory response and organ function can be evaluated[15] :

• C-reactive protein
• Hemoglobin
• Albumin
• Glomerular filtration rate

The frequency of monitoring depends on the severity of presentation, as follows[15] :

• For severe presentation, initially monitoring should be daily
• For less severe presentation, weekly assessment of clinical symptoms and laboratory values is necessary, then biweekly until maximum benefit has occurred

Radiologic evaluation of lymph nodes with computed tomography is as follows[15] :

• Begin at 6 weeks after treatment initiation
• Repeat every 3 months until maximum response is achieved, then reduce to every 6 to 12 months

Siltuximab is the only agent approved by the US Food and Drug Administration for use in Castleman disease—specifically, for idiopathic multicentric Castleman disease. It is also listed as the preferred primary treatment in National Comprehensive Cancer Network guidelines.[14]  Rituximab and tocilizumab have been used off-label for multicentric Castleman disease.

Class Summary

Agents that decrease IL-6 production or actions are emerging for MCD.

Siltuximab (Sylvant)

Siltuximab is a monoclonal antibody that binds IL-6 and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. It is approved by the FDA with an indication for multicentric Castleman disease in patients who are negative for HIV and human herpesvirus-8.

Tocilizumab (Actemra)

Tocilizumab is an IL-6 receptor antagonist. It has been used off-label for multicentric Castleman disease.

Rituximab (Rituxan)

Rituximab is a humanized monoclonal antibody that binds to CD20 antigen, which results in decreased IL-6 production. It has been used off-label for multicentric Castleman disease.