Introduction

Castleman's Disease (CD) is a rare condition that affects the lymph nodes and the immune system. It is characterised by abnormal overgrowth of lymph node tissue and immune dysfunction. While CD is not cancer, it shares some cancer-like features and, if left untreated, can be lethal.¹

Researchers are still learning about the causes of CD, but it is clear that the immune system plays a central role in how the disease develops and progresses.¹

There are different types of CD, each with specific symptoms, causes, and treatment strategies. Understanding how the immune system is involved can help physicians treat patients more effectively and work toward finding a cure.¹

Types of CD

There are two major categories of CD²:

Unicentric castleman disease (UCD)

• Affects only one lymph node or one group of nodes.
• Typically, localised and simple to treat.
• Usually cured by surgery through the removal of the involved nodes.

Multicentric castleman disease (MCD)

• Involves multiple lymph nodes in different parts of the body
• More severe and requires long-term medical treatment
• Often linked to immune system overactivity or viral infections such as human herpesvirus-8 (HHV-8)

Subtypes of MCD include:²

• HHV-8–associated MCD: Triggered by the HHV-8 virus, often in patients with HIV
• Idiopathic MCD (iMCD): Cause unknown, but marked by extreme immune system activation
• POEMS-associated MCD: Occurs in patients with POEMS syndrome and includes symptoms such as nerve damage and skin changes

Symptoms of CD

The symptoms differ according to the type:³

UCD symptoms

• Swelling of a single lymph node region (typically neck, chest, or belly)
• Occasionally, it can go undetected

MCD symptoms

• Fever and night sweats
• Unexplained weight loss
• Fatigue
• Enlarged liver or spleen
• Decreased red blood cell count (anaemia)
• Skin rashes or nerve damage in some cases

Typically, the symptoms occur due to inflammation and excessive production of particular immune system-controlled proteins, particularly interleukin-6 (IL-6).⁴

The role of the immune system in CD

The immune system is designed to protect the body from infections and abnormal cells. In CD, however, the system overreacts and causes injury through inflammation.

Cytokine storms

Cytokine storms represent a complete shift in how we understand bodily threats and are especially impactful in conditions like CD, especially in MCD. These storms arise when there is a hyperproduction of inflammatory proteins in the body, with interleukin-6 (IL-6) being the most detrimental among them. Excessive levels of IL-6 can lead to symptoms such as fever, fatigue, night sweats, anaemia, and even organ failure.⁵

B and T cell dysregulation

Overactive immune cells (B-cells and T-cells) drive excessive production of IL-6 and VEGF (vascular endothelial growth factor), which fuels inflammation and abnormal blood vessel growth.⁵

Autoimmunity

Some researchers believe iMCD involves autoimmune processes, where the immune system mistakenly attacks the body’s own tissues, causing long-term inflammation.⁶

Diagnosis

• Blood tests: High levels of IL-6, CRP (C-reactive protein), ESR (erythrocyte sedimentation rate), and VEGF. Anaemia and low albumin are also frequent.

• Imaging: CT scans or MRI may detect enlarged lymph nodes or organ damage
• Lymph node biopsy: Microscopic examination shows characteristic changes such as "onion skin" layering of lymphocytes and abnormal blood vessel growth
• Viral testing: HHV-8 and HIV testing should be done in suspected MCD cases⁷

Treatment options

The treatment of CD is primarily based on whether the disease is unicentric or multicentric, the cause, and the severity of symptoms. Although UCD typically has a simple treatment and favourable prognosis, MCD is complex and necessitates sophisticated immunotherapy and, in some cases, chemotherapy.

Treatment of UCD

In individuals with UCD, one lymph node or one group of nodes is affected, and the condition is localised. The best and first form of treatment is surgical removal of the enlarged lymph node. Surgery is usually curative, and most patients need no further therapy after the complete procedure. If the lymph node cannot be resected because it is located close to vital organs, radiation therapy can be utilised as a substitute. It shrinks the lymph node and lessens symptoms. If patients do not have any symptoms or if the lymph node cannot be treated entirely, physicians will opt to watch the condition over time with routine follow-ups.⁸

Treatment of MCD

MCD is a more severe manifestation of CD involving multiple lymph node areas and producing generalised symptoms like fever, fatigue, weight loss, and organ enlargement. The therapeutic approach to MCD targets the regulation of the immune system, particularly the excess production of IL-6, which leads to most of the inflammation in this condition.

Anti–IL-6 therapy is one of the most significant therapies for iMCD. The medication Siltuximab (trade name Sylvant) is an intravenous monoclonal antibody that directly binds to IL-6 and inhibits its action. It is FDA-approved for iMCD and is administered every three weeks. It reduces inflammation, normalises lab tests, decreases lymph nodes, and improves general symptoms. Another medication that targets IL-6 is Tocilizumab (Actemra), which is also used in treatment against iMCD. Rather than targeting IL-6 itself, it inhibits the IL-6 receptor on immune cells. Tocilizumab is widely available in Japan and can be an alternative when siltuximab is not tolerated or available. Both medications are ineffective in patients with HHV-8–associated MCD, in which the condition develops due to a viral infection.⁹

In HHV-8-associated MCD, particularly in those HIV-positive patients, treatment with Rituximab is the most effective. Rituximab is a monoclonal antibody that acts on CD20 on B-cells, reducing immune activation and inhibiting IL-6 production. Rituximab is typically administered as an infusion weekly for a few weeks. In select patients, antiviral treatment (e.g., ganciclovir or valganciclovir) is administered in addition to rituximab to manage the underlying virus. It is also necessary to make sure HIV-positive patients are receiving antiretroviral therapy (HAART) to manage their HIV infection, which stabilises their immune system.¹⁰

In patients with extremely severe MCD symptoms, non-responses to IL-6 blockers, or with impending organ failure, chemotherapy can be used. Drugs such as cyclophosphamide, doxorubicin, vincristine, and prednisone (usually together as the CHOP regimen) are administered to manage the disease by eliminating overactive immune cells. These agents are the same as those for treating lymphoma. In others, etoposide or other single-agent chemotherapies are employed, particularly if the patient is not tolerating aggressive therapy.¹¹

Corticosteroids like prednisone or dexamethasone may be used to give quick relief from symptoms by cutting inflammation. But steroids cannot be a long-term treatment as symptoms usually relapse following their withdrawal, and long-term use causes side effects such as high blood sugar, weight gain, thinning of bones, and susceptibility to infection. Hence, steroids are administered with other long-term therapies.

In relapsed or refractory iMCD patients, the alternatives are immunomodulatory drugs like sirolimus (Rapamycin), thalidomide, or lenalidomide. These act by modulating the activity of the immune system and are particularly beneficial in nonresponsive IL-6-targeted patients. Sirolimus is of value in IL-6–independent iMCD by inhibiting the mTOR pathway that plays a role in immune cell activation.¹²

Where CD is found to co-occur with POEMS syndrome (a very rare condition involving nerves and other organs), therapy is aimed at managing the plasma cell disorder that is the underlying cause of the condition. Medications such as lenalidomide, dexamethasone, bortezomib, and even stem cell transplant can be employed in these situations. These are the same therapies applied for multiple myeloma and other cancers.¹²

Irrespective of the form of CD, supportive care is essential in controlling the disease. This can involve blood transfusions to prevent anaemia, nutritional support, fluid management, and infection prevention, particularly in patients on immunosuppressive therapies. Psychiatric support and patient education are also very important, particularly in those with chronic MCD.

Research and future directions

CD is still not well understood, particularly idiopathic forms. Continuing research is investigating:

• Improved diagnostic markers
• Safer and more effective therapy
• Elucidation of the genetic and immune mechanisms involved

The Castleman Disease Collaborative Network (CDCN) has facilitated progress, particularly regarding IL-6 and other cytokines.¹³

Conclusion

CD is a rare and life-threatening immune disorder characterised by abnormal growth of the lymph nodes and immune system dysregulation. It identifies the tendency of the immune system, when out of balance, to create severe consequences. Knowledge of the types, aetiology, and management of CD is essential for early diagnosis and effective treatment. Though treatments such as IL-6 blockers have been beneficial, further investigation is required to better understand and treat this multifaceted disease.