Introduction 

Multicentric Castleman Disease (MCD) is a rare and serious condition of the immune system that leads to widespread inflammation and the unusual enlargement of lymph nodes in different locations across the body.¹ In the United Kingdom, around 12 people per million are diagnosed with MCD in a year.² MCD usually starts occurring around age 60 and is a deadly disease if it is not treated.³

The other type of this disease, called Unicentric Castleman Disease (UCD), affects only one lymph node area unlike MCD. Therefore, the disease is categorised based on the number of enlarged lymph nodes, where patients with MCD have one or more enlarged lymph nodes at different locations in the body.¹ Lymph nodes are small structures in the body and are reserves of white blood cells (lymphocytes), which are part of the immune system and defend the body against infection. The lymph codes tend to cluster in different parts of the body, including the neck, armpit, chest and behind the knees.⁴ 

The effective management of the disease is necessary to prevent its rapid progression and reduce mortality rates.³ The standard treatments include immunotherapies, and in more severe cases, corticosteroids and chemotherapy are administered. This article will give a clear and concise overview of the underlying disease mechanisms and symptoms of MCD, along with the current treatment strategies for different cases of disease type and severity. 

Pathophysiology of multicentric castleman disease 

Besides the enlargement of lymph nodes (lymphadenopathy), the other symptoms of MCD include fever, weight loss and widespread swelling of the body due to the buildup of fluid.¹ UCD is a more common and less severe form of the disease compared to MCD, and it is more treatable with surgery by removing the one enlarged lymph node. On the other hand, MCD has a wide range of different symptoms ranging from mild to severe, therefore its treatment is more difficult and requires a systemic approach, meaning that the therapy has to have widespread effects in the body.⁵ 

MCD patients are classified based on the cause of the disease. If the human herpesvirus-8 (HHV-8) infection is present, they are diagnosed with HHV-8-associated MCD. Patients without the HHV-8 infection are classified as having the idiopathic MCD (iMCD) type, where the cause is unknown. There is no standard treatment strategy for iMCD, and there are limited effective therapies for it.^1,5 

The classification of MCD based on how the disease develops and affects the body is essential for the correct and effective treatment strategy to be employed.¹ In patients with HHV-8-associated MCD, the HHV-8 virus mainly infects the B cells (a type of white blood cell) and travels in the blood in an inactive state. Certain stimuli, such as oxidative stress, a weakened immune system, and other viral infections, can trigger the virus to be activated, where it increases the production of a cytokine called interleukin-6 (IL-6), which causes activation of the immune system and widespread inflammation across the body. The mechanisms underlying iMCD are less clear but still involve increased production of IL-6 and overactivation of the immune response.¹ 

This overproduction of IL-6 and the subsequent activation of the immune system is one of the primary factors underlying the clinical symptoms seen in MCD, including enlarged lymph nodes, fever and weight loss. This relies on the role of IL-6 as a messenger protein that causes swelling in the body, over-activation of immune cells, growth of lymph nodes, increased plasma cells that produce excessive antibodies, anaemia due to blocking iron absorption from the gut, among many other effects.¹ Therefore, immunotherapies are mainly targeted towards reducing IL-6 levels and enabling the proper regulation of the immune response. 

Immunotherapy in MCD management

The immune system has the primary role of defending and protecting the body against infection and disease. Under certain conditions, such as MCD and cancer, immunotherapy is used as a treatment where the way the immune system works is changed or regulated to fight infection and control inflammation ⁶. Multiple types of immunotherapy exist, which all target different components of the immune system.

Anti-CD20 therapy: Rituximab

For patients with HHV-8-associated MCD, rituximab is the main drug of choice, where it is recommended alone for mild cases and in combination with chemotherapy for patients with severe symptoms.¹ Rituximab is a monoclonal antibody that targets the CD20 antigen on B cells, which results in the elimination of the B cells infected with HHV-8 in the lymph node, thus aiming to reduce inflammation.³ It has been demonstrated that the administration of rituximab for 4 weeks at a dose of 375 mg/m2 per week led to a statistically significant improvement in the survival rate of patients.³ Rituximab was found to be a safe and effective treatment, as well as having the potential to resolve the disease. However, in patients who have Kaposi sarcoma, rituximab therapy should be administered carefully as it can worsen this condition.³ 

The effect of rituximab is the greatest for HHV8-associated MCD and it has limited efficacy in patients with iMCD.⁷ Thus, there is an unmet need for treatments for iMCD patients. This is due to the complex mechanisms underlying iMCD, where IL-6 may not have as much of a role as it does for HHV-8-associated MCD.⁸ Overall, rituximab is generally considered the standard therapy for HHV-8-associated MCD, where it has been reported to significantly improve patient survival.⁹

Anti-IL-6 therapies: Siltuximab and tocilizumab 

Siltuximab is another approved monoclonal antibody that targets IL-6, where it directly binds to human IL-6 and prevents it from activating the IL-6 receptor and blocks the downstream activation of inflammatory pathways that are responsible for the progression of the disease.¹⁰ It was reported that siltuximab was a safe treatment and its more prolonged administration was also well tolerated with a minimal risk of adverse events.¹⁰ It was also shown to be effective in patients with the less severe form of iMCD, given at a dose of 11 mg/kg every 3 weeks.¹ 

Siltuximab is helpful in improving the size of enlarged lymph nodes, providing relief from symptoms such as fever, fatigue, and weight loss, and normalising laboratory test results, including blood haemoglobin concentration.⁵ This is the primary therapy for both HHV-8-related and idiopathic MCD, as it is both effective and well-tolerated. It is important to note that long-term use of siltuximab is necessary to prevent the worsening of MCD symptoms in patients; however, the good safety profile and minimal side effects of this drug make it suitable for this type of use.⁵ 

Siltuximab is the only approved treatment for iMCD, and tocilizumab can also be used as a substitute if siltuximab is ineffective.⁷ In the case where patients do not respond to anti-IL-6 immunotherapies, rituximab is used, and in more severe cases, chemotherapy can be considered. Notably, corticosteroids can be administered alongside siltuximab or tocilizumab to increase the effectiveness of the treatment.⁷ However, since the main form of immunotherapy is IL-6 targeted, patients who do not respond to anti-IL6 drugs, due to the complexity of the underlying disease mechanisms, have limited options available besides targeting other cytokines such as vascular endothelial growth factor (VEGF).¹ 

Beyond immunotherapy: additional treatment options

Corticosteroids 

Corticosteroids can also be used alongside existing immunotherapies such as rituximab and tocilizumab to increase the effectiveness of treatment in patients with severe cases of MCD. For example, in a 43-year-old female patient who showed signs of fever, excessive weight loss, fatigue, kidney malfunction and lung infections, the combined use of corticosteroids and tocilizumab for a duration of longer than 2 months led to improved lymph node enlargement, kidney function and other symptoms.¹¹ Initial doses of 1 mg/kg per day for 4-8 weeks for patients with mild symptoms and 2 mg/kg per day for patients with more aggressive symptoms were suggested .¹ 

Corticosteroids alone are not a very effective treatment for MCD, however they show promising outcomes when used alongside existing immunotherapies. They are recommended for critically ill patients where the disease is progressing rapidly.¹¹ 

Chemotherapy 

In the most severe forms of MCD, the combination therapy of chemotherapy alongside standard immunotherapies is applied. In aggressive cases of iMCD where patients do not respond quickly to corticosteroids and anti-IL-6 therapies, as well as having problems with organ function and a high risk of dying, chemotherapy is recommended.¹² Out of the other types of chemotherapy, cytotoxic chemotherapy which includes the use of rituximab, was shown to have the highest response rate in patients with severe MCD.¹² However, the significant toxic effects of cytotoxic chemotherapy makes it unfavourable to clinicians unless the patient does not respond to the standard immunomodulatory drugs.¹² 

Summary 

Multicentric Castleman Disease (MCD) is a rare condition of the immune system that is characterised by widespread inflammation throughout the body, enlarged lymph nodes, and increased levels of IL-6. It can be classified into HHV-8-associated MCD and idiopathic MCD (iMCD), which does not have a clearly understood cause. Immunotherapy involves targeting the immune system for therapy, and it is the primary treatment for MCD. Rituximab is mainly used for HHV-8-associated MCD and targets the CD20 receptor on B cells. Siltuximab is an anti-IL-6 treatment and it is the only approved therapeutic for iMCD. In severe or non-responsive cases, corticosteroids and chemotherapy can also be added to the standard treatments. Overall, the long-term administration of immunotherapy is often required, and the treatment of choice is dependent on the severity and subtype of disease.