Introduction 

Castleman disease (CD) is a rare and complex group of disorders marked by an abnormal growth of lymph node tissue. This lymphoproliferative disorder affects either a singular lymph node or multiple which are followed by systemic symptoms. If you have CD, the long-term effect causes inflammation that will damage your organs and keep the immune system active, but unstable.^1,2

The excessive immune system response in CD is caused by a specific feature that leads to inflammatory symptoms. This concept is called a cytokine storm. The cytokines attack the bloodstream, which causes the hyper immune reaction that makes the whole system go into overdrive.^1,3

In the eye of the cytokine storm, the cytokine interleukin-6 (IL-6) shines as the central role in driving the inflammatory response and contributes to many other disease symptoms like fatigue, anaemia, and organ dysfunctions.^3,4

Since IL-6 triggers the cytokine storm in CD, in this article, we will be exploiting what causes the system to destabilise, contribute, and what preventive measures we can take.

Overview of Castleman disease

There is not much research into CD as it is a rare disease. There are an estimated 4,300 new cases each year.²

There are two types of CD:²

• Unicentric CD (UCD) – localised, enlarges one or more lymph nodes, usually asymptomatic
• Multicentric CD (MCD) – systemic, more severe in several areas in your body as lymph nodes grow. Patients may develop fevers, weight loss, fatigue, night sweats, enlarged spleen and liver

Cases are discovered by accident, usually during surgery or imaging. UCD is treatable, by removing the affected node in surgery. MCD needs medical management and has an unpredictable response.^1,2

There are different forms of MCD:

• Idiopathic MCD (iMCD): common form of MCD. “Idiopathic” means the cause is unknown. iMCD is not associated with viral infections and can affect healthy people. The cause is an imbalance of IL-6 being produced, causing inflammation around the body and organ dysfunction⁵
• POEMS MCD: POEMS is described as Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes. It is less common because it has overlapping systems, which makes it difficult to make a prognosis and provide accurate treatment⁶
• Human herpesvirus-8 associated MCD (HHV-8): CD is linked to HHV-8 for individuals who are HIV-positive. Cytokines, including IL-6, overproduce and since the body is immunocompromised the viral stimulation triggers the production. It has more severe symptoms^2,7

Different subtypes of MCD have different treatment strategies and plans. This suggests that IL-6 needs to be explored as it has an impact on CD, immune dysregulation, and cytokine storms.

What is a cytokine storm?

A cytokine storm is an immune reaction of an overproduction and unstable release of pro-inflammatory cytokines, IL-6 being one of them. It is an uncontrolled form of cytokine release syndrome (CRS) that leads to widespread inflammation in the body, tissue injury, and organ malfunctions. IL-6 is the main cytokine that initiates the inflamed storm.⁸

Elevated levels of IL-6 and other cytokines, like TNF-​​α and IL-1β, are pro-inflammatory. The common symptoms are the fever, anaemia, hypotension, and other causes that are seen in the laboratory, such as C-reactive protein (CRP). So far, the body is in an inflamed state. On top of that, the blood vessels will experience fluid leakage that further complicates the condition. This is called capillary leak syndrome. The fluid leaks out the blood vessels into surrounding tissue that causes swelling, less oxygen and nutrients flowing towards the organs, and reduced blood volume. The organs that are most vulnerable are the lungs, kidney, and heart.^2,9,10

Cytokine storms can appear in other conditions like COVID-19 infections and sepsis. In COVID-19, the storm is triggered by viral infection and respiratory damage. In sepsis, the bacterial infection gives an imbalanced response causing inflammation. In iMCD, IL-6 is overproduced without any viral infections. IL-6 is the main cytokine that is produced in large amounts.^9,11

Unfortunately, there is no official understanding on why the immune system overreacts when there is excess cytokine release. The cytokine storm can feed itself regardless of what happens first in the disease. This can create a continuous loop that damages the body. If not caught early on, the more severe the disease will be that can eventually lead to death.^8,12

Interleukin-6: key driver in Castleman disease 

IL-6 is a pro-inflammatory cytokine that triggers inflammation in the immune system. This is a problem because the immune system will become unstable. In normal conditions, IL-6 is secreted from dendritic cells (DC), macrophages, and endothelial cells. This is a response to tissue damage, infections, or immune activation.^9,13

The IL-6 functions promote B cell activation and antibody production. CRP production is triggered. When IL-6 travels through the bloodstream, the brain sends signals to the body to raise the body temperature and produces a fever. This is a natural defence mechanism towards infection.¹³

In CD, IL-6 is overproduced as it cannot be controlled in an unstable immune system. This can lead to a number of abnormal immune symptoms. If IL-6 sends an excessive amount of signals, it contributes to lymph node hyperplasia that activates B cell growth. This is one of the main points of the CD. It forces many systemic symptoms, which takes the form of fatigue, weight loss, and fever.^9,13

Studies show that IL-6 elevation in iMCD patients correlates with disease activity, as both have high IL-6 it has similar activities.¹⁴ IL-6 causes many issues seen in CD, such as:

• Anaemia of chronic disease: the body’s ability to produce iron properly and how it responds to hormones that make blood vessels, leading to low blood count¹⁵
• Thrombocytosis: increases platelet production¹⁶
• Hypoalbuminemia: lowers albumin levels that causes fluid to leak out in the blood and to the tissues¹⁷

Diagnostic markers and laboratory clues 

In scientific laboratory findings, CD often shows immune dysregulation and multiple organs having problems. Elevated IL-6 contributes to CPR production that suggests that inflammation is ongoing. Vascular Endothelial Growth Factor (VEGF) can stimulate the cytokines and increase the flow of fluids going in and out the blood.^2,18 Another laboratory clue is doing a Ferratin test where it indicates immune activation or iron metabolism detection if it has been disrupted.^2,19

The blood count may expose cytopenias as an abnormality, because of the low count. This can take the form of anemia. Thrombocytosis can be an alternative because of the possibility of an increase in platelets. This depends on the disease stages. Blood protein levels can show a low albumin from blood vessels and a high Immunoglobin G (IgG). This antibody mimics the immune activity, which is quite high in CD.^2,9

Techniques such as MRI and CT scans can expose swollen lymph nodes, called lymphadenopathy, or an enlarged liver or spleen. A radiologist would confirm this with the doctor.²

Other conditions can share the inflammatory or infectious symptoms. Many other diseases can cause cytokine storms. Through diagnostic work, research, and a thorough investigation of viral infections and autoimmune disorders, they can be excluded from any laboratory profile to confidently choose CD.

IL-6 targeted therapies in Castleman disease

To target CD, two main IL-6 inhibitors are used for management.

• Siltuximab (anti–IL-6 antibody): binds itself to IL-6 that interacts with the receptor
• Tocilizumab (anti–IL-6 receptor antibody): Targets the IL-6 receptor itself to prevent it from causing inflammatory responses

Both therapies can block the signalling pathways of IL-6, which reduces inflammation in the body. This can control the immune system well and help out with other systems to get the body back to a normal state, like regulating weight, improve energy levels, decrease the size of lymph nodes, and start getting the body back to its normal body temperature.^14,20

In a laboratory review, when the treatment plan follows through, there will be signs of CPR production decreasing, no longer having low iron, and anaemia is alleviated. These therapies break the cycle and it restores balance to your body.²

When IL-6 blockers are ineffective, other treatments such as corticosteroids, rituximab (target B cells), and other immunosuppressants. These aid the immune system to target other responses that may have been involved and have an alternative treatment for the mechanism to reach further.²

In the long-term, CD needs to be controlled in order to prevent another relapse. Cytokine-blocking therapies help as they prevent any flare-ups. This treatment needs to be continuous otherwise a relapse is most likely to happen, because the inflammatory drivers need to be suppressed all the time. Blocking this pathway will lead to improvement and better control for the patient’s life.²

Prognosis and long-term implications

The long-term implications of CD depends on the type, its subtype, and how well it responds to treatment. The prognosis of CD has a favourable outcome if the lymph node that has been causing problems has been surgically removed. Long-term management requires clinical expertise in MCD.

In iMCD, the effectiveness of therapies can go a long way if it successfully suppresses the inflammatory response. If it fails then even more complicated outcomes can occur, these include the regular organ dysfunctions, fever, severe cytokine storms, and the high risk of developing lymphoma over time. This overreaction can lead to permanent damage to the patient’s immune system and may affect their daily lives.⁵

Early diagnosis will help find the right therapy as quickly as possible. To reduce the risk of high complications, it is important to regularly monitor the cytokine levels and inflammatory markers to plan ahead with the treatment and if there are any changes during the process, and to prevent any relapses because of the risk of permanent damage. This is achievable, but CD is known for its relapsing nature.

FAQs

Is the IL-6 molecule the same as in COVID-19 and Castleman disease?

Yes IL-6 is the same molecule in both COVID-19 and CD. This is because IL-6 is a common cytokine, and IL-6 plays a key part for immune response and inflammation in both diseases.

Can Castleman disease be cured?

CD has different variations, and treatment varies depending on the type. For example, UCD is often curable through surgical removal of the affected node. However, MCD requires multiple different strategies which can include targeted therapies, like anti-IL-6 medication.

What is the role of IL-6 testing?

For someone who has CD, it is important and ideal to have an IL-6 test. The importance of this test is to identify the level of IL-6 within a person who has conditions associated with inflammation. By knowing the level of IL-6 it's also capable of detecting whether conditions may develop into something worse.

Summary

CD is a rare disorder and is best known for its MCD. The highlight in this pathogenesis is the cytokine IL-6. This overproduction of this cytokine in the cytokine storm signals the body to cause inflammation, biochemical abnormalities, swollen organs and other triggers. CD relies on clinical and laboratory diagnosis, along with imaging features, to deal with the key biomarker IL-6 and gather important clues into which therapy and treatment will be the most effective. Targeted therapies will improve outcomes when diagnosed early and managed properly. This happens because IL-6 pathways will be blocked and interrupt the cycle of inflammation. This will restore immune balance and lessen the burden on the disease.