IVIG for Collagen-Vascular Disease-Associated Secondary Immunosuppression

Collagen-vascular disease is a group of conditions that cause chronic inflammation in the collagen (a key component of connective tissue) and surrounding joints. As there is no cure for these diseases, certain immunosuppressive therapies (e.g., corticosteroids, methotrexate, and cyclophosphamide) are commonly used to control the collagen-vascular disease activity. 

However, prolonged use of these therapeutic agents frequently results in significant immunosuppression, also known as secondary immunosuppression, which increases susceptibility to pulmonary and systemic infections in patients.

In such cases, IVIG therapy is used as an immune-supportive therapy to reduce the risk of opportunistic infections. Read on to understand what collagen-vascular diseases are, how secondary immunosuppression develops, the evidence supporting the use of IVIG in this setting, and which patients may benefit most from IVIG therapy.

Collagen Vascular Diseases: Brief Overview

Collagen vascular diseases, also referred to as connective tissue diseases (CTDs), include a group of immune-mediated disorders such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), mixed connective tissue disease (MCTD), rheumatoid arthritis (RA), and vasculitides. 

Most of these conditions arise from immune dysregulation, in which the body’s immune system mistakenly targets its own healthy tissues, causing inflammation. The symptoms of collagen vascular diseases can vary among patients, depending on the type of autoimmune disease they have. 

But most forms of collagen vascular disease do share some common symptoms, for instance, fatigue, muscle weakness, skin rash, body aches, fever, and joint pain. 

Understanding Secondary Immunosuppression in Collagen-Vascular Diseases

Secondary immunosuppression refers to a weakened immune system that happens not because the immune system is dysregulated, but because it is being suppressed, usually as a result of treatments used to control the autoimmune disease itself. 

Many people with collagen-vascular diseases are treated with strong immunosuppressive drugs (like steroids, cyclophosphamide, or newer biologic medicines). These treatments help reduce harmful inflammation but also make the immune system weaker to fight infections. 

Hence, in collagen-vascular diseases (or CTDs), the most common and clinically significant cause of secondary immunosuppression is long-term exposure to immunosuppressive medications. For example, high-dose corticosteroids reduce lymphocyte activity and impair antigen-presenting cell function, which increases the risk of uncontrolled growth of even weakly pathogenic bacteria, viruses, fungi, and mycobacteria.

Likewise, conventional immunosuppressive agents such as methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil, and biologics (e.g., rituximab) suppress lymphocyte proliferation and antibody production, particularly immunoglobulin G (IgG), which further compromises immune defense.

Treatment-Induced Hypogammaglobulinemia

A key manifestation of secondary immunosuppression in collagen-vascular diseases is hypogammaglobulinemia (reduced IgG levels) that occurs as a result of:

• B-cell depletion
• Impaired plasma cell survival
• Suppressed immunoglobulin synthesis

In fact, a retrospective study of pediatric patients with systemic lupus erythematosus (SLE) found that approximately 7% developed hypogammaglobulinemia (IgG < 500 mg/dL) during follow-up, indicating clinically relevant secondary immunosuppression.

Although collagen-vascular diseases are often associated with autoantibody production, total protective immunoglobulin levels may decline over time, particularly following prolonged immunosuppressive therapy. This creates a paradoxical state in which patients exhibit ongoing autoimmune activity alongside reduced effective humoral immunity, leading to an increased risk of recurrent infections.

Clinical Consequences of Secondary Immunosuppression

Many patients with collagen-vascular diseases-associated secondary immunosuppression may experience serious clinical complications, including:

• Hypogammaglobulinemia (a hallmark of secondary immunosuppression)
• Recurrent respiratory infections
• Opportunistic infections
• Increased rates of hospitalization
• Delayed recovery from infections
• Limitations on the use of further immunosuppressive therapies

These complications often necessitate treatment modification or the addition of immune-supportive therapies, such as intravenous immunoglobulin (IVIG), to restore immune competence while allowing continued disease control.

Clinical Use of IVIG for Secondary Immunosuppression in Collagen Vascular Diseases

Various studies reported that IVIG therapy can help manage the clinical consequences occurring as a result of secondary immunosuppression in patients with collagen vascular diseases. 

IVIG in Hypogammaglobulinemia and Reduction of Infection Risk

Since IVIG supplies a concentrated and purified form of IgG antibodies, it can help restore serum immunoglobulin levels in patients with secondary hypogammaglobulinemia. This passive immunity prevents bacterial, viral, and opportunistic infections, which are a major cause of morbidity and mortality in collagen vascular disease patients. 

For instance, a retrospective study showed that most systemic lupus erythematosus (SLE) pediatric patients with low immunoglobulin levels received IVIG replacement to reduce infection risk or active infectious complications. 

Similarly, another retrospective cohort study of autoimmune disease patients treated with rituximab reported that many developed secondary hypogammaglobulinemia, and IVIG replacement was initiated primarily due to recurrent infections or high infection risk, rather than for autoimmune disease control. 

Hence, this and various other studies across autoimmune and inflammatory conditions demonstrate that IVIG significantly reduces the frequency and severity of infections in patients with secondary antibody deficiency, including those receiving B-cell-depleting therapies.

Immune Homeostasis Without Further Suppression

Unlike cytotoxic agents, IVIG does not increase infection risk; instead, it supports immune recovery while allowing continued disease-directed therapy when needed.

Patient Selection and Clinical Considerations

Though IVIG is not a first-line treatment for collagen-vascular diseases or for immunosuppression, it is specifically considered in patients who meet the following criteria:

• Documented hypogammaglobulinemia
• Recurrent or severe infections
• Ongoing need for immunosuppressive therapy
• Contraindications to further immune suppression

In research studies, optimal dosing for secondary immunosuppression typically follows replacement regimens (e.g., 400–600 mg/kg every 3–4 weeks), rather than high immunomodulatory doses used for autoimmune flares.

Risks and Limitations of IVIG

IVIG is generally well-tolerated, but some people can have side effects, including:

• Headaches
• Fever
• Fatigue
• Nausea
• Rarely more serious issues like allergic reactions or kidney stress

The Bottom Line

The standard treatments to control inflammation in patients also pose a unique challenge of secondary immunosuppression. While IVIG is not a cure for collagen-vascular diseases, it is being used as a supportive therapy for those with documented hypogammaglobulinemia and who are at risk of recurrent or severe infections. 

If you are considering IVIG, you should discuss the potential benefits and risks with your healthcare provider to determine if it is the right option for you.