IVIg in autoimmune disease therapies.

Never before have we been faced on such a global scale with the realization of just how important it is to nurture a healthy immune system. While we have learned many lessons from these trying times of COVID 19, there are still a myriad of questions that remain to be answered. However, two undeniable facts have quite clearly emerged: individuals age 65 and older and those who have impaired immune status (e.g. history of cancer, other immunosuppressive condition) are at higher risk of developing severe symptoms if infected.1

Many new as well as older therapies are being utilized and studied in the treatment of this virus. Convalescent plasma or immunoglobulins have been used to improve the survival rate of patients with SARS and now IVIg has entered the forefront as a potential treatment for COVID 19. IVIg is a remarkably safe protocol for our autoimmune patients and one that may offer another layer of protections not just for COVID, but for other pathogenic infections as well given its unique properties that provide helpful autoantibodies including IgG.2

What conditions can be treated with IVIg?

There are numerous applications in both neurology, rheumatology and other fields of medicine where IVIg can be effective treatment option for patients with these and many other diseases* that include:

-    Autoimmune Encephalitis (AE)
-    Chronic B-cell lymphocytic leukemia
-    Chronic inflammatory demyelinating polyneuropathy
-    Guillain-Barre syndrome
-    Infections following bone marrow transplants
-    Inflammatory muscle diseases including dermatomyositis, polymyositis, and juvenile dermatomyositis
-    Immune deficiencies such as common variable immunodeficiency (CVID) and primary immunodeficiency
          disorders associated with defects in humoral immunity.
-    Immune thrombocytopenia  (ITP)  
-    Kawasaki disease
-    Multifocal neuropathy
-    Neurological diseases such as myasthenia gravis or multiple sclerosis (MS).
-    Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS)
-    Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)
-    Pediatric HIV type 1 infection
-    Rheumatic diseases including systemic lupus erythematosus (SLE), Sjogren’s disease, rheumatoid arthritis
          (RA), vasculitis and other related autoimmune disorders.

How does IVIg work?  
Commercial preparations of IVIg are derived from a pool of donors; as such, IVIg products contain smaller amounts of IgA and IgM antibodies as well as Th2 cytokines and cytokine antagonists that may also contribute to therapeutic effects. Numerous targets for IVIg include: T-cells; cytokines; immune cell trafficking; B-cells; complement; and Fc-receptors.

IVIg has been demonstrated to inactivate auto-reactive T-cells by competing for and interrupting their interaction with antigen presenting cells. The balance of cytokines also appears to be restored by IVIg with studies showing that IVIg contains antibodies and antagonists to pro-inflammatory cytokines. In addition, IVIg is thought to interfere with and prevent the passage of auto-immune T-cells into the blood-nerve barrier. The effects of exogenous antibodies on B-cells have been well studied; IVIg is thought to down-regulate antibody production by B-cells, interfere with B-cell proliferation via a blockade of cell surface receptors and prevent the activation of certain subtypes of B-cell. In addition, IVIg can affect innate immunity by interrupting the steps in the complement activation cascade and blocking Fc-receptor mediated activity, which results in down-regulation of macrophage activity. In conclusion, IVIg has numerous modes of action, which culminate in the down-regulation of the immune response; many of which may be relevant to neuromuscular disorders and immune neuropathies.

Combination therapy as a valuable modality in autoimmune disease.
In their concept paper, “Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin,” the authors presented a unique treatment approach using a combination of B-cell depletion therapy (BDT), specifically rituximab (RTX) and intravenous immunoglobulin (IVIg), based on a specifically designed protocol (Ahmed Protocol).3 Twelve infusions of RTX are given in 6–14 months. Once the CD20+ B cells are depleted from the peripheral blood, IVIg is given monthly until B-cells repopulation occurs. Six additional cycles are given to end the protocol.

There are several primary reasons as to why and how IVIG can be beneficial in treatment for any autoimmune disease:  
1.  IVIg works to enhance immune protection in a microenvironment of infectious triggers and toxins, all resulting in high levels of inflammation and immune dysregulation. IVIg has a multimodal method of action (MOA). A number of studies have shown the benefits of IVIg and its anti-inflammatory effects as well as an ability to regulate immune balance. IVIg additionally has the capacity to eliminate clinical autoimmunity, restore a state of tolerance, and reinstate physiologic homeostasis.
2.  The synergy between IVIg and and BDT’s (like Rituxan) are remarkable. When the effects of RTX begin to wear off, IVIg exerts immune restoration by increasing regulatory T-cells (Tregs), regulatory B-cells (Bregs), macrophages, dendritic cells, and promoting more CD138+, normal plasma cells in addition to multiple other immune enhancing mechanisms. With the reduction and/or absence of inflammation, the tissue microenvironment now has the opportunity to return to physiologic homeostasis.
3. IVIg also works to reduce and eradicate harmful autoantibodies.
4. IVIg can enhance B-cell-depleting therapies (BDTs) by its multiple MOAs culminating in profound anti-inflammatory actions as it also provides immune protection.
5. IVIg is considered highly safe and has multiple MOAs in virtually all autoimmune diseases.
Ideally, the full prescribing dose, e.g. 2 grams/ kg, should be used in the course of treatment (predicated upon individual patient criteria, tolerance or other considerations).

It is estimated that approximately one in five Americans now has a diagnosed autoimmune disease. Each year, within our own practice and the medical community as a whole, we continue to face an increasing number of challenges as the incidence of chronic disease rises commensurate with the need for appropriate therapies. New challenges such as COVID 19 should collectively encourage us to consider all available measures in order to provide our patients optimal care with a low-risk profile. IVIg affords us this opportunity and is one that we believe should continue to be explored and included as appropriate in our treatment protocols.   

In health,
Suzanne K. Gazda, MD 

*Additional resources
For more information about IVIg and other health conditions for which it may be used see:
https://emedicine.medscape.com/article/210367-overview#a2

References:

1 https://www.nm.org/conditions-and-care-areas/infectious-disease/covid-19/high-risk-groups/autoimmune-disorders

2 https://www.ncbi.nlm.nih.gov/pubmed/32218340

3 https://www.frontiersin.org/articles/10.3389/fimmu.2018.01189/full