Still’s Disease Complications: Part I Primary Immune Deficiency Disorders

by: Shalla Newton MSN, RN, NE-BC and David Maher

See the Introduction to the series HERE.

Where Still’s Disease and Infections Meet

As the first part of our series on Still’s disease complications, we are examining the innate immune dysregulation of Still’s and related immune system disorders and deficiencies. 

We wanted to start our discussion of Still’s disease complications with the ramifications of immune disorders as they are the broadest category, and may be most relevant to understanding the core disease process. 

We often hear Still’s patients (or parents/caregivers) stating “I (they) also have an immune disorder.” These frequent comments prompted us to highlight the fact that Still’s disease is, first and foremost, a disorder of innate immune dysregulation. As Still’s disease patients we all definitionally have an immune disorder. However, there are specific genetically linked immune diseases that may be either causational or correlational to Still’s. One may not be mutually exclusive of the other. 

Are You like that Girl in The Big Sick?

Zoe Kazen in The Big Sick playing the character based on Emily Gordan. Source

We have previously talked about the association between Still’s and bacterial and viral infections in our post Immune Overdrive: Cytokine Storms & COVID-19. This post also discussed the hurricane of cytokine storms known as macrophage activation syndrome (MAS). Subclinical cytokine storms and MAS episodes are extremely dangerous and can be precipitated by uncontrolled inflammation from inappropriate medication dosing, wrong medication, worsening disease, or truly an infection. 

Sub-clinical MAS and cytokine storms are the warning signs of impending or worsening infections/flares and should not be ignored. Normal (i.e. within normal range) laboratory results can be deceptive and symptomatic presentations should be a warning to any provider that subclinical cytokine storms are occurring and there may be an infection and/or flare brewing. 

Still’s patients are often asked if they have seen the movie The Big Sick. Providers might first take recognition of Still’s disease from the movie. In The Big Sick, the protagonist’s mystery progressive illness lands her in the emergency room and then in intensive care in a medically induced coma due to what is believed to be sepsis and other critical complications. However, the medical experts finally learn of her Still’s diagnosis from what seemed as a mundane swollen ankle that would not heal. Like many newly onset Still’s diagnoses, medical experts explore every infectious etiology for the onset of symptoms without a resolute answer. 

Spoiler alert! She is enduring a massive cytokine storm from undiagnosed Still’s and chronic unchecked inflammation. The Big Sick is based on Emily Gordon’s real life battle with Still’s disease. Her husband, Kumail Nanjiani, portrays a version of himself as the boyfriend of the main protagonist, while Gordan’s character is played by Zoe Kazen. Gordon and Nanjiani wrote and produced the movie based on their real life experiences with Gordon’s onset of Still’s disease. 

Emily Gordon and Kumail Nanjiani behind the scenes of The Big Sick Source

The Role of Genetics

While there are no population level genetic associations in Still’s disease, many Still’s disease patients show mutations in multiple genes associated with the innate immune system. In some cases the mutations may be pathological (causational) or driving factors (correlational) behind the innate immune disorders and Still’s onset. 

There is now genetic testing available from multiple diagnostic companies who focus on both primary immunodeficiency and autoinflammatory genetic panels which can lead to further clues behind both immune disorders and Still’s. The Autoinflammatory Alliance has an excellent blog post with details on the various testing and companies providing the testing.

Keep in mind, there is a subset of patients without discernible genetic mutations driving the disease. This has prompted theories that epigenetics and somatic mosaicism may be at play in Still’s pathology in some cases. 

Ultimately, we know that Still’s disease and immune system disorders and deficiencies happen together fairly often, but we do not know which is the cart and which is the horse.

Primary Immune Deficiency Disorders

Primary Immune Deficiency Disorders (PIDD)s are genetically linked disorders that decrease the ability of the immune system to fight or recognize pathogens. With how complicated the immune system is, there are a huge number of potential genes that can cause over 400 currently recognized disease variants. Some of the more commonly known PIDDs are: specific antibody disorder (SAD), idiopathic thrombocytopenic purpura (ITP), hypogammaglobulinemia, common variable immunodeficiency disorder (CVID), and Kawasaki disease.

With more genetic testing available, PIDDs are being more readily discovered in the pediatric population prior to onset in adulthood. Adult cases can be more severe due to missed or delayed diagnosis from childhood (or birth).

Kawasaki’s disease has recently been in the news regarding the mysterious post-viral response to children infected with COVID-19. We discussed Kawasaki’s disease in our previous cytokine storm/MAS and COVID-19 post as well. Kawasaki’s is a rare pediatric disorder with prominent systemic vasculitis, hematologic, inflammatory and immunologic findings requiring multiple specialists of care.

The key unifying factor here is that PIDD patients are generally very susceptible to certain pathogens, though the exact type(s) depend heavily on the genetic mutations present. Driven by the innate immune system, it should be no surprise some of the PIDDs and Still’s can occur together.

Thus, some Still’s patients must also suppress their body’s systemic inflammatory responses with appropriate therapeutics (biologics, DMARDs, corticosteroids and immunosuppressants). However, they must also treat frequent and recurrent infections appropriately with immunoglobulin therapy (IVIG) and/or antibiotics/antivirals depending on the nature of the pathogen. Let’s discuss treatment algorithms a bit more below for those with PIDDs and Still’s. 

Treating PIDDs and Still’s

First line treatment for PIDDs is often IVIG to boost the immune system with acute or long-term antibiotic or antiviral therapy to circumvent more aggressive infections. Let’s dig a bit deeper with some examples of how IVIG works with some common PIDDs:

CVID attacks the body’s innate immune system (macrophages and neutrophils), but also dysregulates both T and B-cell regulation. IVIG boosts the body’s response to macrophages and neutrophils as well as appropriately regulates the T and B-cell disruptions (which can be an issue with autoinflammatory disorders upregulating the inflammatory cytokines causing inflammation).  

In hypogammaglobulinemia, the body is not producing enough antibody responses to the immunoglobulin subtype IgG. IVIG targets the poor or non-response to produce more IgG. In SAD and ITP, IVIG generally regulates T cell homeostasis and increases platelet destruction as well as boosts the immune response to specific non-responsive antibody titers (usually pneumococcal titers).

Broad spectrum antibiotics and antivirals are often adjunctively used with IVIG or intermittently when an infection is suspected. During seasonal surges in influenza and pneumonia, antibiotics may be utilized prophylactically to prevent more aggressive infections in those with PIDDs who present routinely with viral and bacterial infections. 

If a defined targeted therapeutic is commercially available for the genetic deletion or mutation, that therapy may be utilized to treat the underlying genetic condition driving the PIDD. Shalla has an extremely rare genetic deletion driving a PIDD known as CTLA4 Haploinsufficiency which is treated with a repurposed RA biologic, abatacept (Orencia). Abatacept tricks the immune system to convert T-cells to produce the CTLA4 missing in the deletion to then produce immunoglobulins (both antigens and antibodies) artificially. See more about this CTLA4 Haploinsufficiency genetic disorder in Shalla’s Story.

Investigational and off-label targeted therapies are also utilized for genetically-linked PIDDs. 

Stay Tuned for Still’s Disease Complications: Part II – Autoimmune Comorbidities

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