by: Shalla Newton MSN, RN, NE-BC and David Maher
As AOSD patients ourselves we deeply feel a need for further information specifically on our diagnosis. We advocate for the two continuums to be denoted under the larger umbrella term of Still’s disease, but literature, FDA treatments and support groups/advocacy organizations have leaned into the SJIA diagnosis to date, leaving out the affected population in the adult presentation of AOSD. That being said, we will be circling back to SJIA in future posts. However, we firmly believe a separate dedicated discussion to AOSD is warranted and will also benefit the SJIA population as well.
The SJIA demographic will age out of the pediatric system that currently fosters a more collaborative, metacognitive and research-driven environment, whereas adult rheumatology and subsequent specialty care for AOSD is fragmented as part of our current adult healthcare system. We feel the SJIA patients and their families will need their AOSD counterparts of Still’s to help shephard the way into their adult care and conversely, the AOSD community needs the access to research, treatment and advocacy the SJIA population retains. Those adults diagnosed with SJIA as a child often feel more comfortable retaining their SJIA diagnosis and segregate the term SJIA from Still’s due to wanting their own identity (and we get that too). SJIA patients, like those of us with AOSD are subjected to erroneous diagnostic interchanges as well with the term JIA (juvenile idiopathic arthritis). JIA is not a rare systemic autoinflammatory disease, but rather generalized arthritis presenting in the pediatric population. So, as AOSD patients, we get the desire to want to be heard and differentiated from arthritis as our disease is so much more than some joint pain as often described which feel to be rather marginalizing and demeaning to us as patients living with the complexities of the disease. Thus, we advocate for the universal nomenclature of Still’s disease terminology.
We’re going to start at the very beginning, which we hear is a very good place to start, with two related topics in one post: an overview of AOSD and the difference between an autoinflammatory and an autoimmune disease, as these terms are erroneously interchanged by both patients and providers.
AOSD in a nutshell…let’s define the dragon
The short version is that AOSD is a rare, systemic autoinflammatory disease. Let’s unpack what that means, and then we’ll dig a bit deeper into the science.
When we say rare, that means in terms of the U.S. population of about 350 million, there are approximately 280-1,400 people per year diagnosed and about 350-11,900 living with Still’s disease. You can see a full explanation of these numbers in our first post.
Systemic disease means that it can affect any system or organ in the body.
Autoinflammation implies an inflammatory process of the innate immune system.
The Innate Immune System = Autoinflammation
The innate immune system comprises the body’s basic defenses against an invader, it includes functions like swelling, fever and skin barriers. Innate immune functions are carried out by neutrophils, macrophages, natural killer cells, etc.
Diseases of the innate immune system are called autoinflammatory diseases, with auto being the Greek word for “self,” so it literally means “self-caused inflammation.” Generally, autoinflammation leads to elevated inflammatory markers called cytokines which are derived from a few different pathways: interleukin, complement, interferons, and growth factors.
If you’re already reaching for your high school biology textbook, don’t worry that is a natural response. But, there is a helpful little diagram below to better organize the information about the immune system for you.
Beyond AOSD, some other autoinflammatory diseases include Familial Mediterranean Fever (FMF), Bechect’s disease, Blau syndrome, Cryopyrin Associated Periodic Syndrome (CAPS), and Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome (PFAPA). Most of the identified autoinflammatory disorders are monogenic, meaning derived from an identified mutation in a single gene, although some may be polygenic, or derived from multiple affected genes.
There is quite a lot of debate as to whether AOSD is monogenic or polygenic. However, AOSD is currently classified as a polygenic disease. The honest truth is providers and scientists currently do not have enough data at present to definitively make that call.
Textbook definitions & diagnostic criteria remain antiquated
You might be asking why we referenced a dragon above, well the universal symbol for AOSD is a dragon due to the high grade fevers, often feeling like your skin is on fire. We, like many patients, find that our experience of “the dragon” is only faintly echoed in the textbook definition of AOSD. We are also not immune (pun intended) to the crazy looks while we scratch our skin in a cytokine flare complaining our skin is both itching and burning. However, little gross evidence exists to others other than maybe a rash at times or generalized erythema.
We present the textbook definition of AOSD here because it’s what we have. It’s decidedly imperfect because it focuses on specific symptoms rather than viewing symptoms and comorbidities (additional diagnoses) as the consequences of uncontrolled autoinflammation. This is largely because we have vastly more insight into the disease process than scientists did in the 1970s-1990s when this definition solidified. We’ll be digging deeper into this soon in the upcoming post on the history of Still’s disease.
The textbook comprehensive definition of AOSD includes a list of symptoms and serology (lab work) laid out below. We discuss diagnosing AOSD further below as well, but know that a comprehensive list of symptoms and inclusive serology truly does not exist as AOSD is a diagnosis of exclusion with the variance between individual presentations is quite vast, being a rare disease.
- persisting quotidian (daily) high grade fevers
- evanescent rash (salmon colored)
- abdominal pain
- sore throat
- mouth ulcers
- Koebner’s dermatographia
- ↑ liver enzymes
- Primarily ALT & AST
- ↑ LDH
- ↑ Ferritin
- ↑ leukocytes
- ↑ neutrophils
- ↑ acute phase reactants
- ESR, CRP, etc.
- lymphocyte dysregulation
A large part of the problem with this definition is that these symptoms are neither exhaustive nor will they present the same in every patient, varying in degree, frequency and presentation. Further complicating this picture, the textbook definition fails to account for different subtypes – briefly discussed below – which can confuse providers and delay diagnosis.
The subtypes of AOSD…let’s make this more complicated
We are only going to introduce the notion of subtypes (or phenotypes) and the uniqueness of its presentations per patient. The sub-classifications and such variance within the Still’s spectrum is vast, especially among the AOSD population. Research is polarized on the nomenclature and further sub-classification, thus we will just give a high level overview of the subtypes.
In general, there are two subtypes of AOSD but within these subtypes there are extreme variants as well. Type 1, or AOSD with Rheumatoid Arthritis (RA) and Type 2, or AOSD with non-RA presentation, but both subtypes can have further sub-variant presentations. Patients with AOSD can present with the traditionally elevated ferritin levels with either the RA or non-RA subtypes. Though, generally, the non-RA subtype (Type 2), more formally known as seronegative RA AOSD, typically includes some form of erosive arthritis, low to normal ferritin levels and is more systemic and often much more aggressive in presentation than its Type 1 seropositive RA AOSD counterpart. As the name suggests, the Type 1 seropositive RA subtype typically features prominent arthritis as the “baseline” symptom.
The most generally accepted diagnostic algorithm is based off Yamaguchi’s criteria defining a set of major and minor criteria for diagnosis: fever, rash, arthralgia and leukocytosis as the major criteria as well as sore throat, lymphadenopathy, splenomegaly, liver dysfunction, negative RA factor, negative ANA (for Lupus) as minor criteria. A suspected AOSD patient must present with a minimum number of criteria from these major and minor criteria, but again often we have learned textbook definitions have not caught up with the genetics and further variants of a disease, especially rare diseases. Koebner’s dermatographia (graphic rash presentation on the skin) is also used as an inclusionary diagnostic tool for an active flare of AOSD.
The primary difficulty in diagnosis, even guided by all available criteria sets is that all of these symptoms are incredibly nonspecific, They show up in many diseases making AOSD a diagnosis of exclusion. This means providers and patients must work together to exclude other possible diagnostic reasons for their symptoms, whether that is infection, cancer, autoimmune disease, or genetic mutation. Confounding this further is the reality that not all AOSD patients show traditional inflammation-related abnormalities in their blood work. At this point, your rheumatologist may be contemplating his or her career choices while debating the “punt punt pass” of your case to an academic center of excellence if you are not presenting at one. Diagnosis takes dedication and advocacy on behalf of the patient, family and provider as a team. Today’s insurance requirements often preclude many good rheumatologists from fighting the good fight dedicating time to your complex case, hence sending you off to someone more versed in autoinflammation and reimbursed for his or her metacognitive approach.
Generally, both autoimmune and autoinflammatory diseases are identified by diagnostic or previous disease criteria based on the American College of Rheumatology’s (ACR) or European League Against Rheumatism (EULAR) guidelines for serology for positive or negative disease markers, symptoms, and/or diagnosis based on exclusion of other similar diseases. We’ll dig deep into this in our post about diagnosis and complications of AOSD, which will discuss in detail the complexity of the disease and severe complications.
Due to the complexity and variety of treatments for AOSD, we will only briefly mention the major classes of treatments now and then dig deeper into these various treatments and even in the future discuss procurement and reimbursement challenges. Often, many patients and providers find procuring the medication via your insurance company very challenging.
AOSD patients use several rheumatology medications, however the two major classes are: conventional synthetic disease-modifying antirheumatic drugs (sDMARDS) and biologics (or sometimes known as bDMARDS). Some of the biologic classes have generic versions now available called biosimilars. Both DMARDS and biologics target a particular pathway in the disease process, generally suppressing the overactive immune system or inflammation regulation. DMARDS and biologics are often used in adjunction with non-steroidal anti-inflammatory drugs (NSAIDS) and corticosteroids.
We put the main AOSD Treatments in a table below listed alphabetically by generic name. This list is not all inclusive for treatment options.
It looks like a duck and quacks like a ……wait AOSD is not an autoimmune disease?
In contrast to the innate immune system discussed above is the adaptive immune system. The adaptive (or humoral) immune system learns from pathogens that have infected the body so it can efficiently clear them if encountered later. Adaptive immune functions are carried out by B cells and T cells (but generally more readily driven by B cell activity). Diseases of the adaptive immune system are called autoimmune diseases, meaning an adaptive response to a self-generated substance. Autoimmune diseases include Rheumatoid Arthritis (RA), Lupus, Sjogren’s Syndrome, Hashimoto’s Thyroiditis, and many more.
It is well known that people with autoimmune diseases are at risk for developing other autoimmune diseases. And indeed, those with autoinflammatory diseases can also develop autoimmune issues on top of their existing problems and often do, creating this autoinflammatory-autoimmune continuum (making it harder to discern the two diseases for patients and providers when this happens). However, this continuum appears to be more of an unidirectional pendulum where having an autoimmune disease does not put you at risk for developing an autoinflammatory disease. This is because an innate response naturally leads to an adaptive response, while the reverse is not true. There can be redundancy between the immune systems. It has become clear some cells carry out roles on both sides of the divide. The algorithm model below is a general purpose model.
The Consequences of Chronic Inflammation
We wanted to conclude this discussion by wrapping everything up and discussing why chronic, unchecked inflammation is dangerous with unpredictable consequences. Chronic systemic inflammation affects any organ (hence systemic). Unchecked inflammation leads to ischemia and is particularly problematic in the cardiovascular and respiratory systems with some of the resulting complications: heart attack (myocardial infarction), pericarditis, myocarditis and vascular damage-blood clots (thrombosis), such as deep vein thrombosis (DVT) or pulmonary embolism.
Indeed, blood clots are reported among the AOSD patient population and in the medical literature. Additional risk appears correlated with use of biologic therapy, IVIG therapies, and if the patient has a central catheter for infusion therapy (central chest port). Thus, there are primary and secondary implications of chronic inflammation.
Blood clots feature heavily in Shalla’s disease presentation:
“I am not new to infusion therapy with other comorbidities, such as a history of severe anemia and an orphan (extremely rare) immunodeficiency genetic disease, thus I have had both IV iron and IVIG and frequent hospitalizations, imaging etc. requiring venous access. It was determined I needed a central catheter (chest port) to continue therapy for AOSD as well. Initially it was believed the subsequent blood clots developed in my jugular vein (known as innominate-jugular (IJ) subclavian clots)) were a result of the port placement. Long story short, I failed multiple anticoagulants developing several blood clots with required interventions due to the incorrect notion the port caused the clots. I am doing well (knock on wood) on my current anticoagulation therapy and will remain on said therapy for life. My providers not realizing my thrombosis history was due to chronic inflammation causing vascular damage, delayed optimum and effective treatment and led to additional complications from the blood clots. AOSD truly can lead to the domino effect and a learning experience for both the patient and providers!”
Chronic inflammation can lead to damage in any organ or system in the body and it does so among the AOSD patient population. It’s a bit like the old children’s song “Head, shoulders, knees and toes” but instead of listing a few body parts, we would end up listing every organ in the lyrics…. “Head, shoulders, knees and toes….and spleen, liver, kidney, lungs, heart etc…” it is no longer such a catchy children’s lyric is it?
By far the most dangerous, even fatal consequence of AOSD associated inflammation, is Macrophage Activation Syndrome (MAS), a cytokine storm syndrome. We mention MAS briefly here as it is a complex subject matter with vast implications deserving it’s own post. Both of us have experience with cytokine storms, with Shalla having a confirmed MAS diagnosis as well and post-viral MAS activity, which she can attest to, is very scary.
MAS is startlingly similar to the inflammatory process driven by COVID-19, both can result in multisystem organ failure. Many of the same treatments in Still’s (AOSD and SJIA)/MAS are used to calm the immune system in this post-viral syndrome we are seeing in both the pediatric and adult populations affected by COVID19. In light of this, we’ve decided to move up our discussion on this topic. Thus, we’ll be focusing on that as our next post. We’ll also discuss the connection between Still’s disease and viral infection in general, a pattern that’s been noted since the 1980s.
There’s a lot of information we’ve presented here, because AOSD is such a complex subject. We will be diving deeper into each of these subjects in depth in the future.
Next time!…Stay Tuned for our discussion on Still’s disease, the Cytokine Storm/MAS & COVID19