by: Shalla Newton MSN, RN, NE-BC and David Maher
If you are going to stand on the shoulders of giants, it only seems fair that you should learn their names. History, however, transcends names in a textbook. A medical history is a chronicle of problem solving and an accumulated observational diary of patterns.
Discovery by Sir G. F. Still
It is easy to imagine Sir G.F. Still as the basis for a reality-based reboot of House MD. Still did not share Dr. House’s many television-ready qualities like the epic crankiness and rather obtuse aversion to humanity, so perhaps recasting the protagonist would be in order. But, Still was a brilliant diagnostician and scientist, prompting some medical historians to refer to him as the father of British pediatrics.
In 1896 Still, then Doctor Still, published his first paper, the seminal work on the disease that now bears his name, On a form of Chronic Joint Disease in Children. There is some argument that another group may have published earlier that same decade, but it is unclear if these other authors are describing the same disease entity. Eventually, Sir Still’s overarching disease framework probably played a role in ensuring the disease bore his name.
The early focus on “Chronic Joint Disease” explains the tradition of considering Still’s disease a form of arthritis. Still can be excused for failing to recognize the autoinflammatory nature of the disease, since it was not until long after his death that the concept developed and he was doing the difficult work of discovery. With more than 100 years of evidence and a good molecular picture of the disease, it is clear that Still’s disease is radically different, and more severe, than other diseases lumped into the arthritis category. Moreover, a significant portion of patients (up to 50% of children in some studies) do not exhibit any arthritis.
Still was a pediatrician, and thus his work included only children. In the decades between his initial description and its connection to an adult disease, the pediatric-only Still’s disease went through a succession of names as the field of pediatrics developed internationally. It is currently known as Systemic Juvenile Idiopathic Arthritis (SJIA).
Looking back at the extraordinary detail in his work, there were two observations by Still that stood out to us as patients with the disease:
Sweating is often profuse, and not related to temperature.On a Form of Chronic Joint Disease in Children pg. 5
Many patients experience hot flashes with profuse sweating any time of day while afebrile, however this symptom is not discussed in the modern literature.
Curiously enough, some accidental complications have been followed by marked improvement; thus I have known measles, scarlet fever, and catarrhal jaundice, to be each followed by distinct improvement of the joint symptoms.On a Form of Chronic Joint Disease in Children pg. 6
Sir Still’s work reads like many of his Victorian era colleagues, embedded with odd flourishes based on classic Greek and Latin medical texts. Medical language is derived from an odd fusion of historical Greek and Latin, which follows grammatical tenses for the order of sentence structures much like Yoda from Star Wars. That said, from our modern frame of reference it is clear that the association with infections is not accidental, but rather correlational.
While the infectious agents that cause measles and scarlet fever are vastly different, the only tool Still had to separate them was his clinical observation. However, as Still’s disease can easily mimic both measles and scarlet fever, it is unclear from our perspective if Still is noting symptoms improved post-infection or if symptoms improved post-disease flare. More to the point, catarrhal jaundice, which would now be some form of liver disease based on testing, would have been diagnosed based on the presence of hepatomegaly. The liver is a targeted organ of Still’s pathology. Thus, Still might have been describing the early science behind the correlation.
In our past articles, we have discussed the association of Still’s disease flares (cytokine storms) with viral and bacterial infections. It is fascinating to look back at the conversation of pathogen-driven onset and exacerbation of Still’s disease since its inception. It appears Sir Still’s findings were inline with modern literature correlating pathogen exposure with cytokine storms or even MAS. However, again with historical Victorian etiquette-driven contextual writing, it is rather hard to discern the disposition of some of his findings and causational outcomes.
Calling All Adult Patients!
It took almost 50 years before anyone recognized a similar disease in adults, although early authors of research were unaware of what are now known diagnostic markers. Described in 1944 by Wissler and 1946 by Fanconi, Wissler-Fanconi Syndrome appears to paint a picture of what we would now call Adult Onset Still’s Disease (AOSD). Though it was not until 1971 that Dr. E.G. Bywaters put the whole picture together.
Bywaters work, Still’s disease in the Adult, is based on his observations of 14 cases of adult onset of the formerly pediatric-only Still’s disease. Bywaters carefully draws a connection between Sir Still’s earlier work in pediatrics, Wissler-Fanconi Syndrome, and the new adult-onset Still’s disease he observed in patients. Bywaters’ work is an illuminating marriage of science and history.
It is clear from a modern perspective that Bywaters is wrestling with observations of autoinflammatory disease decades beyond what was understood when Still’s disease in the Adult was published. In a stroke of largely unappreciated genius, Bywaters appears to recognize the similarities with Still’s disease and Muckle-Wells Syndrome (now known as Cryopyrin Associated Periodic Syndrome, or CAPS, another autoinflammatory syndrome) as well as the marked distinction in pathology and probable causation.
The Birth of Evidence-Based Practice
The medical establishment underwent a radical change in the second half of the 20th century with the birth of the concept of Evidence Based Practice (EBP). The older system of diagnosis and treatment in place was based solely on clinical experience, and did not include wider statistical data as part of the decision making process. By the late 1980s enough data was available that EBP became more predominant, but it was the landmark 1999 Institute of Medicine’s (IOM) report To Err is Human, describing the concepts of medication anddiagnostic errors linked to scientific mitigated observations, that made EBP the resolute gold standard of modern medicine. The landmark 1999 IOM report also based EBP on the benchmarked safety standards of the aviation industry.
The different criteria used to diagnose Still’s disease arose out of the need to find evidence-based solutions to diagnose rheumatological (and other) diseases. Limited historical rheumatology criteria was injected into the American College of Rheumatology (ACR)’s new criteria to add a measure of objectivity into diagnosis. Autoinflammatory diseases, to date, hold little relevance in the ACR diagnostic criteria. However, as we now know, Still’s is a diagnosis of exclusion with pathophysiology based in autoinflammation and innate immune dysregulation. Thus, serology of positive autoantibodies does not discern autoinflammatory diagnoses.
Autoinflammation is the incorrect activation of the innate immune system, releasing inflammatory mediators (cytokines, eicosanoids, etc), while simultaneously disarming key components of the immune system leading to immunocompromised states. As a disease class, autoinflammatory diseases are very new, having only been recognized in the late 90s with the discovery of the monogenic basis of Familial Mediterrean Fever, Muckle-Wells Syndrome/CAPS, and other diseases.
In the years since autoinflammatory diseases were discovered as a disease class, a number of entities have been moved into the class. The majority of diseases are based in clear genetic causation and heritability, which often means disease clusters are found in extended family groups. Finally in 2012, a pair of researchers asked the question, Is Still’s Disease an Autoinflammatory Syndrome? This most recent research revolutionized how we think about Still’s disease.