Evanescent Salmon-Colored Rash
What's shared between Juvenile idiopathic arthritis and Adult-onset Still's disease, sometimes, maybe.
I’ve been hard at work on the Diagnosis Description for Juvenile idiopathic arthritis/Adult-onset Still’s disease. Please check it out when you get a chance. I have listed them as synonyms, which may lead close readers to consider the innate contradiction in terms of Juvenile and Adult naming conventions listed synonymously. How can an age-divided classification be synonymous? Does the scientific evidence show that they’re both the same disease? Predictably, it’s complicated. And in this particular case, it’s very complicated.
In the search for a comprehensive list of autoimmune disorders, I found that the Global Autoimmune Institute lists Juvenile idiopathic arthritis and Adult-onset Still’s disease as synonymous under “J”. The Autoimmune Association lists “Juvenile arthritis” separately under “J” and “Adult Still’s Disease” under “A.” To compile an expansive list, I had a choice to make. List these two diagnoses together or list them separately. There were some list choices that made me consider the Global Autoimmune Institute’s list to be more expansive, and perhaps, more accurate. The little bit of reading I did at the time indicated some overlap between the two diagnoses, despite the contradictions of age classification. I really didn’t want confusing redundancies in my list. I also wanted a prompt to explore the question of whether scientific research shows these diseases are based on the same underlying disease mechanisms. For all of these reasons, I chose the Global Autoimmune Institute’s choice of listing Juvenile idiopathic arthritis and Adult-onset Still’s disease together, and synonymously. Are they really synonymous? No. Except sort of, partly, maybe.
Juvenile idiopathic arthritis is a non-specific catchall name encompassing everyone under the age of 16, experiencing arthritis of unknown cause for six weeks or longer. The difficulty in studying this disparate basket of conditions is clear. In 2001, the International League of Associations for Rheumatology published study classification criteria for Juvenile idiopathic arthritis, dividing it into six subtypes: Oligoarthritis, Polyarthritis, Systemic-onset (Still’s Disease), Psoriatic arthritis (PsA), Enthesitis-related, and Undifferentiated. And here is where it becomes clear that only one sub-type of Juvenile idiopathic arthritis is provisionally considered synonymous with Adult-onset Still’s disease: Systemic-onset Juvenile idiopathic arthritis. The other sub-types are likely to be unrelated. A different organization is in the process of developing a new, “evidence-based” classification criteria for all of Juvenile idiopathic arthritis, implying that the criteria of the past 20 years is not evidence-based. You can read more about that in the Diagnosis Description, under “Study Classification Criteria.” For the rest of this post, I will only be addressing the systemic Juvenile idiopathic arthritis subtype and Adult-onset Still’s disease.
A brief background of systemic Juvenile idiopathic arthritis and Adult-onset Still’s disease
Still’s disease was originally described in children in 1897 by George F. Still as a “triad of daily spiking fever, arthritis and evanescent salmon-coloured skin rash.” In 1971, another physician described the characteristic triad in adults.
Other compelling commonalities between the two have been researched including
shared clinical manifestations: liver enlargement, spleen enlargement, lymph node enlargement, and inflammation of serous tissues, which can include areas around the lungs, heart, abdomen and abdominal organs
common laboratory abnormalities: increased white blood cell count, estimated sedimentation rate (ESR), C-reactive protein (CRP) and excess blood levels of ferritin (the storage form of iron)
similar disease course and prognosis
two distinct collections of signs and symptoms
a more systemic inflammatory collection of signs and symptoms
a more joint-specific collection of signs and symptoms
the development of a life-threatening complication called macrophage activation syndrome
the innate (immediate immune defense), as opposed to the adaptive (learned immune defense), immune system has been shown to play a prominent role in both disease processes, including
over expression of inflammatory cytokines (proteins that exert an effect on the immune system) IL-1, IL-6, IL-18 and calcium binding proteins
response to treatment that counteracts IL-1 and IL-6 overexpression
similar association with HLA alleles and cytokine gene variations (mutations)
(Ruscitti et. al, 2022)
Ruscitti et. al blow up their own study introduction (summarized above)
Their study looks at prevalence rates of clinical signs and symptoms of systemic Juvenile idiopathic arthritis and Adult-onset Still’s disease. The results are summarized in the table below.
Turns out, clinically, systemic Juvenile idiopathic arthritis and Adult-onset Still’s disease are really not that similar. The authors note
In conclusion, although our results support the hypothesis of sJIA and AOSD being a continuum of the same disease, we found remarkable disparities in the prevalence of some clinical manifestations between the two illnesses. Therapeutic approaches were also partly different. Large prospective cohort studies incorporating the newly proposed criteria for sJIA are needed to gain further insights into the relationship between the two conditions. The research agenda also calls for consensus efforts among paediatric and adult rheumatologists aimed to harmonize nomenclature, classification and treatment protocols.
(Ruscitti et. al, 2022)
What about the rash as a defining feature?
In an effort to understand whether these two diseases are the same, I focused on the evanescent salmon-colored rash because fever and arthritis are so common to so many different autoimmune diseases. The rash sounded very specific. Evanescent is, first of all, such a pretty word. I couldn’t help but envision the roiling, chaotic surface of a salmon run when I read “characteristic evanescent salmon-colored rash.” The classification criteria define “evanescent” as “non fixed.” The dictionary defines it as “disappearing.” The two mean different things to me—non fixed means traveling around the body, and disappearing means going away quickly.
I started looking at case studies for descriptions and pictures. No joke, every case study picture was a very different looking rash. On darker skin tones, it was not “salmon-colored.” Some case studies described how quickly the rash went away, some described the rash occurring with the fever, and resolving when the fever resolved, some omitted duration altogether. I began to wonder if there was a time frame on “evanescent.” 24 hours or less? Many rash types resolve over different time frames, depending on the person, and cause. Without objective criteria for diagnosis, who’s to say one doctor’s evanescent salmon-colored rash is consistent with another’s? The case studies indicated exactly the opposite.
Turns out there’s a study on atypical rashes in Adult-onset Still’s disease. Biopsy of non-evanescent, non-salmon-colored rashes show strikingly similar underlying tissue changes to the evanescent salmon-colored rashes biopsied. Further evidence that the characteristic rash is not the silver bullet connecting the two diseases.
And then there’s the surprise twist…
There’s evidence to suggest that neither one is autoimmune. Surprise! Because of the outsized role of the innate (immediate) immune system, instead of the adaptive (learned) immune system, in both the juvenile and adult form of Still’s disease, they may soon be classified as auto-inflammatory, instead of autoimmune. What’s the difference? You can read about it here. This German study already characterized Adult-onset Still’s disease as autoinflammatory.
The Global Autoimmune Institute charts auto inflammation and autoimmunity on a spectrum. To capture this difference, I’ll be revising “Multiple interactive immune system pathologies” in Organized Autoimmunity to include the distinction between innate and adaptive immune system pathologies.
Incidentally…
I’ll also revise the “I” designation that stands for “Inherited gene variations that cause increased susceptibility.” I realized that narrowing this category down to “Inherited” knocks the acquired UBA1 variants that cause disease in VEXAS out of my classification system, Organized Autoimmunity. It may yet be discovered that the acquisition of disease-causing variants on the gene UBA1 is a heritable condition, but that is not yet known. I am amending this category to be “Inherited and acquired gene variation that cause increased susceptibility.” I am still using “I” as the anchor for my acronym for the prosaic reason that it is a vowel, but also because it seems likely that autoimmune disease-causing genetic variations will be predominately inherited.
References
Narváez Garcia FJ, Pascual M, López de Recalde M, Juarez P, Morales-Ivorra I, Notario J, Jucglà A, Nolla JM. Adult-onset Still's disease with atypical cutaneous manifestations. Medicine (Baltimore). 2017 Mar;96(11):e6318. doi: 10.1097/MD.0000000000006318. PMID: 28296747; PMCID: PMC5369902.
Ruscitti P, Natoli V, Consolaro A, Caorsi R, Rosina S, Giancane G, Naddei R, Di Cola I, Di Muzio C, Berardicurti O, Iacono D, Pantano I, Rozza G, Rossi S, De Stefano L, Balduzzi S, Vitale A, Caso F, Costa L, Prete M, Navarini L, Iagnocco A, Atzeni F, Guggino G, Perosa F, Cantarini L, Frediani B, Montecucco C, Ciccia F, Cipriani P, Gattorno M, Giacomelli R, Ravelli A. Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease. Rheumatology (Oxford). 2022 Oct 6;61(10):4124-4129. doi: 10.1093/rheumatology/keac027. PMID: 35078234; PMCID: PMC9536787.