Running head: ADULT-ONSET STILL'S DISEASE
Adult-Onset Still's Disease
Crystal Gilligan
Wright State University
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ADULT-ONSET STILL'S DISEASE
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Adult-Onset Still's Disease
Significance of the Problem
Adult-onset Still’s disease (AOSD) is a rare inflammatory disease that was first described
in 1971 by a man named Eric Bywaters in which he defined adults with similar signs and
symptoms as pediatric Still’s disease (Owlia & Mehrpoor, 2009). The rarity of this disease is
what makes it important for practitioners to be able to recognize the signs and symptoms of the
disease because the sooner it is diagnosed the better the outcomes of this disease (GerfaudValentin et al., 2014). Usually, this disease is benign and self-limiting; however, for some of the
patients that are inflicted with the disease it will become chronic leading to the development of
complications that lead to a poor prognosis for the patient (Jung, Park, Ha, Lee, & Lee, 2010).
Many times it presents like an infection with a high fever, rash, sore throat, lymphadenopathy,
and myalgia (Rau et al., 2010). This fever of unknown origin (FOU) would be confusing due to
the fact the signs point to an infection, but when an infection is not found valuable time is lost.
Discussion of the Problem
The problem with AOSD is diagnosing it with the vague symptomatology that presents,
and determining its severity such as its disease course. The vague signs and symptoms could
lead the practitioner to order various tests and bloodwork to diagnose the patient appearing to
have an infection, malignancy, or other systemic inflammatory disease. From the literature
review more women than men are affected with AOSD, and are diagnosed around age of midtwenties to early fifties. There are three courses this disease can take. The first one is selflimiting and is also referred to as the acute or monocyclic systemic course; the second is referred
to as polycyclic systemic course or intermittent. The third disease course is referred to as the
chronic articular course and is often the worst of the courses due to life-threatening
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complications (Gerfaud-Valentin et al., 2014). Such complications include macrophage
activation syndrome (MAS), reactive hemophagocytic syndrome (RHS), disseminated
intravascular coagulopathy (DIC), pericarditis, cardiac tamponade, hepatic failure, and
respiratory failure resulting in death (Jung et al., 2010; Owlia & Mehrpoor, 2009).
AOSD is a disease of exclusion; however, the stage or chronicity of the disease may be defined
by some markers described in the literature review.
Over the years there have been criteria such as the Yamaguchi criteria, Fautrel criteria,
and Pouchot score to aid in the diagnosis and severity of the disease. Yamaguchi’s criteria had a
sensitivity of 79.2% and 93.8% specificity (Fautrel et al., 2002), but this was before the
discovery of high ferritin levels and low glycosylated fraction of ferritin that are indicative of
AOSD ((Fautrel et al., 2002; Gerfaud-Valentin et al., 2014; Rau et al., 2010). Yamaguchi’s
criteria are used more often in the studies reviewed than the other criteria defined.
Yamaguchi’s criteria consist of excluding other disease processes first such as infections,
malignancies, and other rheumatoid diseases. There are major and minor criteria the patient
must have at least five or more of the criteria of which two or more must be from the major
criteria (Lichauco, Sinha, & Barland, 2015). The diseases that must be excluded include
infections, granulomatous disorders, malignancies, and connective tissues diseases (Lichauco et
al., 2015). The patient must have two or more of the major criteria which include a daily spike in
fever (39º Celsius or 102.2 º Fahrenheit or higher) over a week or longer, arthragias enduring two
weeks or longer, the characteristic salmon rash, or leukocytosis of 10,000 mm/³ or greater with
greater that 80% granulocytes. The minor criteria include sore throat, lymphadenopathy and/or
splenomegaly, liver dysfunction, or negative rheumatoid factor and negative antinuclear antibody
(ANA) (Lichauco et al., 2015).
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Fautrel’s criteria were similar to Yamaguchi’s, but it did not require exclusion criteria of
diseases. When evaluated the sensitivity was 80.6% and the specificity was 98.5% (Fautrel et
al., 2002). This proposed tool was divided into major and minor criteria like Yamaguchi’s. One
must have four or more major criteria or three major criteria plus two minor criteria to be
diagnosed with AOSD. The major criteria included a fever spike (39º Celsius or 102.2 º
Fahrenheit or higher), arthralgia, transient erythema, pharyngitis, granulocytes of 80% or greater,
or a glycosylated ferritin of 20% or less. The minor criteria included maculopapular rash or
leukocytosis of 10,000 mm/³ or greater (Fautrel et al., 2002).
The Pouchot score aids in uncovering the severity/activity of the disease. It includes
clinical signs/symptoms and laboratory findings which included fever, rash, sore throat, arthritis,
myalgia, pleuritis, pericarditis, pneumonia, lymphadenopathy, hepatomegaly or abnormal liver
function tests, leukocytosis (greater than 15,000/µl), and was modified to include serum ferritin
greater than 3000/µl due to recent publications observing high serum ferritin levels in AOSD
(Rau et al., 2010). The original criteria included splenomegaly and abdominal pain; however
arthritis and serum ferritin greater than or equal to 3000/ µl took their place when modified by
Rau et al., 2010. The patient gets a point for every criterion met for a score of 0-12. If the
patient had four or greater of the above criteria the sensitivity was 92% and the specificity was
93% for a diagnosis of active AOSD versus sepsis (Rau et al., 2010).
Literature Review
A thorough search of the literature revealed multiple studies that dealt with different
markers for AOSD. The studies included two retrospective reviews, a case control study, and a
cohort study. No systematic reviews or randomized control trials were found. The first article
reviewed was a retrospective review of medical records of 71 AOSD patients to identify a
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marker in patients with AOSD that would aid in defining the course of the disease (Lee, Park,
Song, & Lee, 2009). The study took place at Yonsei University Severance Hospital and ChungAng University Hospital from January 2000 to May 2007 (Lee, Park, Song, & Lee, 2009). Of
the 71 patients, 63 were women and eight were men in which the Yamaguchi criteria were used
and all patients satisfied the criteria with other disease processes being ruled out. The mean age
of the patients was 39.7 plus or minus 13.5 years (Lee et al., 2009). In this study the three
clinical manifestations that were seen the most included fever seen in 100% (71) of the patients,
arthralgia seen in 84.5% (60) of the patients, and the typical salmon-pink maculopapular rash
seen in 84.3% (59) of the patients. The disease course for the patients included 42.3% (30) had
the self-limiting course, 12.7% (9) had the intermittent course, 32.4% (23) developed the chronic
disease course, and 12.7% (9) of the patients died. The number one cause of death being DIC
with 6 of the patients and the other causes included fulminant hepatitis, pulmonary hypertension,
and intraperitoneal hemorrhage (Lee et al., 2009). The major findings of this study relate to the
level of ferritin could be a marker for the chronic disease course. However, it was noted that the
extreme value of ferritin such as greater than 4120 ng/mL did not have any significance with the
chronicity of the disease, but the mid-range level 784-4120 ng/ml did show significance with the
chronic disease (Lee et al., 2009). Although, the study had limitations such as the retrospective
design that was limited to chart reviews, the small number of patients, and that the data was only
collected from two locations. In practice, once a patient has been diagnosed with AOSD a
ferritin level could help the practitioner in discovering the chronicity of the disease.
Another article reviewed brought up the marker of serum calprotectin for AOSD activity
and severity to determine if there is any correlation due to serum calprotectin increasing with
inflammatory diseases(Jung et al., 2010). The study was a case control that included 25 Korean
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patients with AOSD (21 women, and 4 men) with the mean age of 37 years old, and the control
included 30 healthy people (24 women, and 6 men) with the mean age of 36 years old. The
Yamaguchi criteria were used for the diagnosis of the AOSD patients and the severity of the
disease was classified in accordance to the original Pouchot criteria. The disease activity was
measured with the markers of the white blood cell (WBC) count, erythrocyte sedimentation rate
(ESR), C-reactive protein (CRP), lactate dehydrogenase (LDH), liver function tests such as
aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and serum ferritin levels.
Also, these values were tested to determine if any correlation was seen with the serum
calprotectin level. The patients were from the Severance Hospital, Yonsei University College of
Medicine in Seoul, Korea over a period of eight years (Jung et al., 2010). Blood samples were
taken from the patients with AOSD and from the healthy control participants. Calprotectin
concentration levels were obtained by using the enzyme-linked immunosorbent assay (ELISA).
Of the 25 patients with AOSD, 21 were in active AOSD and untreated at the time, and four were
being treated and inactive at time of the blood sample. After the 21 patients in the active disease
state were treated, only follow-up samples from six of them were attained. This study found that
fever (n= 21), rash (n= 17), and arthritis (n=16) were the three highest clinical manifestations of
AOSD. Also, AOSD patients in the active untreated state had a significantly higher serum
calprotectin mean level of 61 ng/mL than the control mean level of 35 ng/mL. The six patients
that had follow-up calprotectin levels drawn showed a substantial decrease in the level. No
significance was seen with patients in the inactive treated state of AOSD versus the control.
With the disease activity level, there was a strong correlation with increased calprotectin levels
and increased WBC count, CRP, LDH, AST, and serum ferritin. No significant correlation was
seen with calprotectin levels and ESR or ALT. There was a significant correlation between an
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increased level of serum calprotectin level and the disease severity score described by Pouchot.
Therefore, in clinical practice a serum calprotectin level could help determine if AOSD is active,
how severe the disease courses is, and monitor treatment (Jung et al., 2010). Limitations of this
study include the small number of the study and only one location was used.
Another article reviewed aimed its focus towards the biomarker interleukin 18 (IL-18),
and if it can be used to differentiate between AOSD and sepsis (Priori et al., 2014). The
population of the study consisted of 39 patients with AOSD diagnosed using the Yamaguchi
criteria, and 18 patients with sepsis of which two of the 18 septic patients met the Yamaguchi
criteria of AOSD. In the cohort of AOSD patients 25 were female and 14 were male with the
mean age of 35, and in the cohort of septic patients eight were female and ten were male with the
mean age of 54 (Priori et al., 2014). The cohorts were selected using the Yamaguchi criteria for
AOSD, and Pouchot’s and Rau’s criteria were used to evaluate their disease activity. The
American College of Chest Physicians/Society of Critical Care Medicine criteria for sepsis was
used to diagnose the septic patients. Enzyme-linked immunosorbent assay (ELISA) was used to
detect the levels of IL-18. In AOSD the three most common clinical manifestations include
fever (n=39), rash (n=30), and arthritis (n=25). In sepsis the three most common clinical
manifestations include fever (n=18), hepatomegaly/increased liver enzymes (n=8), and
splenomegaly (n=6). The major finding was the mean number of IL-18 in AOSD patients was
1044 pg/mL and the mean number of IL-18 in septic patients was 91 which is significantly lower
and these were both clinically significant (Priori et al., 2014). This is useful to a practitioner
when trying to figure out if the disease process is AOSD or sepsis to draw an IL-18 level. The
limitation of this article is the sample size of both cohorts.
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An original article that retrospectively studied liver abnormalities in AOSD was
reviewed. This study aimed at analyzing liver abnormalities clinically and laboratory results in
Chinese AOSD patients (Zhu, Liu, Liu, Xie, & Shi, 2009). The population of the study was 77
hospitalized Chinese patients in a West China hospital over the span of four years from 2003 to
2007. Of the 77 patients 54 were women and 23 were men with the mean age of diagnosis being
33 years old. The Yamaguchi criteria were used to diagnose AOSD. Patients with a history of
alcohol abuse, admitted for infection, have a malignancy or other rheumatic disorders were
excluded from the study (Zhu et al., 2009). This was a retrospective cohort study that reviewed
charts of the patients. The study defined liver involvement by having an elevation in the at least
two or more of the liver enzymes with one having to be alanine transaminase (ALT) or aspartate
transaminase (AST), and/or having hepatomegaly via ultrasound. There were five liver enzymes
studied including ALT, AST, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and
gamma-glutamyltransferase (GGT). The study defined acute liver failure as transaminases
elevated greater than five times of the upper normal limit (cytolysis), albumin less than 30 g/L,
hyperbilirubinemia, and prothrombin time greater than 1.3 times the control (Zhu et al., 2009).
The three clinical manifestations that were seen the most were fever (n=74), arthralgia/arthritis
(n=67), and the typical rash (n=66). The results of this study showed that there is a correlation
between AOSD and liver abnormalities. Abnormally elevated transaminase levels were
observed in 62% (n=48) of the 77, nine had hepatomegaly, increased ALP was observed in 25
patients, elevated GGT was observed in 37 of the patients, and elevated LDH was seen in 49 of
the patients. In practice, this study shows practitioners to be aware that patients with AOSD may
develop or already have some form of liver abnormality and to assess liver function in these
patients. Many of these patients were taking medications such as nonsteroidal anti-inflammatory
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drugs (NSAIDS), immunosuppressant, and antibiotics for treatment and one could hypothesize
the liver abnormalities were due to the medications (Zhu, Liu, Liu, Xie, & Shi, 2009). Other
limitations of this study include the fact it only involves the Chinese population, it’s a
retrospective chart review, and the number of the patients.
Summary
In summary of the literature review, the studies brought awareness that in every study the
most prevalent clinical manifestations of the disease are fever, the typical salmon rash, and
arthritis/arthralgia. This disease can mimic an infectious disease so for a practitioner it may be
hard to diagnose especially since it is still a disease of exclusion. However, these studies have
shown that there are markers available to better aid in the diagnosis and severity of the disease.
Such as obtaining a ferritin level could aid in diagnosing the disease, if its active, and if it is a
chronic disease giving warning to watch out for certain complications such as DIC, pericarditis,
macrophage activation syndrome (MAS), or reactive hemophagocytic syndrome (RHS) (Lee et
al., 2009).
Obtaining a serum calprotectin level could aid in determining if AOSD is active, the
disease severity, and help monitor treatment (Jung et al., 2010). Interleukin-18 has been brought
to the forefront by a study showing how AOSD will yield a significantly higher IL-18 than sepsis
will; therefore, aiding in differentiating AOSD from sepsis (Priori et al., 2014). Lastly, it has
been determined that many AOSD patients develop liver abnormalities so a liver abnormality in
the setting of a fever, salmon rash, and arthritis/arthralgia could lead one to suspect AOSD.
Also, in the setting of AOSD the practitioner should be aware of possible liver abnormalities and
to check liver enzymes and perform an ultrasound of the liver (Zhu et al., 2009).
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Role of the AG-ACNP
The Adult Gerontology-Acute Care Nurse Practitioner (AG-ACNP) will be up to date on
the clinical manifestations and certain biomarkers that can be useful in diagnosing Adult-onset
Still’s disease (AOSD). The AG-ACNP should be able to recognize three biggest clinical
manifestations of AOSD which include a daily fever (usually greater than 39º C), salmon colored
rash, and arthritis/arthralgia (Imboden, 2013). The AG-ACNP will know the laboratory work
needed to aid in the diagnosis such as complete blood count, liver profile, serum ferritin, serum
calprotectin, interleukin-18, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR)
(Jung et al., 2010; Lee et al., 2009; Priori et al., 2014; Zhu et al., 2009). The typical rash that is
described is salmon colored one that occurs most often on trunk with may come and go with the
fever (Imboden, 2013). Using the data gathered the AG-ACNP will know complications of the
chronic disease course such as disseminated intravascular coagulopathy (DIC), pericarditis,
macrophage activation syndrome (MAS), reactive hemophagocytic syndrome (RHS), cardiac
tamponade, liver or respiratory failure (Jung et al., 2010; Owlia & Mehrpoor, 2009).
The mean age for diagnosis of AOSD is around 35 years old (Imboden, 2013).
Nevertheless, the older adult may be newly diagnosed with it. Considerations with this
population are that their fever may not be as high or inflammatory markers may not be as high
(WBC, ESR, CRP, and ferritin). However, there were no studies that were reviewed specifically
spoke to the considerations of the elderly. More evidence in this population needs to be
obtained.
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Conclusion
Although, there have been many studies on Adult-onset Still’s disease (AOSD) since its
discovery in 1971 the studies are limited by population and by number of subjects. AOSD is rare
and many of the studies are conducted over years just to have a number of 35-40 subjects. Also,
it remains a disease of exclusion even with the Yamaguchi criteria used for diagnosis. Its rarity
has limited its research capabilities. Many of the studies are conducted in Asia; therefore,
studies in other populations may have different conclusions.
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