CHAPTER 23
Adult-Onset Still’s Disease
JOHN M. ESDAILE MD, MPH
䊏 Diagnosis is one of exclusion and is suggested by the
characteristic febrile pattern, evanescent rash,
organomegaly, elevated white blood cell count, and
a markedly elevated serum ferritin, serum IL-18 when
available, and a reduced glycosylated fraction of
ferritin.
䊏 A predominance of T-helper cell (Th1) cytokines such
as interleukin (IL)-2, IL-6, IL-18, interferon gamma,
ADULT STILL’S DISEASE
The clinical features of adult Still’s disease resemble
the systemic form of juvenile rheumatoid arthritis. The
disorder is rare, affects both genders equally, and exists
worldwide. The majority of patients are 16 to 35 years
of age (1).
Pathogenesis
The etiology of adult Still’s disease is unknown. Studies
of linkage to human leukocyte antigens (HLA) have
been inconclusive (2). It has been suggested that immune
complexes play a pathogenic role, but this suspicion has
not been confirmed (1,2). The principal hypothesis is
that Still’s disease results from a virus or other infec-
tious agent, but study results lack consistency (1). Preg-
nancy or use of female hormones have not been
associated with the development of Still’s disease (3).
The possible role of stress as an inducing phenomenon
has been raised, but lacks confirmation (3).
A predominance of T-helper (Th1) cytokines have
been reported in the blood and tissues of persons
with active adult Still’s disease (4). Increased levels of
interleukin (IL)-2, IL-6, IL-18, interferon gamma, and
tumor necrosis factor (TNF) alpha have been described
(1,4–6). Alterations in cytokines may be important
in the pathogenesis of the disorder and in its future
treatment.
tumor necrosis factor (TNF) alpha have been reported
in persons with active adult Still’s disease and
therapy against these cytokines is an active area of
investigation.
䊏 Most have a chronic course with morbidity arising
from a polyarthritis.
Clinical, Laboratory, and
Radiographic Findings
The clinical manifestations and laboratory findings of
adult Still’s disease (2,7) are summarized in Table 23-1.
Usually the initial symptom is sudden onset of a high
spiking fever. The fever spikes once daily (rarely, twice
daily), usually in the evening, and the temperature
returns to normal in 80% of patients untreated with
antipyretics. Arthralgia and severe myalgia are univer-
sal. Arthritis is almost universal but may be mild and
overlooked by a physician whose attention is drawn to
more dramatic manifestations. Initially the arthritis
affects only a few joints but may then evolve into poly-
articular disease. The most commonly affected joints
are the knee (84%) and wrist (74%). The ankle, shoul-
der, elbow, and proximal interphalangeal joints are
involved in one half of patients and the metacarpopha-
langeal joints are involved in one third of patients.
Involvement of the distal interphalangeal joints in one-
fifth of patients is notable (2,8). Still’s rash, present in
more than 85% of patients, is almost pathognomonic.
The rash is salmon pink, macular or maculopapular,
frequently evanescent, and often occurs with the evening
fever spike. Because the rash may not be noticed by the
patient, a check during evening rounds can lead to the
detection of this almost diagnostic finding. The rash is
most common on the trunk and proximal extremities,
but is present on the face in 15% of patients. It can be
455
456 JOHN M. ESDAILE

TABLE 23-1. CLINICAL MANIFESTATIONS AND LABORATORY TESTS IN ADULT

STILL’S DISEASE.a
CHARACTERISTICb PATIENTS POSITIVE/PATIENTS TOTAL PERCENTAGE

Clinical manifestations
Female 145/283 51
Childhood episode (≤15 years) 38/236 16
Onset 16–35 years 178/233 76
Arthralgia 282/283 100
Arthritis 249/265 94
Fever ≥ 39°C 258/266 97
Fever ≥ 39.5°C 54/62 87
Sore throat 57/62 92
JRA rash 248/281 88
Myalgia 52/62 84
Weight loss ≥ 10% 41/54 76
Lymphadenopathy 167/264 63
Splenomegaly 138/265 52
Abdominal pain 30/62 48
Hepatomegaly 108/258 42
Pleuritis 79/259 31
Pericarditis 75/254 30
Pneumonitis 17/62 27
Alopecia 15/62 24

Laboratory tests
Elevated ESR 265/267 99
WBC ≥ 10,000 cells/mm3 228/248 92
WBC ≥ 15,000 cells/mm3 50/62 81
Neutrophils ≥ 80% 55/62 88
Serum albumin < 3.5 g/dL 143/177 81
Elevated hepatic enzymesb 169/232 73
Anemia (hemoglobin ≤ 10 g/dL) 159/233 68
Platelets ≥ 400,000/mm3 37/60 62
Negative antinuclear antibody test 256/278 92
Negative rheumatoid factor 259/280 93

ABBREVIATIONS: ESR, erythrocyte sedimentation rate; JRA, juvenile rheumatoid arthritis; WBC, white blood cell.
a
Data from Pouchot and colleagues(2), including patients reviewed by Ohta and colleagues (J Rheumatol
1987;14:1139–1146). Data for fever ≥ 39.5°C, sore throat, myalgia, weight loss, abdominal pain, pneumonitis,
alopecia, WBC ≥ 15,000 cells/mm3, neutrophils, and platelets are from Pouchot and colleagues only, as these data
were likely underreported in early studies.
b
Any elevated liver function test.

precipitated by mechanical irritation from clothing,
rubbing (Koebner’s phenomenon), or a hot bath. The
rash may be mildly pruritic.
An elevated erythrocyte sedimentation rate is uni-
versal. Leukocytosis is present in 90% of cases, and in
80% the white blood cell count is 15,000/mm3 or more.
The liver function tests may be elevated in up to three
fourths of patients (1,2,9). Anemia, sometimes pro-
found, is common. Rheumatoid factor and antinuclear
antibody tests are generally negative and, if present, are
of low titer. Synovial and serosal fluids are inflamma-
tory with a predominance of neutrophils (2).
Radiographic findings at presentation are nonspe-
cific. Early in the disease course, soft tissue swelling and
periarticular osteoporosis may be found. With time, car-
tilage narrowing or erosion develop in most patients.
Characteristic radiographic findings are typically found
in the wrist, including nonerosive narrowing of the car-
pometacarpal and intercarpal joints, which progresses
to bony ankylosis (2,10,11).
Diagnosis
Although several sets of diagnostic criteria have been
proposed (8,12,13), the criteria of Cush and colleagues
(8) are a practical guide (Table 23-2). It is important to
note that most patients do not present with the full-
blown syndrome. Fever is the most common first mani-
festation, and other features develop over a period of a
couple of weeks or occasionally months. A patient with
high daily fever spikes, severe myalgia, arthralgia,
arthritis, Still’s rash, and leukocytosis (frequently in
combination with other manifestations outlined in Table
 C H A P T E R 2 3 • A D U L T - O N S E T S T I L L ’ S D I S E A S E 457

TABLE 23-2. CRITERIA FOR THE DIAGNOSIS OF
ADULT STILL’S DISEASE.
A diagnosis of adult Still’s disease requires the presence of all of
the following:
Fever ≥ 39°C (102.2°F)
Arthralgia or arthritis
Rheumatoid factor < 1 : 80
Antinuclear antibody < 1 : 100
In addition, any two of the following are required:
White blood cell count ≥ 15,000 cells/mm3
Still’s rash
Pleuritis or pericarditis
Hepatomegaly or splenomegaly or generalized
lymphadenopathy
SOURCE: From Cush JJ, Medsger TA Jr, Christy WC, et al. Arthritis Rheum
1987;30:186–194, by permission of Arthritis and Rheumatism.
23-1) is unlikely to have anything other than adult Still’s
disease. Thus, this diagnosis should top the differential
diagnosis list (Table 23-3). Most other diagnoses can be
excluded on clinical grounds or by simple diagnostic
tests. Recently, a markedly elevated serum ferritin and
a reduced glycosylated fraction of ferritin has been
proposed as suggesting Still’s disease (12,14,15). The
elevated ferritin likely results from the increased inflam-
matory cytokines and it has been suggested that IL-18
may be a better marker.
with adult Still’s disease were lower than in other chronic
rheumatic diseases. Educational attainment, occupa-
tional prestige, social functioning, and family income
did not differ between the Still’s patients and the con-
trols (16). The results suggest that patients with Still’s
disease are remarkably resilient in overcoming handi-
caps. However, premature death may be slightly
increased above that expected. Causes of fatality include
hepatic failure, disseminated intravascular coagulation,
amyloidosis, and sepsis, all of which were likely due to
the Still’s disease (1,2,7,8).
Treatment
Acute Disease
Nonsteroidal anti-inflammatory drugs (NSAIDs),
including aspirin, are first-line treatment. Response to
NSAIDs may be slow but responders usually have a
good prognosis (2).
A major concern with NSAID therapy has been
severe hepatotoxicity. Liver function test abnormalities,
a common finding on presentation, are likely an integral
part of the disease and may return to normal despite
continued NSAID therapy (2). However, frequent
TABLE 23-3. DIFFERENTIAL DIAGNOSIS OF ADULT
STILL’S DISEASE.

Disease Course and Outcome Granulomatous disorders

Sarcoidosis
Approximately one fifth of patients with Still’s disease Idiopathic granulomatosis hepatitis
experience long-term remission within 1 year. One- Crohn’s disease
third of patients have a complete remission followed by Vasculitis
one or more relapses. The timing of relapse is unpre- Serum sickness
dictable, although relapse tends to be less severe and Polyarteritis nodosa
Wegener’s granulomatosis
of shorter duration than the initial episode (2,8). The
Thrombotic thrombocytopenic purpura
remaining patients have a chronic disease course. The Takayasu’s arteritis
principal problem is chronic arthritis, and some patients
with severe involvement of the hips and, to a lesser Infection
Viral infection (e.g., hepatitis B, rubella, parvovirus, Coxsackie
extent, the knees have required total joint replacement
virus, Epstein–Barr, cytomegalovirus, human immunodefi-
(2,8). ciency virus)
The presence of polyarthritis (four or more joints Subacute bacterial endocarditis
involved) or root joint involvement (shoulders or hips) Chronic meningococcemia
has been identified as markers for a chronic disease Gonococcemia
Tuberculosis
course in a number of studies (2,8). A prior episode in
Lyme disease
childhood (which occurs in about 1 of 6 patients) and a Syphilis
need for more than 2 years of therapy with systemic Rheumatic fever 23
corticosteroids may also be poor prognostic markers
Malignancy
(8).
Leukemia
Overall, the prognosis is good. A recent controlled Lymphoma
study noted that an average of 10 years after diagnosis, Angioblastic lymphadenopathy
patients with adult Still’s disease had significantly higher
Connective tissue disease
levels of pain, physical disability, and psychologic dis-
Systemic lupus erythematosus
ability than their unaffected siblings of the same gender. Mixed connective tissue disease
However, the levels of pain and disability in patients
458 JOHN M. ESDAILE
monitoring of liver function, even after hospital dis-
charge, is mandatory for patients receiving NSAIDs.
NSAIDs may also increase the risk of intravascular
coagulopathy.
In patients who fail to respond to NSAIDs and those
with severe disease require systemic intravascular coag-
ulopathy, rising values on liver function tests during
NSAID treatment, and individuals who do not respond
to NSAIDs may require corticosteriod treatment. Gen-
erally, prednisone in a dose of 0.5 to 1.0 mg/kg/day is
needed initially, but relapse can occur with tapering and
continued treatment does not prevent progressive
destructive arthropathy (1,2). Intravenous pulse meth-
ylprednisolone has been used for life-threatening acute
disease (2).
Chronic Disease
No controlled studies of second-line agents for the
treatment of Still’s disease have been published. The
most common cause of chronicity is arthritis. Low-dose
weekly methotrexate in doses similar to that used in
adult rheumatoid arthritis has been used to control both
chronic arthritis and chronic systemic disease (1,17,18).
While methotrexate is potentially hepatotoxic, this
agent is being used increasingly. Approximately two
thirds of patients will respond to methotrexate (17).
Mild chronic systemic disease (e.g., fatigue, fever, rash,
serositis) may also respond to hydroxychloroquine and
this agent can be combined with methotrexate. Increased
toxicity with sulfasalazine has been reported, thereby
limiting its use (19).
Immunosuppressive agents, including azathioprine,
cyclophosphamide, and, most recently, cyclosporin A
(20), have been used in resistant cases. Intravenous
immunoglobulin (21) has been used, alone (21) or in
combination with mycophenolate mofetil (22), but its
use is controversial.
Elevated serum levels of cytokines including TNF
alpha, IL-6, interferon gamma, and especially IL-18
(1,4–6), although nonspecific, have suggested the possi-
ble benefit of anticytokine therapies. TNF-alpha block-
ing treatments, especially infliximab, appear effective
(23,24), although a recent report noted that they were
not continued in 17 of 20 patients because of adverse
effects or loss of efficacy (25). Anakinra (100 mg subcu-
taneous daily) shows great promise as a treatment. It
has been reported in a small number of cases to have
dramatic benefits (1,26,27). A decade after disease
onset, approximately one half of patients require
second-line agents, and one third of these require low
dose corticosteroids (16).
Adult Still’s disease affects primarily young adults at
a time when they are completing their education, start-
ing a career, or starting a family, which can make it
particularly devastating. Physiotherapists, occupational
therapists, psychologists, or arthritis support groups
may all be needed to care for individual patients. A
knowledgeable, caring physician can make a tremen-
dous difference. It is important to realize that Still’s
disease can remit even years after onset and that the
vast majority of patients are leading remarkably full
lives a decade after the onset of the disease.
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