Clinical Manifestations and Diagnosis of Adult Still's Disease

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Clinical manifestations and diagnosis of adult Still's disease
Author: Lisa A Mandl, MD, MPH

Section Editor: James R O'Dell, MD
Deputy Editor: Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2018. | This topic last updated: Jul 24, 2017.
INTRODUCTION — Adult Still's disease (ASD) is an inflammatory disorder characterized by quotidian (daily)
fevers, arthritis, and an evanescent rash. First described in children by George Still in 1896, "Still's disease" has
become the eponymous term for systemic juvenile idiopathic arthritis [1]. In 1971, the term "adult Still's disease"
was used to describe a series of adult patients who had features similar to the children with systemic juvenile
idiopathic arthritis and did not fulfill criteria for classic rheumatoid arthritis (RA) [2]. (See "Systemic juvenile
idiopathic arthritis: Clinical manifestations and diagnosis".)
The clinical manifestations and diagnosis of ASD will be reviewed here. The treatment and prognosis of ASD are
presented separately. (See "Treatment of adult Still's disease".)
ETIOLOGY — The etiology of adult Still's disease (ASD) is unknown; both genetic factors and a variety of
infectious triggers have been suggested as important, but there has been no proof of an infectious etiology, and
the evidence supporting a role for genetic factors has been mixed. It is uncertain whether all patients with ASD
share the same etiopathogenic factors.
Proposed pathogens have included numerous viruses [3-7]; suspected bacterial pathogens include Yersinia
enterocolitica and Mycoplasma pneumoniae [5,8].
As an example of studies of the immunogenetics of ASD, in a series of 62 French patients, human leukocyte
antigen (HLA)-B17, -B18, -B35, and -DR2 were associated with ASD [9]. However, other studies have not
confirmed these findings [10]. Familial cases are uncommon, and there have been few reports of cases in twins
[11].
EPIDEMIOLOGY — Adult Still's disease is very uncommon. A retrospective French study estimated the annual
incidence of adult Still's disease (ASD) to be 0.16 cases per 100,000 people, with an equal distribution between
the sexes [12]. There is a bimodal age distribution, with one peak between the ages of 15 and 25 and the second
between the ages of 36 and 46. However, patients older than age 70 have been reported [13,14].
NATURAL HISTORY/DISEASE COURSE — The clinical course of adult Still's disease (ASD) can be divided into
three main patterns: monophasic (or monocyclic), intermittent, and chronic [15-17]. Approximately one-third of
patients fall into each category; however, in some studies the chronic articular pattern is more common. It is not
uncommon for the first two patterns (monophasic and intermittent) to evolve into the chronic articular pattern
[15,18].
● Monophasic pattern – Patients with monophasic ASD have a disease course that typically lasts only weeks
to months, completely resolving within less than a year in most patients. Systemic features, including fever,
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rash, serositis, and hepatosplenomegaly, predominate in this group.

● Intermittent pattern – Patients with intermittent
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or more disease flares, with or without
articular symptoms, with complete remissions between episodes lasting from weeks up to one or two years.
Although subsequent flares cannot be predicted, they tend to be less severe and of shorter duration than the
initial disease episode.
● Chronic pattern – Patients with chronic ASD have persistently active disease, in which articular symptoms
usually predominate. A destructive arthritis may occur in patients in this group.
CLINICAL FEATURES — The major clinical features of adult Still's disease (ASD) include fever, rash, and
arthritis or arthralgia; each occur in about 75 to 95 percent of patients (see 'Fever' below and 'Rash' below and
'Musculoskeletal' below) [19]. A majority of patients experienced each of a number of other symptoms or
findings, including myalgia, pharyngitis, lymphadenopathy, and splenomegaly. (See 'Musculoskeletal' below and
'Pharyngitis' below and 'Lymphadenopathy and splenomegaly' below.)
Other features that occur in a minority of patients include hepatomegaly, pleurisy, pericarditis, and abdominal
pain (see 'Liver disease' below and 'Cardiopulmonary disease' below). An infrequent but serious, potentially fatal
complication is the macrophage activation syndrome. (See 'Macrophage activation syndrome' below.)
Fever — The fever of ASD is usually quotidian (a daily recurring fever) or double-quotidian (two fever spikes per
day). Fever often precedes other manifestations. The temperature swings can be dramatic, with changes of 4ºC
(7.2ºF) occurring within four hours [1,20]. Complete defervescence is not always a characteristic of the quotidian
fevers in patients with ASD, as fever persists between spikes in approximately 20 percent of cases [9]. ASD can
also present as fever of unknown origin (FUO) and may be a common cause of FUO in some regions [21]. A
temperature of greater than 39.5ºC is associated more strongly with the monophasic pattern of ASD [17]. (See
"Etiologies of fever of unknown origin in adults" and 'Natural history/disease course' above.)
Rash — The classic skin rash of ASD is an evanescent, salmon-colored, macular or maculopapular cutaneous
eruption that is usually nonpruritic and tends to occur with the fever and disappear during afebrile periods. The
rash predominantly involves the trunk and extremities but can also involve the palms, the soles, and,
occasionally, the face. The Koebner phenomenon may be present, in which the cutaneous eruption can
sometimes be elicited by stroking the skin; the rash may sometimes be found on physical examination in areas
where there is pressure on the skin from tight clothing, such as at the beltline or beneath the breasts.
The cutaneous histopathology in ASD reveals nonspecific findings, including dermal edema and mild
perivascular inflammation in the superficial dermis, consisting primarily of lymphocytes and histiocytes (picture
1A-B). Immunofluorescence of the skin biopsy may show slight deposition of complement component 3 (C3) in
the blood vessel walls [22].
Musculoskeletal — Arthralgias or arthritis are universal features of ASD, and myalgias are common:
● Arthralgia and arthritis – Initially, the arthritis may be mild, transient, and oligoarticular. These
manifestations evolve over a period of months in some patients into a more severe and potentially
destructive polyarthritis [22]. The most commonly involved joints, in descending order, are the knees, wrists,
ankles, elbows, proximal interphalangeal joints, and shoulders. Fusion of the wrist joints is a characteristic of
ASD, although it occurs in only a minority of patients. Synovial fluid and tissue findings are consistent with
the inflammatory arthritis. (See 'Synovial fluid and tissue' below.)
In one study from Japan, which included 71 patients who satisfied criteria for ASD, but not rheumatoid
arthritis (RA) or other rheumatic diseases, 16 of 71 patients (23 percent) subsequently met the 1987
American College of Rheumatology (ACR) classification criteria for RA after a median follow-up of 18
months (range 6 to 132 months) [23]. Few of the patients had positive tests for rheumatoid factor (RF) or
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had lower levels of ferritin or interleukin (IL)-18
than the other patients with ASD.
● Myalgia – Myalgia is common, often worse with fever spikes, and can sometimes be severe and debilitating.
Muscle weakness is not present, but the serum creatinine kinase and aldolase concentrations can be slightly
elevated [9]. Electromyographic studies and muscle biopsy are usually normal or show a nonspecific
inflammatory myopathy.
Pharyngitis — A severe, nonsuppurative pharyngitis is common in ASD. In a literature review of 341 cases, sore
throat was noted in 69 percent [24]. Pharyngitis can occasionally precede the development of fever or rash and
can also occur with disease relapses. A study using magnetic resonance imaging (MRI) of the neck suggested
that cricothyroid perichondritis or aseptic nonexudative pharyngitis could be the etiology of the sore throat
[24,25].
Liver disease — Hepatomegaly is reported in a significant minority of patients; the frequency in different studies
ranges from 12 to 45 percent [19]. Modest elevations of serum hepatic aminotransferases and alkaline
phosphatase are even more common (see 'Liver function studies' below). These changes are generally related to
the disease, rather than drugs used to treat ASD, as they usually antedate the use of nonsteroidal
antiinflammatory drugs (NSAIDs) and improve as the disease responds [26].
At least eight cases of fulminant liver failure in association with ASD have been described, with four fatalities
[9,27]. All patients had been treated with NSAIDs. (See 'Macrophage activation syndrome' below.)
Cardiopulmonary disease — Pericarditis, pleural effusions, and transient pulmonary infiltrates have been
observed in 30 to 40 percent of patients with ASD [18,19,28]. Affected patients may complain of a slight cough,
pleuritic chest pain, or mild dyspnea. However, severe interstitial lung disease has also been described [29].
Uncommonly, some patients progress to acute respiratory distress syndrome [28,30,31]. Another rare
complication is myocarditis, which can cause arrhythmias, heart failure, and cardiac tamponade [32]. Pleuritis
and acute respiratory distress syndrome (ARDS) are more common in ASD when it is associated with
macrophage activation syndrome (MAS). (See 'Macrophage activation syndrome' below.)
Lymphadenopathy and splenomegaly — Slightly tender, enlarged cervical lymph nodes are seen in about
one-half of patients with ASD. Lymphadenopathy is present in up to two thirds of patients, and splenomegaly
may also occur in one-third to one-half of patients with ASD [19]. Typically, the lymphadenopathy is symmetrical.
Because of the frequent presence of fever and leukocytosis, there may be diagnostic confusion with lymphoma
in patients with ASD who also have lymphadenopathy. (See 'Differential diagnosis' below.)
Lymph node biopsy in ASD typically shows intense, paracortical immunoblastic hyperplasia, which is distinct
from the changes observed with RA, systemic lupus erythematosus (SLE), Sjögren's syndrome, or Kikuchi's
disease [33]. Changes on light microscopy may resemble lymphoma, but immunohistochemistry reveals a
benign polyclonal B-cell hyperplasia [34,35].
Macrophage activation syndrome — ASD can be associated with the MAS, which is also referred to as
hemophagocytic lymphohistiocytosis (HLH) or reactive hemophagocytic syndrome (RHS), but is usually termed
MAS (or RHS) when it occurs either in ASD or in systemic juvenile idiopathic arthritis. This complication of ASD
has been thought to occur in a small minority of patients but may be underdiagnosed, as suggested by
retrospective studies in which MAS occurred in 6 (12 percent) of 50 patients [36] and 21 (19 percent) of 109
patients [37] who fulfilled the Yamaguchi classification criteria for ASD. Other studies have reported MAS in 15
percent of 52 patients [38] and in 14 percent of 57 patients [17]; MAS was the presenting symptom in seven of
the eight patients in the former study and six of the eight patients in the latter study. MAS can occur at any time
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Flares of ASD and the development of MAS can be similar clinically. Anemia and marked elevation of serum
ferritin and C-reactive protein (CRP) may occur in either condition. Unlike ASD, patients with MAS may have
leukopenia and/or thrombocytopenia, and very high levels of serum triglyceride. Additionally, despite elevations
in ferritin and CRP, the levels of haptoglobin and fibrinogen may be normal or low in the patients with ASD who
develop MAS, and some of these patients have normal or unexpectedly low erythrocyte sedimentation rates
(ESR) [36,38,39]. One study suggests that MAS is particularly likely in patients with at least two of the following:
thrombocytopenia, anemia, and hepatomegaly [37]. The diagnostic hallmark of MAS is the presence on bone
marrow examination of numerous, well-differentiated macrophages (histiocytes) that are engaged actively in the
phagocytosis of hematopoietic elements [36,40]. Pancytopenia is more common in ASD when it is associated
with MAS.
MAS and HLH unassociated with ASD should also be considered in the differential diagnosis of ASD. (See
'Differential diagnosis' below.)
Other hematologic manifestations — Other hematologic manifestations may be associated with ASD,
including laboratory abnormalities associated with the inflammatory response (see 'Hematologic findings' below)
and additional clinical disorders, including microangiopathic hemolytic anemia associated with thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome [41-43], and disseminated intravascular coagulation [36].
(See "Acquired TTP: Clinical manifestations and diagnosis" and "Clinical features, diagnosis, and treatment of
disseminated intravascular coagulation in adults".)
Gastrointestinal symptoms — Abdominal pain may occur in up to half of patients with ASD, but estimates of its
frequency vary widely, from 1 to 48 percent [19]. Nausea, anorexia, and weight loss may also occur, often
together with other constitutional symptoms. Abdominal symptoms may be related to lymphadenitis, aseptic
peritonitis, or acute pancreatitis [18].
Other clinical features — Rare manifestations of ASD include renal disease, with proteinuria that may be
associated with interstitial nephritis, mesangial glomerulonephritis, collapsing glomerulopathy, or secondary
amyloidosis; neurologic involvement, such as seizures, aseptic meningitis, reversible posterior
leukoencephalopathy or encephalitis; and ophthalmologic manifestations, such as keratoconjunctivitis sicca,
conjunctivitis, episcleritis, and uveitis [16,19,27,44].
LABORATORY FINDINGS — A number of laboratory findings are characteristic of adult Still's disease (ASD)
(table 1), including an elevation in acute phase reactants, including ferritin, that is usually accompanied by
leukocytosis, with increased numbers of granulocytes that are sometimes immature in appearance. Anemia,
elevated hepatic aminotransferases, and other changes are also seen. The laboratory findings in ASD are
nonspecific, although the elevations in serum ferritin can be striking, and are commonly seen at levels that are
above those typical of acute phase responses in other disorders.
Acute phase response
ESR and CRP — Marked elevations in acute phase reactants (eg, ESR and CRP) are seen in virtually all
patients with ASD [9].
Serum ferritin — ASD has been associated with markedly elevated serum ferritin concentrations in as much
as 70 percent of patients [5]. This is probably an acute phase response, since hepatocytes responding to
inflammatory cytokines can increase ferritin synthesis [45]. The elevations correlate with disease activity and
have been suggested as a serologic marker to monitor the response to treatment [46-48].
Serum ferritin concentrations exceeding 3000 ng/mL (normal is 40 to 200 ng/mL) have been observed in ASD,
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The percentage of the ferritin that is glycosylated in ASD tends to be lower than in other rheumatic diseases
[47,50-52]. In one study, for example, the respective values were 3.7 and 30 percent [47]. The percentage of
glycosylated ferritin may remain low both in the active phase of disease and in remission [51].
Hematologic findings — The acute phase response in patients with ASD is typically accompanied by a
leukocytosis, with a peripheral white blood cell count that exceeds 15,000 cells/microL. There is a predominance
of granulocytes. The presence of immature forms, including bands, may mimic the findings in a septic process. A
normocytic, normochromic anemia with a hemoglobin less than or equal to 10 g/dL is seen in the majority of
patients, and reactive thrombocytosis is also common. Rarely, pure red cell aplasia may occur [53].
Findings on bone marrow examination in a series of 12 patients with ASD revealed hyperplasia of granulocytic
precursors in all of the marrow samples [54]. Other features that were less frequent included hypercellularity (75
percent), increased histiocytes (25 percent), and the presence of hemophagocytosis (17 percent). (See
"Evaluation of bone marrow aspirate smears".)
Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura, with microangiopathic hemolytic anemia, and

disseminated intravascular coagulation occur very infrequently. (See 'Other hematologic manifestations' above.)
Liver function studies — Elevations in the serum alanine and aspartate aminotransferases, as well as lactate
dehydrogenase, are seen in 75 percent of patients with ASD [9]. The liver biopsy findings are nonspecific but
range in severity from minimally abnormal to fulminant hepatic necrosis [9,27].
Immunologic studies — Antinuclear antibodies (ANA) and rheumatoid factor (RF) are present in less than 10
percent of patients and typically only in low titer. Elevated serum levels of interleukin (IL)-6, tumor necrosis factor
(TNF)-alpha, and interferon gamma are frequently present in patients with ASD but are not specific for this
disorder [55]. IL-18 is also elevated in ASD, and the elevation appears to be more specific for ASD than for other
systemic rheumatic diseases [56]. None of the cytokine tests are available for routine clinical use.
Synovial fluid and tissue — The synovial fluid is usually inflammatory with a mean leukocyte count of 13,000
cells/microL but with a reported range of 100 to 48,000 cells/microL [9,57]. Synovial biopsy reveals a chronic
synovitis with slight cell proliferation in the synovial lining layers, moderate vascular engorgement, and a
mononuclear cell infiltrate.
IMAGING FINDINGS — Early in disease the radiographs are typically normal or show signs of soft tissue
swelling and sometimes joint effusions [9]. Changes of periarticular osteopenia may develop. The classic
radiographic finding of adult Still's disease (ASD) is a nonerosive narrowing of the carpometacarpal and
intercarpal joint spaces of the wrist, which can progress to bony ankylosis [58,59]. Radiographic abnormalities
are eventually seen in about 40 percent of patients [9].
Ankylosis of the cervical spine, tarsal joints, or distal interphalangeal joints is a less common finding. An unusual
complication of ASD is the rapid destruction of the hip and, less commonly, the knee, which can require total joint
arthroplasty [1,9,60,61].
Computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) may be
abnormal. In one series, changes demonstrated on CT have included pulmonary abnormalities, lymph node
enlargement, splenomegaly, and hepatomegaly, and 18FDG-PET scans revealed increased uptake in lymph
nodes, salivary glands, and other tissues [17].
DIAGNOSTIC EVALUATION — We suggest a thorough history and physical examination in patients suspected
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● History – A detailed medical history should be obtained, with particular attention to a history of daily fever,
rash, joint pain or swelling, myalgia, sore throat, and enlarged lymph nodes, which may all be consistent with
ASD. Patients should be queried regarding symptoms or signs of conditions in the differential diagnosis,
including infection, diarrhea, urethritis, muscle weakness, easy bleeding or bruising, swelling of feet or legs,
and antecedent drug exposures. They should also be questioned regarding their response to prior therapy,
as many patients report a striking response to nonsteroidal antiinflammatory drugs (NSAIDS).
● Physical examination – A thorough physical examination should be performed, with particular attention to a
careful skin exam, preferably during the patient's febrile period, with particular attention to regions where
there is pressure (eg, under an elastic waistband) that may increase the likelihood of the rash and to skin
lesions or injuries that may be a source of infection; evaluation for lymphadenopathy, splenomegaly, and
hepatomegaly; and a thorough joint examination of the upper and lower extremities and spine.
● Laboratory testing and imaging – We suggest obtaining the following laboratory studies:
• Complete blood count, differential, and platelet count
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
• Serum ferritin and, if available, glycosylated ferritin determination
• Antinuclear antibody (ANA), rheumatoid factor (RF), and anti-citrullinated peptide antibody testing
• Blood cultures
• Serologic testing for hepatitis B and C, human parvovirus B19, and Epstein Barr virus; and testing for
human immunodeficiency virus
• Blood urea nitrogen, creatinine, and urinalysis with microscopic examination and urine culture
• Liver enzymes, including aminotransferases and alkaline phosphatase, bilirubin, and serum albumin
• Arthrocentesis and synovial fluid analysis, including cell count, differential, Gram stain and culture, and
crystal search
• Plain radiographs of the chest (posterior to anterior and lateral views)
● Histopathologic studies - Lymph node biopsy, bone marrow aspiration, and/or bone marrow biopsy should
be obtained in patients suspected of lymphoproliferative malignancy.
● Additional evaluation – In patients who meet criteria for a fever of unknown origin (FUO), additional
evaluation is indicated to exclude other causes of these symptoms. (See 'Differential diagnosis' below.)
Other tests may be indicated depending upon the findings and clinical probability, such as imaging studies,
especially hand and foot radiographs in patients with a history of recurring arthritic symptoms;
echocardiography; anti-neutrophil cytoplasmic antibody testing; and serologic or polymerase chain reaction
studies for specific infectious diseases, but are not required to make the diagnosis of ASD.
Use of both the total serum ferritin and the glycosylated fraction may provide more diagnostic specificity for
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percent but a relatively high specificity of 93 percent [52]. However, the test for the glycosylated ferritin
isoform is not widely available.
Negative testing for ANA and RF is one of the minor criteria that may contribute to the classification of a
patient as having ASD (see 'Classification criteria' below); however, the presence of either of these
antibodies does not exclude the diagnosis of ASD.
DIAGNOSIS — The diagnosis of adult Still's disease (ASD) is, in part, a diagnosis of exclusion that can generally
be made based upon the presence of the characteristic clinical and laboratory features in the absence of another
condition that may cause similar symptoms and findings [7,16,18,19]. (See 'Diagnostic evaluation' above and
'Differential diagnosis' below.)
The clinical presentation is heterogeneous, but the most characteristic features are (see 'Clinical features' above
and 'Laboratory findings' above):
● Daily spiking fever
● A cutaneous evanescent salmon-pink maculopapular eruption, most often present during the febrile hours
● Arthritis or arthralgia
● Leukocytosis with predominance of neutrophils
● A marked elevation in serum ferritin
The presence of additional clinical and laboratory features further supports the diagnosis; such features include
pharyngitis, elevated hepatic aminotransferases, lymphadenopathy, elevated acute phase reactants, and
thrombocytosis. Some patients with ASD exhibit only a transient erythematous cutaneous eruption.
The important categories of disease to exclude are (see 'Differential diagnosis' below):
● Infectious diseases, especially acute viral infection
● Malignancy, especially lymphoproliferative disorders
● Systemic autoimmune rheumatic diseases, such as rheumatoid arthritis (RA) and systemic lupus
● Vasculitis, such as polyarteritis nodosa
● Auto-inflammatory diseases
● Drug reactions
● Neutrophilic dermatoses, such as Sweet syndrome
Several different sets of classification criteria have been developed that are useful for research, but which lack
the combined sensitivity and specificity to be useful for clinical diagnosis. However, these criteria may be helpful
in guiding the diagnostic evaluation and in identifying patients more likely to have ASD; most of them rely upon
the exclusion of other conditions, including the most commonly used criteria, termed the Yamaguchi classification
criteria. (See 'Classification criteria' below.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of adult Still's disease (ASD) is extensive, including a
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as fever, rash, arthritis, lymphadenopathy, and with elevated acute phase responses, leukocytosis, and
abnormalities in liver enzymes. The differential diagnosis of a fever of unknown origin (FUO) is also quite broad,
and should be considered in the differential diagnosis of ASD. (See "Etiologies of fever of unknown origin in
adults" and "Approach to the adult with fever of unknown origin".)
Infection
● Acute viral syndromes – Acute viral infections, including hepatitis, parvovirus B19, and others may cause
fever, arthritis, and rash. Abnormal liver chemistries are present in hepatitis and may be present in ASD. The
pattern of fever in viral infections usually differs from the typical daily fever spikes of ASD, the appearance
and timing of the cutaneous eruption of ASD usually differs from that in most viral infections, and many viral
syndromes are self-limited. Serologic studies can often help to differentiate such disorders from ASD.
Human immunodeficiency virus infection can be associated with fever and lymphadenopathy but can also be
diagnosed by appropriate laboratory testing. (See "Specific viruses that cause arthritis" and "Approach to the
adult with fever of unknown origin" and "Microbiology, epidemiology, and pathogenesis of parvovirus B19
infection" and "Hepatitis B virus: Screening and diagnosis" and "Diagnosis and evaluation of chronic
hepatitis C virus infection" and "Acute and early HIV infection: Clinical manifestations and diagnosis".)
● Bacterial infection and endocarditis – Fever, leukocytosis, and elevated acute phase reactants are nearly
universal in patients with ASD, but also consistent with an infectious disease, such as septicemia due to
bacterial infection. Blood cultures are usually positive in patients with bacteremia, and the presence of
immature forms of granulocytes, including bands, in the differential white blood cell count may suggest a
septic process rather than ASD, although some immature forms may also be seen in patients with ASD.
Other occult infections may also be confused with ASD. (See "Approach to the adult with fever of unknown
origin" and "Blood cultures for the detection of bacteremia" and "Clinical manifestations and evaluation of
adults with suspected native valve endocarditis".)
Rheumatologic
● Systemic rheumatic diseases – The arthritis and elevated acute phase reactants of ASD may mimic a
broad range of other rheumatic diseases, including rheumatoid arthritis (RA), reactive arthritis, and systemic
lupus erythematosus (SLE). Other features not characteristic of ASD may be present in such patients,
including recent gastrointestinal or urinary tract infection in reactive arthritis; and alopecia, Raynaud
phenomenon, cutaneous lupus, significant glomerulonephritis, anti-double stranded DNA and/or anti-Smith
antibodies, and other findings in SLE. Patients with RA lack the typical daily spiking fever, rash, and
lymphadenopathy of ASD, and many patients with RA have positive tests for rheumatoid factor (RF) or anti-
CCP antibodies. The cutaneous eruptions of SLE are unlike that seen in ASD, and antinuclear antibody
(ANA) testing is positive in SLE. RF and ANA are only present in less than 10 percent of patients with ASD,
and when present are usually in a low titer. Serum ferritin values above 3000 ng/mL are generally not
observed in rheumatic diseases other than ASD. (See "Diagnosis and differential diagnosis of rheumatoid
arthritis" and "Reactive arthritis" and "Diagnosis and differential diagnosis of systemic lupus erythematosus
in adults".)
Patients with dermatomyositis (DM) may have rash, arthritis, fever, and myalgia, but the cutaneous eruptions
in DM differ from ASD, and the myalgia is associated with significant inflammatory myositis. Polymyositis
(PM) may also occasionally mimic ASD, with similar findings to DM, although no rash is present. The
evaluation for these conditions is directed towards documentation of the inflammatory myopathy, which is
not typical of ASD, and usually mild if present. (See "Diagnosis and differential diagnosis of dermatomyositis
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in adults".)
● Vasculitis – Vasculitic disorders, such as polyarteritis nodosa (PAN), which may present with fever,
arthralgia, constitutional symptoms, skin lesions, and abdominal pain, can mimic ASD. The ischemic organ
involvement, renal disease, and skin lesions of PAN, if present, differ from ASD, and a biopsy of an affected
organ, or less often, vascular imaging studies, can be diagnostic. (See "Clinical manifestations and
diagnosis of polyarteritis nodosa in adults".)
Malignancy
● Malignancy – Because of the frequent presence of fever, lymphadenopathy, and leukocytosis, there may be
diagnostic confusion with lymphoma, especially non-Hodgkin lymphoma or Hodgkin disease, especially
when lymphadenopathy and constitutional symptoms are the predominant findings. Lymph node biopsy can
help distinguish these conditions from ASD, in which the biopsy typically shows intense, paracortical
immunoblastic hyperplasia. These light microscopic changes may resemble lymphoma, but
immunohistochemistry reveals a benign polyclonal B-cell hyperplasia, which distinguishes ASD from
lymphoma [34,35]. (See "Evaluation of peripheral lymphadenopathy in adults" and "Clinical presentation and
diagnosis of non-Hodgkin lymphoma" and "Initial evaluation and diagnosis of classical Hodgkin lymphoma in
adults".)
Other less common malignant disorders reported to mimic ASD include angioimmunoblastic T cell
lymphoma, multicentric Castleman disease, myeloproliferative disorder, and solid cancers or paraneoplastic
syndromes [18,19].
Drug reactions
● Drug reactions – Certain drug hypersensitivity reactions can also mimic ASD [62], and the evanescent
cutaneous eruptions with characteristic coloration of ASD or only transient erythema may be mistaken for a
drug reaction before the diagnosis of ASD is established. Drug reactions may also present with fever and
constitutional symptoms, and a skin biopsy may help to distinguish drug hypersensitivity from ASD. The
syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS) may mimic ASD with fever,
rash, lymphadenopathy, and abnormal liver chemistries but eosinophilia is not usually present in ASD, and
the cutaneous eruption and skin biopsy findings also differ between the disorders. DRESS also typically
occurs two to six weeks after exposure to one of the drugs suspected to cause this syndrome and patients
may have an atypical lymphocytosis, rather than granulocytosis. (See "Drug allergy: Classification and
clinical features" and "Drug eruptions" and "Drug fever" and "Drug reaction with eosinophilia and systemic
symptoms (DRESS)".)
Auto-inflammatory and other
● Auto-inflammatory diseases – These conditions more often begin in childhood, but may first present in
adults with fevers, cutaneous eruptions, arthralgia or arthritis, and abdominal pain. Examples include the
hyperimmunoglobulin D (hyper-IgD) syndrome, which may also present with lymphadenopathy and
splenomegaly; and the tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), which
may also include symptoms of focal myalgia, unlike the more diffuse myalgia of ASD, and in which the fever
recurs periodically and in self-limited episodes, which is unlike the fever pattern of ASD. Eye and periorbital
involvement is often seen in TRAPS, unlike ASD. Hyper-IgD syndrome may be diagnosed based upon
elevations in serum IgD and/or IgA, and a family history may be present. Genetic testing can be performed if
needed. TRAPS can be diagnosed by the clinical presentation and confirmed by commercially available
genetic testing. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Tumor
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● Schnitzler's syndrome – Schnitzler's syndrome, like ASD, may present with arthralgia, intermittent fever,
and lymphadenopathy; but unlike ASD, Schnitzler's syndrome is characterized by chronic urticaria
associated with monoclonal gammopathy (most often IgM kappa). Other features may include bone pain
and skeletal hyperostosis. It is associated with hematologic malignancy in about a third of patients. A
neutrophilic urticarial dermatosis or less often, an urticarial vasculitis, may be present, which together with
the other clinical and laboratory findings help to distinguish the disorders. (See "Urticarial vasculitis", section
on 'Differential diagnosis'.)
● Sweet syndrome – ASD and Sweet syndrome may occasionally be confused. Sweet syndrome (acute
febrile neutrophilic dermatosis) is an uncommon inflammatory disorder characterized by the abrupt
appearance of painful, edematous, and erythematous papules, plaques, or nodules on the skin. Fever and
leukocytosis, as in patients with ASD, frequently accompany the cutaneous lesions, and involvement of the
eyes, musculoskeletal system, and internal organs may occur. A careful history and skin examination, along
with skin biopsy can readily distinguish these disorders. (See "Sweet syndrome (acute febrile neutrophilic
dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
● Sarcoidosis – Patients with sarcoid may present with fever, mild respiratory symptoms, and arthralgia or
arthritis that can resemble ASD to some degree, but can be distinguished based upon a careful history and
examination and if needed by tissue biopsy demonstrating the characteristic noncaseating granulomas of
sarcoid. (See "Sarcoid arthropathy" and "Sarcoid: Muscle, bone, and vascular disease manifestations" and
"Clinical manifestations and diagnosis of pulmonary sarcoidosis".)
● Kikuchi disease – Kikuchi disease, also called Kikuchi-Fujimoto disease or Kikuchi histiocytic necrotizing
lymphadenitis, is a rare, benign condition of unknown cause usually characterized by cervical
lymphadenopathy and fever. Histopathology of the involved lymph nodes differentiates Kikuchi disease from
ASD and other conditions that it may mimic. Patients may also have fatigue, arthralgia or arthritis, rash,
hepatosplenomegaly, night sweats, nausea, vomiting, weight loss, and/or diarrhea. (See "Kikuchi disease".)
● Hemophagocytic lymphohistiocytosis – The distinction between secondary (non-hereditary)

hemophagocytic lymphohistiocytosis (HLH) and ASD is difficult; macrophage activation syndrome (MAS) is
the name usually used to denote HLH that arises in patients with ASD (see 'Macrophage activation
syndrome' above). Another term for this form of HLH is reactive hemophagocytic syndrome. Patients with
HLH unrelated to ASD and with patients with MAS may have similar degrees of hyperferritinemia to ASD,
but a distinction can sometimes be made clinically based upon cytopenia in multiple lineages, as leukopenia,
including granulocytopenia and lymphopenia, as well as thrombocytopenia are characteristic of HLH/MAS
but not of ASD. Some differences in the pattern of acute phase reactants may also be seen. The diagnosis
of HLH/MAS can be confirmed by bone marrow biopsy. Both marked hyperferritinemia and a low fraction of
glycosylated serum ferritin also occur in MAS as well as in various syndromes associated with
hemophagocytosis, such as those due to lymphoma and to severe drug reactions [36,63,64]. (See "Clinical
features and diagnosis of hemophagocytic lymphohistiocytosis".)
CLASSIFICATION CRITERIA — At least seven sets of diagnostic or classification criteria have been proposed
for adult Still's disease (ASD), given the lack of a definitive diagnostic test [20,57,60,65-68]. These are useful for
research but lack the sensitivity and specificity needed for clinical diagnosis. The approach to the diagnosis of
ASD is described separately, as is the role of specific clinical and laboratory features used to support the
diagnosis. (See 'Diagnostic evaluation' above and 'Diagnosis' above.)
All of these sets are similar, differing generally in the number of major and minor criteria required for diagnosis,
withThis
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variation among the Byindividual
continuing to browse
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demonstrated that
Continuecriteria
the Japanese criteria, often termed the Yamaguchi or find outhave
[60], more.the highest sensitivity in patients with a
definite diagnosis of ASD [69].
● Yamaguchi criteria – The Yamaguchi criteria require the presence of five features, with at least two being
major diagnostic criteria [60]. In addition, the presence of any infection, malignancy, or other rheumatic
disorder known to mimic ASD in its clinical features precludes the diagnosis of ASD, at least for the purpose
of research.
The four major Yamaguchi criteria are:
• Fever of at least 39ºC (102.2ºF) lasting at least one week
• Arthralgias or arthritis lasting two weeks or longer
• A nonpruritic macular or maculopapular skin rash that is salmon-colored in appearance and usually
found over the trunk or extremities during febrile episodes
• Leukocytosis (10,000/microL or greater), with at least 80 percent granulocytes
The minor Yamaguchi criteria include:
• Sore throat
• Lymphadenopathy
• Hepatomegaly or splenomegaly
• Abnormal liver function studies, particularly elevations in aspartate and alanine aminotransferase and
lactate dehydrogenase concentrations
• Negative tests for antinuclear antibody (ANA) and rheumatoid factor (RF)
SUMMARY
● Adult Still's disease (ASD) is an inflammatory disorder characterized by quotidian fevers, arthritis, and an
evanescent salmon-colored rash typically found on the trunk. Pharyngitis, lymphadenopathy, and a number
of nonspecific hematologic findings, including leukocytosis, may be present. (See 'Clinical features' above
and 'Laboratory findings' above.)
● The clinical course of ASD can be divided into three main patterns: monophasic, intermittent, and chronic.
Systemic manifestations predominate in the two former patterns, while articular involvement predominates in
patients with chronic disease. (See 'Natural history/disease course' above.)
● The macrophage activation syndrome (MAS) occurs in a minority of patients with ASD. MAS is the term
used for hemophagocytic lymphohistiocytosis (HLH) occurring in the context of ASD or Still's disease in
children. Bone marrow aspiration is the most sensitive means of diagnosing reactive hemophagocytic
syndrome (RHS). (See 'Macrophage activation syndrome' above and 'Hematologic findings' above.)
● ASD has been associated with markedly elevated serum ferritin concentrations in as much as 70 percent of
patients. Serum ferritin values above 3000 ng/mL in a patient with compatible symptoms should lead to
suspicion of ASD in the absence of a bacterial or viral infection. (See 'Serum ferritin' above.)
● ASD is usually seronegative for antinuclear antibodies (ANA) or rheumatoid factor (RF). However, a low titer
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● ASD is a diagnosis of exclusion. The diagnosis is based upon the presence of characteristic clinical and
laboratory findings, such as daily spiking fever, the characteristic evanescent rash, arthralgia or arthritis, and
leukocytosis; and the exclusion of infectious, malignant, autoimmune and other conditions that may be
confused with ASD. A markedly elevated serum ferritin may also be present. There is no specific test or
combination of tests that can be used to establish the diagnosis of ASD. (See 'Diagnosis' above and
'Differential diagnosis' above.)
● A variety of classification criteria have been proposed for use in research; the Yamaguchi criteria are most
widely used. (See 'Classification criteria' above.)
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circulation of patients with adult-onset Still's disease. Arthritis Rheum 2001; 44:550.
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59. Björkengren AG, Pathria MN, Sartoris DJ, et al. Carpal alterations in adult-onset Still disease, juvenile
chronic arthritis, and adult-onset rheumatoid arthritis: comparative study. Radiology 1987; 165:545.
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Still's disease, both followed up for more than 10 years. Ann Rheum Dis 1990; 49:283.
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63. Esumi N, Ikushima S, Hibi S, et al. High serum ferritin level as a marker of malignant histiocytosis and
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Rheumatol 1996; 23:495.
Topic 5611 Version 22.0
GRAPHICS
Skin biospy from adult onset Still's disease
This skin biopsy demonstrates some mild perivascular inflammation and dermal
edema in an area of skin involved with the rash of adult Still's disease.
Courtesy of Lisa Mandl, MD.
Graphic 56878 Version 1.0
Skin biopsy
This site usesof adult Still's
cookies. diseaseto browse this site you are agreeing to our use of cookies.
By continuing
In this micrograph of a biopsy specimen from the involved skin from a patient
with adult Still's disease, perivascular infiltration of inflammatory cells and
edema separating collagen bundles in the dermis is apparent.
Courtesy of Lisa Mandl, MD.
Laboratory
This site usestests in adult
cookies. Still's disease
By continuing to browse this site you are agreeing to our use of cookies.
Elevated ESR Continue or find out more. 99 percent
WBC
≥ 10,000/mm 3 92 percent
≥ 15,000/mm 3 81 percent
Neutrophils ≥ 80 percent 88 percent
Serum Albumin ≤3.5 g/dL 81 percent
Elevated liver enzymes (any) 73 percent
Anemia (Hgb ≤10 g/dL) 68 percent
Platelets ≥400,000/mm 3 62 percent
Negative ANA 92 percent
Negative RF 93 percent
Adapted from Pouchot et al and Ohta et al.
Contributor Disclosures
Lisa A Mandl, MD, MPH Nothing to disclose Continue
JamesorRfind outMD
O'Dell, more.
Consultant/Advisory Boards: AbbVie
[Rheumatoid arthritis (TNF inhibitor)]; Lilly [Rheumatoid arthritis (JAK kinase inhibitor)]; BMS [Rheumatoid
arthritis (abatacept)]; GlaxoSmithKline [Rheumatoid arthritis (Anti-IL-6)]; Medac [Rheumatoid arthritis
(methotrexate)]. Paul L Romain, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
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2/6/2018 Clinical manifestations and diagnosis of adult Still's disease - UpToDate

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Author: Lisa A Mandl, MD, MPH

rash, serositis, and hepatosplenomegaly, predominate in this group.

Acute phase response

Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura, with microangiopathic hemolytic anemia, and

• Complete blood count, differential, and platelet count

• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

• Serum ferritin and, if available, glycosylated ferritin determination

• Plain radiographs of the chest (posterior to anterior and lateral views)

● Daily spiking fever

● Leukocytosis with predominance of neutrophils

● A marked elevation in serum ferritin

● Infectious diseases, especially acute viral infection

● Malignancy, especially lymphoproliferative disorders

● Vasculitis, such as polyarteritis nodosa

● Neutrophilic dermatoses, such as Sweet syndrome

Auto-inflammatory and other

● Hemophagocytic lymphohistiocytosis – The distinction between secondary (non-hereditary)

The four major Yamaguchi criteria are:

• Fever of at least 39ºC (102.2ºF) lasting at least one week

• Arthralgias or arthritis lasting two weeks or longer

• Leukocytosis (10,000/microL or greater), with at least 80 percent granulocytes

The minor Yamaguchi criteria include:

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 5611 Version 22.0

Courtesy of Lisa Mandl, MD.

Graphic 56878 Version 1.0

Courtesy of Lisa Mandl, MD.

Graphic 72353 Version 1.0

Neutrophils ≥ 80 percent 88 percent

Serum Albumin ≤3.5 g/dL 81 percent

Elevated liver enzymes (any) 73 percent

Anemia (Hgb ≤10 g/dL) 68 percent

Platelets ≥400,000/mm 3 62 percent

Negative ANA 92 percent

Adapted from Pouchot et al and Ohta et al.

Graphic 75048 Version 2.0

Conflict of interest policy

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Clinical Manifestations and Diagnosis of Adult Still's Disease - UpToDate

Clinical Manifestations and Diagnosis of Adult Still's Disease - UpToDate