INTRODUCTION — Adult-onset Still's disease (AOSD) 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 "Still's disease in the adult" 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]. "Adult-onset Still's disease" is now the most widely used term for the condition when it begins after the patient's 16th birthday. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
The clinical manifestations and diagnosis of AOSD will be reviewed here. The treatment and prognosis of AOSD are presented separately. (See "Treatment of adult-onset Still's disease".)
ETIOLOGY — The etiology of adult-onset Still's disease (AOSD) 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 AOSD share the same etiopathogenic factors.
Proposed pathogens have included numerous viruses [3-7]; suspected bacterial pathogens include Yersinia enterocolitica and Mycoplasma pneumoniae [5,8].
While AOSD is similar in phenotype to systemic juvenile inflammatory arthritis, both having high levels of interleukin 6 (IL-6) and IL-18 as well as similar peripheral blood gene expression signatures, there are no genetic loci clearly established as specifically associated with AOSD [9].
For example, in a series of 62 French patients, human leukocyte antigen (HLA)-B17, -B18, -B35, and -DR2 were associated with AOSD [10]. However, other studies have not confirmed these findings [11]. Familial cases are uncommon, and there have been few reports of cases in twins [12].
EPIDEMIOLOGY — Adult-onset Still's disease (AOSD) is very uncommon. A retrospective French study estimated the annual incidence of AOSD to be 0.16 cases per 100,000 people, with an equal distribution between the sexes [13]. 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 [14,15].
NATURAL HISTORY/DISEASE COURSE — The clinical course of adult-onset Still's disease (AOSD) can be divided into three main patterns: monophasic (or monocyclic), intermittent, and chronic [10,16,17]. 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 [10,18].
●Monophasic pattern – Patients with monophasic AOSD 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, rash, serositis, and hepatosplenomegaly, predominate in this group.
●Intermittent pattern – Patients with intermittent AOSD have one 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 AOSD 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-onset Still's disease (AOSD) 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 AOSD 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 AOSD, as fever persists between spikes in approximately 20 percent of cases [10]. AOSD 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 AOSD [17]. (See "Etiologies of fever of unknown origin in adults" and 'Natural history/disease course' above.)
Rash — The classic skin rash of AOSD 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 AOSD 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 AOSD, 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 AOSD, 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 AOSD, 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 anti-citrullinated peptide antibodies, and unlike RA 6 out of 16 (38 percent) had inflammatory arthritis affecting the distal interphalangeal joints. These patients also had lower levels of ferritin or interleukin (IL) 18 than the other patients with AOSD.
●Myalgia – Myalgia is common, often worse with fever spikes, and can sometimes be severe and debilitating. Muscle weakness is not present, but the serum creatine kinase and aldolase concentrations can be slightly elevated [10]. Electromyographic studies and muscle biopsy are usually normal or show a nonspecific inflammatory myopathy.
Pharyngitis — A severe, nonsuppurative pharyngitis is common in AOSD. 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 AOSD, 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 AOSD have been described, with four fatalities [10,27]. 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 AOSD [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 AOSD when it is associated with macrophage activation syndrome (MAS). (See 'Macrophage activation syndrome' below.)
Since the introduction of anti-IL-1 and anti-IL-6 therapies for systemic juvenile idiopathic arthritis, there has been an increase in reports of systemic juvenile idiopathic arthritis patients with severe pulmonary arterial hypertension, interstitial lung disease, and pulmonary alveolar proteinosis [33], often accompanied by MAS. Whether parenchymal lung disease in AOSD is similarly increasing, is associated with worse outcomes, or reflects increased use of anti-IL therapy is an area of active investigation [34].
Lymphadenopathy and splenomegaly — Slightly tender, enlarged cervical lymph nodes are seen in about one-half of patients with AOSD. Lymphadenopathy is present in up to two thirds of patients, and splenomegaly may also occur in one-third to one-half of patients with AOSD [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 AOSD who also have lymphadenopathy. (See 'Differential diagnosis' below.)
Lymph node biopsy in AOSD 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 [35]. Changes on light microscopy may resemble lymphoma, but immunohistochemistry reveals a benign polyclonal B-cell hyperplasia [36,37].
Macrophage activation syndrome — AOSD can be associated with MAS, which is also referred to as hemophagocytic lymphohistiocytosis (HLH), but is usually termed MAS when it occurs with systemic rheumatic disease, most commonly AOSD or systemic juvenile idiopathic arthritis. This complication of AOSD 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 [38] and 21 (19 percent) of 109 patients [39] who fulfilled the Yamaguchi classification criteria for AOSD. Other studies have reported MAS in 15 percent of 52 patients [40] 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. However, these small studies may reflect a referral bias of the sickest patients. In a large retrospective study using the United States nationwide inpatient sample, only 1.7 percent of patients with AOSD developed MAS [41]. MAS can occur at any time during AOSD, and simultaneous presentations of AOSD and MAS are not unusual. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS'.)
Flares of AOSD 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 AOSD, 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 AOSD who develop MAS, and some of these patients have normal or unexpectedly low erythrocyte sedimentation rates (ESR) [38,40,42]. One study suggests that MAS is particularly likely in patients with at least two of the following: thrombocytopenia, anemia, and hepatomegaly [39]. 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 [38,43]. Pancytopenia is more common in AOSD when it is associated with MAS. It is critical to determine whether MAS is present on presentation of AOSD as this will guide therapy. (See "Treatment of adult-onset Still's disease", section on 'Concern for incipient or active MAS' and "Treatment of adult-onset Still's disease", section on 'Monitoring for MAS'.)
HLH unassociated with AOSD should also be considered in the differential diagnosis of AOSD. (See 'Differential diagnosis' below.)
Other hematologic manifestations — Other hematologic manifestations may be associated with AOSD, 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 [44-46], and disseminated intravascular coagulation [38,41]. (See "Diagnosis of immune TTP" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
Gastrointestinal symptoms — Abdominal pain may occur in up to half of patients with AOSD, 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 AOSD 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 [16,19,27,47].
LABORATORY FINDINGS — A number of laboratory findings are characteristic of adult-onset Still's disease (AOSD) (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 AOSD 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. Adenosine deaminase 2 has been identified as a potential a biomarker of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis [48].
Acute phase response
ESR and CRP — Marked elevations in acute phase reactants (eg, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) are seen in virtually all patients with AOSD [10]. In systemic juvenile idiopathic arthritis, a paradoxical drop in ESR when liver function tests (LFTs) and CRP are increasing suggests the development of MAS rather than a flare of systemic juvenile idiopathic arthritis [49]. (See "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications".)
Serum ferritin — AOSD 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 [50]. The elevations correlate with disease activity and have been suggested as a serologic marker to monitor the response to treatment [51-53].
Serum ferritin concentrations exceeding 3000 ng/mL (normal is 40 to 200 ng/mL) have been observed in AOSD, with some patients having values above 10,000 ng/mL [43,54].
The percentage of the ferritin that is glycosylated in AOSD tends to be lower than in other rheumatic diseases [52,55-57]. In one study, for example, the respective values were 3.7 and 30 percent [52]. The percentage of glycosylated ferritin may remain low both in the active phase of disease and in remission [56].
Hematologic findings — The acute phase response in patients with AOSD 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 [58].
Findings on bone marrow examination in a series of 12 patients with AOSD revealed hyperplasia of granulocytic precursors in all of the marrow samples [59]. 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 AOSD [10]. The liver biopsy findings are nonspecific but range in severity from minimally abnormal to fulminant hepatic necrosis [10,27].
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 AOSD but are not specific for this disorder [60]. IL-18 is also elevated in AOSD, and the elevation appears to be more specific for AOSD than for other systemic rheumatic diseases [61]. 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 [10,62]. 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 [10]. Changes of periarticular osteopenia may develop. The classic radiographic finding of adult-onset Still's disease (AOSD) is a nonerosive narrowing of the carpometacarpal and intercarpal joint spaces of the wrist, which can progress to bony ankylosis [63,64]. Radiographic abnormalities are eventually seen in about 40 percent of patients [10].
Ankylosis of the cervical spine, tarsal joints, or distal interphalangeal joints is a less common finding. An unusual complication of AOSD is the rapid destruction of the hip and, less commonly, the knee, which can require total joint arthroplasty [1,10,65,66].
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 of adult-onset Still's disease (AOSD) based upon the presence of several features typical of the disorder and the absence of a readily recognized alternative diagnosis, as AOSD is a diagnosis of exclusion; selected laboratory testing should also be performed.
●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 AOSD. 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, 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)
•CT of the chest could be considered to identify occult lung disease
●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 AOSD.
Use of both the total serum ferritin and the glycosylated fraction may provide more diagnostic specificity for AOSD than does reliance upon either test alone. In one report, the combination of a fivefold or greater elevation in serum ferritin and a glycosylated fraction of ≤20 percent had a modest sensitivity for AOSD of 43 percent but a relatively high specificity of 93 percent [57]. 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 AOSD (see 'Classification criteria' below); however, the presence of either of these antibodies does not exclude the diagnosis of AOSD.
DIAGNOSIS — The diagnosis of adult-onset Still's disease (AOSD) 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 AOSD 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 AOSD; 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-onset Still's disease (AOSD) is extensive, including a wide variety of infections, systemic autoimmune and inflammatory rheumatic diseases, malignancy, and adverse reactions to medications [16,18]. Many conditions may present with combinations of features seen in AOSD, such 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 AOSD. (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 AOSD. The pattern of fever in viral infections usually differs from the typical daily fever spikes of AOSD, the appearance and timing of the cutaneous eruption of AOSD 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 AOSD. Human immunodeficiency virus infection can be associated with fever and lymphadenopathy but can also be diagnosed by appropriate laboratory testing. (See "Viruses that cause arthritis" and "Approach to the adult with fever of unknown origin" and "Virology, epidemiology, and pathogenesis of parvovirus B19 infection" and "Hepatitis B virus: Screening and diagnosis" and "Screening and diagnosis 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 AOSD, 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 AOSD, although some immature forms may also be seen in patients with AOSD. Other occult infections may also be confused with AOSD. (See "Approach to the adult with fever of unknown origin" and "Detection of bacteremia: Blood cultures and other diagnostic tests" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)
Rheumatologic
●Systemic rheumatic diseases – The arthritis and elevated acute phase reactants of AOSD 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 AOSD 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 deoxyribonucleic acid (DNA) and/or anti-Smith antibodies, and other findings in SLE. Patients with RA lack the typical daily spiking fever, rash, and lymphadenopathy of AOSD, and many patients with RA have positive tests for rheumatoid factor (RF) or anti-citrullinated peptide antibodies. The cutaneous eruptions of SLE are unlike that seen in AOSD, and antinuclear antibody (ANA) testing is positive in SLE. RF and ANA are only present in less than 10 percent of patients with AOSD, 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 AOSD. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Reactive arthritis" and "Clinical manifestations and 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 AOSD, and the myalgia is associated with significant inflammatory myositis. Polymyositis (PM) may also occasionally mimic AOSD, 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 AOSD, and usually mild if present. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Clinical manifestations'.)
●Vasculitis – Vasculitic disorders, such as polyarteritis nodosa (PAN), which may present with fever, arthralgia, constitutional symptoms, skin lesions, and abdominal pain, can mimic AOSD. The ischemic organ involvement, renal disease, and skin lesions of PAN, if present, differ from AOSD, 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 AOSD, 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 AOSD from lymphoma [36,37]. (See "Evaluation of peripheral lymphadenopathy in adults" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)
Other less common malignant disorders reported to mimic AOSD 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 AOSD [67], and the evanescent cutaneous eruptions with characteristic coloration of AOSD or only transient erythema may be mistaken for a drug reaction before the diagnosis of AOSD is established. Drug reactions may also present with fever and constitutional symptoms, and a skin biopsy may help to distinguish drug hypersensitivity from AOSD. The syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS) may mimic AOSD with fever, rash, lymphadenopathy, and abnormal liver chemistries but eosinophilia is not usually present in AOSD, 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 hypersensitivity: 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 AOSD, and in which the fever recurs periodically and in self-limited episodes, which is unlike the fever pattern of AOSD. Eye and periorbital involvement is often seen in TRAPS, unlike AOSD. 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 necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)
●Schnitzler's syndrome – Schnitzler's syndrome, like AOSD, may present with arthralgia, intermittent fever, and lymphadenopathy; but unlike AOSD, 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 – AOSD 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 AOSD, 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 AOSD 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 myopathy" 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 AOSD 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 hemophagocytic lymphohistiocytosis (HLH) and AOSD, or AOSD with macrophage activation syndrome (MAS) can be challenging. Patients with HLH unrelated to AOSD may have similar degrees of hyperferritinemia to AOSD, 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 AOSD. Interleukin (IL) 18 levels, reflecting a "cytokine storm," may be higher in AOSD/MAS compared with HLH [68]. 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 [38,69,70]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
CLASSIFICATION CRITERIA — At least seven sets of diagnostic or classification criteria have been proposed for adult-onset Still's disease (AOSD), given the lack of a definitive diagnostic test [20,62,65,71-74]. These are useful for research but lack the sensitivity and specificity needed for clinical diagnosis. The approach to the diagnosis of AOSD 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, with some variation among the individual criteria. A comparison of these seven sets of criteria demonstrated that the Japanese criteria, often termed the Yamaguchi criteria [65], have the highest sensitivity in patients with a definite diagnosis of AOSD [75].
●Yamaguchi criteria – The Yamaguchi criteria require the presence of five features, with at least two being major diagnostic criteria [65]. In addition, the presence of any infection, malignancy, or other rheumatic disorder known to mimic AOSD in its clinical features precludes the diagnosis of AOSD, 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)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adult-onset Still's disease".)
SUMMARY
●Major clinical and laboratory features – Adult-onset Still's disease (AOSD) 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 (table 1). (See 'Clinical features' above and 'Laboratory findings' above.)
●Natural history and disease course – The clinical course of AOSD 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.)
●Macrophage activation syndrome – The macrophage activation syndrome (MAS) occurs in a minority of patients with AOSD but can be fatal. Bone marrow aspiration is the most sensitive means of diagnosing MAS. (See 'Macrophage activation syndrome' above and 'Hematologic findings' above.)
●Elevation of serum ferritin – AOSD 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 AOSD in the absence of a bacterial or viral infection. (See 'Serum ferritin' above.)
●Infrequency of autoantibodies – AOSD is usually seronegative for antinuclear antibodies (ANA) or rheumatoid factor (RF). However, a low titer ANA or RF can occur and do not exclude the diagnosis. (See 'Immunologic studies' above.)
●Diagnosis and differential diagnosis – AOSD 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 AOSD. 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 AOSD. (See 'Diagnosis' above and 'Differential diagnosis' above.)
●Classification criteria – A variety of classification criteria have been proposed for use in research; the Yamaguchi criteria are most widely used. (See 'Classification criteria' above.)
