Clinical manifestations and diagnosis of adult-onset Still's disease

INTRODUCTION — Adult-onset Still's disease (AOSD) is an inflammatory disorder characterized by quotidian (daily) fevers, arthritis, and an evanescent rash. Diagnosing AOSD is challenging as patients may have a variety of nonspecific symptoms and laboratory abnormalities.

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".)

NOMENCLATURE — ASOD and systemic juvenile idiopathic arthritis (sJIA) are terms that refer to a common clinical condition that can present at different ages. AOSD is used to describe patients who are diagnosed after 16 years of age, while sJIA is used to describe those who are diagnosed at 16 years of age or younger. The clinical manifestations and diagnosis of sJIA are discussed in detail elsewhere. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)

EPIDEMIOLOGY — AOSD is very uncommon [1-3]. A retrospective observational study in Japan found an incidence of 0.22 and 0.34 cases per 100,000 and a prevalence of 0.73 and 1.47 cases per 100,000 for males and females, respectively [1]. A subsequent Japanese study cited a prevalence of 3.9 cases per 100,000 [2]. It is unclear if prevalence is increasing or there has been increased ascertainment or reporting over time. 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 [4,5].

ETIOLOGY — Although the specific etiology of AOSD remains unknown, it is likely the manifestation of an autoinflammatory cascade due to innate immune cell activation. This differentiates it from autoimmune mediated inflammatory diseases in which autoantibodies or autoantigen-specific T and/or B cells lead to inflammation and tissue damage [6]. The pathologic amplification of the inflammatory response (ie, “cytokine storm”) in AOSD is likely multifactorial, possibly due to infectious and/or genetic triggers. The final common pathway of the inflammatory response has been attributed to NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation with interleukin 18 (IL-18) overproduction [7].

While there is no proof of a causal link between a specific infection and AOSD, it has long been theorized that infection can trigger AOSD in a genetically predisposed host. AOSD is often preceded by a severe pharyngitis [8]. Potential infectious pathogens including both viruses (rubella, measles, echovirus 7, coxsackievirus B4, cytomegalovirus, and Epstein–Barr virus) and bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Yersinia enterocolitica, Brucella abortus, and Borrelia burgdorferi) [6].

Some studies have found an association between certain human leukocyte antigen (HLA) alleles and the development of AOSD or its disease course [9-13]. Polymorphisms in the IL-18 gene and in macrophage migration inhibitory factor (MIF) gene may also be associated with genetic susceptibility to AOSD [14,15].

Both solid cancers and hematological malignancies have been proposed as possible triggers of AOSD. However, it is challenging to know whether and how malignancy and AOSD may be related when they are diagnosed in the same patient, since symptoms of malignancy may initially be misclassified as AOSD, and a malignancy may be incidentally diagnosed during the extensive workup required to diagnose AOSD [16].

CLINICAL PRESENTATION

Clinical symptoms — 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 [17]. In addition, a majority of patients also have other symptoms or findings, including myalgia, pharyngitis, lymphadenopathy, and splenomegaly.

Other features that occur in a minority of patients include hepatomegaly, pleurisy, pericarditis, and abdominal pain. Macrophage activation syndrome (MAS) is an infrequent but serious and potentially fatal complication.

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, and some patients with AOSD may present as fever of unknown origin [18]. The temperature swings can be dramatic, with changes of 4ºC (7.2ºF) occurring within four hours [19,20]. Patients with AOSD do not always completely defervesce, as fever persists between spikes in approximately 20 percent of cases [13]. A temperature of greater than 39.5ºC (103.1ºF) is more strongly associated with the monophasic pattern of AOSD [21]. (See "Fever of unknown origin in adults: Etiologies" and 'Natural history/disease course' below.)

Rash — The classic skin rash of AOSD is an evanescent, salmon-colored, macular or maculopapular cutaneous eruption that is usually nonpruritic. It is similar to the one seen in systemic juvenile idiopathic arthritis (sJIA) (picture 1). It 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 may be elicited by stroking the skin (picture 2). 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.

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. Distal interphalangeal joints and sacroiliac joints can also be affected in some patients [23]. 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 an inflammatory arthritis.

●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 [13]. 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 [8]. 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 [8,24].

Liver disease — Hepatomegaly is reported in a significant minority of patients; the frequency in different studies ranges from 12 to 45 percent [17]. Modest elevations of serum hepatic aminotransferases and alkaline phosphatase are even more common. These laboratory 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 [25]. (See 'Liver function studies' below.)

At least eight cases of fulminant liver failure in association with AOSD have been described, with four fatalities [13,26]. All patients had been treated with NSAIDs.

Pulmonary disease — Pleurisy, pleural effusions, and transient pulmonary infiltrates have been observed in 6 to 50 percent of patients with AOSD [27]. Affected patients may complain of a slight cough, pleuritic chest pain, or mild dyspnea. However, severe interstitial lung disease has also been described [28-31]. Uncommonly, some patients progress to acute respiratory distress syndrome (ARDS) [27,28,32]. Pleuritis and ARDS are more common in AOSD when it is associated with MAS. (See 'Macrophage activation syndrome' below.)

Since the introduction of anti-IL-1 and anti-IL-6 therapies for sJIA, there has been an increase in reports of sJIA 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 [30]. (See "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Lung disease'.)

Lymphadenopathy and splenomegaly — Lymphadenopathy is present in up to two-thirds of patients with AOSD and is typically symmetrical [17]. Slightly tender, enlarged cervical lymph nodes are seen in about one-half of patients. Splenomegaly may also occur in one-third to one-half of patients with AOSD [17].

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 [17]. 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 [34].

Macrophage activation syndrome — AOSD can be associated with MAS, which is a subtype of hemophagocytic lymphohistiocytosis (HLH) that occurs in the setting of systemic rheumatic disease, most commonly AOSD or sJIA. MAS and HLH are driven by a hyperinflammatory state or "cytokine storm." MAS is chiefly characterized by fever, hepatosplenomegaly, and multiple laboratory abnormalities including high levels of inflammation, high ferritin, cytopenias, and transaminitis. MAS is the leading cause of death for patients with AOSD [35]. A more detailed discussion of the clinical features of MAS is presented elsewhere. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders/MAS'.)

MAS is a serious but rare manifestation of AOSD. Assessing its exact frequency is challenging given that MAS may be underdiagnosed and the studies are small and subject to referral bias of the sickest patients. Only 1.7 percent of patients with AOSD developed MAS in a large retrospective study using the United States nationwide inpatient sample [36]. Other smaller retrospective cohort studies have reported MAS in 10 to 19 percent of patients with AOSD [21,37-39].

MAS can occur at any time during AOSD, and simultaneous presentation of AOSD and MAS is not unusual. Both MAS and AOSD were present at the time of diagnosis of AOSD in 7 of 8 patients, 6 of 8 patients, and 12 of 20 patients described in retrospective case series [37-40].

When MAS/HLH is present in a patient with AOSD, it may be due to the AOSD itself or due to an infection in the setting of immunosuppression, such as reactivation of latent viruses. HLH associated with causes other than AOSD should also be considered in the differential diagnosis of patients suspected of having AOSD. (See 'Other differential diagnoses' below.)

It is critical to distinguish when a flare of AOSD is evolving into MAS since MAS can progress rapidly and is associated with significant morbidity and mortality. Differentiating AOSD with MAS from AOSD alone can be challenging because of their similar clinical presentations. However, certain clinical features that can be helpful in distinguishing patients with AOSD and concurrent MAS include the following:

●Symptoms or signs that may occur more commonly in patients with AOSD and MAS include lymphadenopathy, weight loss, hepatomegaly or liver dysfunction, splenomegaly, and neurologic symptoms [35,40,41].

●Serum ferritin levels are typically much higher in AOSD with concurrent MAS [35,40,41]. In a retrospective cohort study of 206 patients with AOSD, including 20 who developed MAS, a ferritin threshold of 3500 micrograms per liter had a sensitivity of 85 percent and a negative predictive value of 97 percent for identifying MAS [40].

●Transaminitis is more pronounced in AOSD with MAS but can be present in AOSD alone [35,40].

●Serum triglycerides, which are typically in the normal range in patients with AOSD alone, may be very high in AOSD with MAS, although this typically happens later in the disease course [35,40].

●Patients with AOSD and MAS have higher rates of cytopenias including leukopenia, thrombocytopenia, or pancytopenia [35,40]. Since patients with AOSD commonly have leukocytosis or thrombocytosis, white blood cell count and platelets may be normal early in the course of AOSD with MAS as cytopenia evolves.

●Erythrocyte sedimentation rate (ESR) in patients with both AOSD and MAS may be lower than expected for the degree of inflammation, or even normal, due to low or normal levels of haptoglobin and fibrinogen [37,39,42].

●The presence on bone marrow examination of numerous, well-differentiated macrophages (histiocytes) that are engaged actively in the phagocytosis of hematopoietic elements is a diagnostic hallmark of MAS and is more common in patients with AOSD with MAS, but this finding has also been described in patients with AOSD who did not have concurrent MAS [35,37,40,43].

Other clinical features — Rare clinical manifestations of AOSD may include the following:

●Neurologic involvement, including seizures, aseptic meningitis, reversible posterior leukoencephalopathy, and encephalitis.

●Cardiac manifestations, including myocarditis (which can cause arrhythmias), heart failure, and cardiac tamponade [44].

●Kidney involvement, including proteinuria that may be associated with interstitial nephritis, mesangial glomerulonephritis, collapsing glomerulopathy, and secondary amyloidosis.

●Hematologic involvement, including associated microangiopathic hemolytic anemia associated with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome [45-47], and disseminated intravascular coagulation [36,37]. (See "Diagnosis of immune TTP" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

●Neurologic involvement, including seizures, aseptic meningitis, reversible posterior leukoencephalopathy and encephalitis.

●Ophthalmologic involvement, including keratoconjunctivitis sicca, conjunctivitis, episcleritis, and uveitis [17,26,48,49].

Laboratory findings — While a number of laboratory findings are characteristic of AOSD (table 1), they are also nonspecific, adding to the challenge of accurate and timely diagnosis. Common findings include signs of a systemic inflammatory response such as elevated acute phase reactants, leukocytosis with neutrophilia, thrombocytosis, anemia, and elevated hepatic aminotransferases. Elevations in serum ferritin can be striking and are commonly above levels seen in other disorders.

Acute phase reactants

ESR and CRP — Marked elevations in acute phase reactants (eg, ESR and C-reactive protein [CRP]) are seen in virtually all patients with AOSD [13]. A paradoxical drop in ESR when liver function tests and CRP are stable or increasing can suggest the development of concurrent MAS, as has been described in patients with sJIA [50]. (See 'Macrophage activation syndrome' above and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications".)

Serum ferritin — AOSD has been associated with markedly elevated serum ferritin concentrations, which are seen in over 90 percent of patients [51]. Hepatocytes increase ferritin synthesis as part of the acute phase response to inflammatory cytokines [52]. However, the extremely high levels of ferritin seen in AOSD may reflect a dysregulated feedback loop that augments the autoinflammatory response [53].

Serum ferritin concentrations exceeding 3000 ng/mL (normal is 40 to 200 ng/mL) have been observed in up to 60 percent of patients with AOSD [51], with some patients having values above 10,000 ng/mL [43,54]. The degree of ferritin elevation correlates with AOSD disease activity and has been suggested as a serologic marker to monitor the response to treatment [55-57]. Levels are typically higher when AOSD is complicated by MAS [58,59]. (See 'Macrophage activation syndrome' above.)

High ferritin levels are not sufficient to diagnose AOSD and may be seen other syndromes such as MAS unrelated to AOSD, catastrophic antiphospholipid antibody syndrome, and septic shock [58].

The percentage of the ferritin that is glycosylated in AOSD tends to be lower than in other rheumatic diseases [56,60-62]. In one study, for example, the respective values were 3.7 and 30 percent [56]. The percentage of glycosylated ferritin may remain low both in the active phase of disease and in remission [61].

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 [63].

Evidence of hemolysis, thrombocytopenia, and/or coagulopathy may be present in patients with other infrequent but serious hematologic manifestations of AOSD including hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura, with microangiopathic hemolytic anemia, and disseminated intravascular coagulation. (See 'Other clinical features' 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 [13].

Immunologic studies — Antinuclear antibodies (ANA) and rheumatoid factor (RF) are present in fewer than 10 percent of patients with AOSD and typically only in low titer.

Multiple proinflammatory cytokines and chemokines have been proposed as potential biomarkers, although most are not specific. None of these cytokine or chemokine tests are available for routine clinical use, but several can be ordered through specialized testing facilities. Potential biomarkers include the following:

●Proinflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon gamma, are frequently elevated in AOSD, but none have high specificity [64-66].

●IL-18 is elevated in AOSD, and the elevation appears to be more specific for AOSD than for other systemic rheumatic diseases [67-69]. Normalization of IL-18 has been association with disease remission [70], and high IL-18 has been associated with the development of MAS [71].

●Multiple chemokines have found to be increased in AOSD, including chemokine ligand 9 (CXCL9), CXCL10, CXCL11, and CXCL13. These may be inherently pathogenic and/or represent markers of disease activity [68,72].

●Adenosine deaminase 2 has been identified as a potential biomarker of MAS in patients with AOSD and sJIA [73,74].

Imaging findings — Early in disease, hand radiographs are typically normal or show signs of soft tissue swelling and sometimes joint effusions [13]. Changes of periarticular osteopenia may develop. The classic radiographic finding of AOSD is a nonerosive narrowing of the carpometacarpal and intercarpal joint spaces of the wrist, which can progress to bony ankylosis [75-77]. While it is likely that modern treatment regimens will decrease rates of severe arthritis, the intercarpal and/or carpometacarpal joint spaces still appear to be affected in up to 75 percent of patients [78].

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 [13,19,79,80].

Computed tomography (CT) and ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) may be abnormal. In one series, changes demonstrated on CT included pulmonary abnormalities, lymph node enlargement, splenomegaly, and hepatomegaly, and ¹⁸FDG-PET scans revealed increased uptake in lymph nodes, salivary glands, and other tissues [21,81].

Natural history/disease course — The clinical course of AOSD can be divided into three main patterns: monophasic (or monocyclic), intermittent, and chronic [13,21,48]. 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 [13,34].

●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 predominate in this group, including fever, rash, serositis, and hepatosplenomegaly.

●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 are not predictable, 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.

EVALUATION AND DIAGNOSIS

When to suspect adult-onset Still's disease — The diagnosis of adult-onset Still's disease (AOSD) should be suspected in any patient who presents with persistent fever without a clear source plus any of the following clinical features:

●Fever spiking once to twice per day (quotidian or double quotidian pattern) (see 'Fever' above)

●Evanescent, salmon-colored, nonpruritic, macular or maculopapular rash on the trunk and extremities, often most prominent when the patient is febrile (see 'Rash' above)

●Arthralgia and/or arthritis (see 'Musculoskeletal' above)

●Markedly elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) (see 'ESR and CRP' above)

●Markedly elevated serum ferritin (especially >3000 ng/mL) (see 'Serum ferritin' above)

●Features concerning for macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), including high levels of inflammation, high ferritin, cytopenias, and transaminitis (see 'Macrophage activation syndrome' above)

Initial evaluation — For all patients suspected of having AOSD, we perform a thorough history and physical examination as well as laboratory and imaging studies to help identify typical features and to exclude other possible diagnoses. In selected patients, tissue biopsy may also be indicated.

History and physical examination — In all patients with suspected AOSD, we obtain a detailed medical history with particular attention to presence of daily fever, rash, joint pain or swelling, myalgia, sore throat, and enlarged lymph nodes. Patients should be asked about symptoms or signs related to conditions in the differential diagnosis, including recent infection, diarrhea, dysuria, muscle weakness, easy bleeding or bruising, swelling of feet or legs, and antecedent drug exposures. They should also be questioned about their response to prior therapy, as many patients report a striking response to nonsteroidal antiinflammatory drugs (NSAIDS).

We perform a thorough physical examination including a detailed skin examination; evaluation for lymphadenopathy, splenomegaly, and hepatomegaly; and a thorough joint examination of the upper and lower extremities and spine. It is optimal to do a skin examination when the patient is febrile, given the rash's evanescent nature. We perform a skin examination with particular attention to regions where there is pressure (eg, under an elastic waistband) as well as to lesions or injuries that may be a source of infection.

Laboratory and imaging studies — In all patients with suspected AOSD, we obtain the following laboratory and imaging studies:

●Complete blood count, differential, and platelet count

●Blood urea nitrogen, creatinine, urinalysis with microscopic examination, and urine culture

●Liver function tests, including aminotransferases and alkaline phosphatase, bilirubin, and serum albumin

●ESR and 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

●If arthritis is present, arthrocentesis and synovial fluid analysis, including cell count, differential, Gram stain and culture, and crystal search

●Chest radiograph (or CT of the chest in patients with suspicion for occult lung disease)

Use of both the total serum ferritin and the glycosylated fraction may provide more diagnostic specificity for AOSD than either test alone, although the test for the glycosylated ferritin isoform is not widely available. 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 [62]. However, an elevated ferritin alone is not diagnostic, and it is most helpful when viewed in the context of other clinical signs and symptoms.

Other tests may be indicated depending on a patient's symptoms, examination findings, and the clinical probability of alternative diagnoses but are not required to make the diagnosis of AOSD. These may include:

●Hand and foot radiographs in patients with a history of recurring arthritic symptoms

●Echocardiography for patients with cardiac symptoms or concern for endocarditis

●Anti-neutrophil cytoplasmic antibody testing in patient with suspicion of systemic vasculitis

●Serologic or polymerase chain reaction studies for specific infectious diseases depending on symptoms and potential exposures (eg, malaria, syphilis, streptococcal or viral pharyngitis)

●Hand and foot radiographs in patients with a history of recurring arthritic symptoms

Patients with concern for AOSD are often being simultaneously evaluated for fever of unknown origin. A comprehensive evaluation for fever of unknown origin is discussed elsewhere. (See "Fever of unknown origin in adults: Evaluation and management".)

Tissue biopsy in selected patients

●Indications – Tissue biopsy is not required to establish the diagnosis of AOSD, and there is no biopsy that is sufficient to diagnose AOSD in isolation. However, tissue biopsy may be indicated to evaluate for complications from AOSD or to exclude alternative possible diagnoses if the diagnosis is unclear (see 'Differential diagnosis' below). As an example, bone marrow biopsy would be indicated in a patient in whom there is a concern for MAS or for a lymphoproliferative malignancy. The need for and timing of a biopsy depend on multiple factors including the clinical utility, severity of symptoms, overall stability of the patient, and risks of a biopsy. In cases where patients may receive systemic glucocorticoids, it is important to obtain any indicated biopsies prior to initiating treatment if possible, as glucocorticoids may impact the interpretation of biopsy results (eg, lowering the sensitivity of lymph node biopsy for malignancy).

●Choice of biopsy site – Choice of a potential biopsy site should be guided by focal symptoms or examination findings and the need to exclude alternative diagnoses. For example:

•Bone marrow biopsy should be performed for patients suspected of having lymphoproliferative malignancy, HLH, or MAS. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Indications'.)

•Lymph node biopsy should be performed for patients with lymphadenopathy when considering hematologic malignancy, atypical infection, or granulomatous disease. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Lymph node biopsy'.)

•Skin biopsy may be indicated in patients with rash when considering neutrophilic dermatoses, drug hypersensitivity reactions, or a malignancy such as cutaneous lymphoma. (See "Skin biopsy techniques", section on 'Indications'.)

•Liver biopsy may be indicated for patients with hepatic dysfunction, especially when being evaluated for fever of unknown origin. (See "Approach to liver biopsy".)

•Synovial biopsy may be indicated in patients with arthritis to exclude atypical infections, sarcoidosis, or intraarticular tumors. (See "Monoarthritis in adults: Etiology and evaluation", section on 'Synovial biopsy'.)

•Muscle biopsy may be considered in patients with muscle weakness to evaluate for possible inflammatory myopathy, especially if advanced muscle imaging is not available.

●Histopathologic findings – Typical histopathologic findings in AOSD are described below:

•Lymph node biopsy – Lymph node biopsy typically shows intense, paracortical immunoblastic hyperplasia, which is distinct from the changes observed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's disease, or Kikuchi disease [82]. Changes on light microscopy may resemble lymphoma, but immunohistochemistry reveals a benign polyclonal B-cell hyperplasia [83,84].

•Bone marrow biopsy – Findings on bone marrow examination in a series of 12 patients with AOSD revealed hyperplasia of granulocytic precursors in all of the marrow samples [85]. Other features that were less frequent included hypercellularity (75 percent), increased histiocytes (25 percent), and the presence of hemophagocytosis (17 percent).

•Skin biopsy – The cutaneous histopathology reveals nonspecific findings, including dermal edema and mild perivascular inflammation in the superficial dermis, consisting primarily of lymphocytes and histiocytes (picture 3A-B). Immunofluorescence of the skin biopsy may show slight deposition of complement component 3 (C3) in the blood vessel walls [22].

•Liver biopsy – Liver biopsy findings are nonspecific but range in severity from minimally abnormal to fulminant hepatic necrosis [13,26].

•Synovial fluid and tissue – 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 [13,86]. Synovial biopsy in AOSD reveals a chronic synovitis with slight cell proliferation in the synovial lining layers, moderate vascular engorgement, and a mononuclear cell infiltrate.

•Muscle biopsy – Muscle biopsy in AOSD is usually normal or shows a nonspecific inflammation. Rarely, pathology may be consistent with an inflammatory myopathy [87].

Establishing the diagnosis — The diagnosis of AOSD is a diagnosis of exclusion that can generally be made based upon the presence of the characteristic clinical and laboratory features and the absence of another condition that may cause similar symptoms and findings [17,34,48,88]. (See 'Evaluation and diagnosis' above and 'Differential diagnosis' below.)

The clinical presentation is heterogeneous, but the most characteristic features are (see 'Clinical presentation' above and 'Laboratory findings' above):

●Daily spiking fever

●A cutaneous evanescent salmon-pink maculopapular eruption, most often present during the febrile hours

●Arthritis and/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, lymphadenopathy, elevated hepatic aminotransferases, elevated acute phase reactants, and thrombocytosis.

The important categories of disease to exclude are:

●Infectious diseases, especially acute viral infection

●Malignancy, especially lymphoproliferative disorders

●Drug reactions

●Systemic autoimmune rheumatic diseases, such as RA and SLE

●Autoinflammatory diseases

●Neutrophilic dermatoses, such as Sweet syndrome

There are several sets of classification criteria that are useful for research but 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 [34,48]. 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 is also quite broad and should be considered in the differential diagnosis of AOSD. (See "Fever of unknown origin in adults: Etiologies" and "Fever of unknown origin in adults: Evaluation and management".)

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. Human immunodeficiency virus (HIV) infection can be associated with fever and lymphadenopathy and can be diagnosed by appropriate laboratory testing. Differences between acute viral infection and AOSD may include the pattern and duration of fever, the appearance and timing of rash, and the self-limiting nature of many viral syndromes. (See "Fever of unknown origin in adults: Evaluation and management" and "Virology, epidemiology, and pathogenesis of parvovirus B19 infection" and "Hepatitis B virus: Screening and diagnosis in adults" and "Screening and diagnosis of chronic hepatitis C virus infection" and "Acute and early HIV infection: Clinical manifestations and diagnosis" and "Viral arthritis: Causes and approach to evaluation and management".)

●Bacterial infection and endocarditis – Fever, leukocytosis, and elevated acute phase reactants are nearly universal in patients with AOSD but are 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 "Fever of unknown origin in adults: Evaluation and management" and "Detection of bacteremia: Blood cultures and other diagnostic tests" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

●Parasitic infections – Parasitic infections such as malaria, toxoplasmosis, and trypanosomiasis share clinical similarities with AOSD. Fever in malaria typically has high spikes like that in AOSD but occurs irregularly each day early in infection and evolves to every second to third day later in the infection depending on the subtype. Toxoplasmosis can present with fever and lymphadenopathy but usually only causes acute infection in immunocompromised hosts. Trypanosomiasis can also be associated with fever and lymphadenopathy, as well as musculoskeletal pain and hepatosplenomegaly. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Toxoplasmosis: Acute systemic disease" and "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)

Malignancy — There may be diagnostic confusion with lymphoma, especially non-Hodgkin lymphoma or Hodgkin disease, due to the frequent presence of fever, lymphadenopathy, and leukocytosis, 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 [83,84]. (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 [17,34].

Drug reactions — Some drug hypersensitivity reactions can mimic features of AOSD, including drug fever and the syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS). In particular, DRESS and AOSD both present with fever, rash, lymphadenopathy, and abnormal liver chemistries [89]. However, 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)".)

Systemic autoimmune rheumatic diseases — The arthritis and elevated acute phase reactants of AOSD may mimic a broad range of other rheumatic diseases, including reactive arthritis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), and vasculitis. Serum ferritin values above 3000 ng/mL are generally not observed in rheumatic diseases other than AOSD. Distinguishing features of these rheumatic diseases include the following:

●Reactive arthritis – Patients with reactive arthritis may develop oligoarticular arthritis within several days to weeks following infections, most commonly gastrointestinal or urinary tract infections. Fever may occur with the infection but should resolve as infectious symptoms subside, unlike in AOSD. In addition, reactive arthritis tends to be less responsive to NSAIDs than AOSD. (See "Reactive arthritis", section on 'Clinical manifestations'.)

●Rheumatoid arthritis – 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. RF is positive in under 10 percent of patients with AOSD and is usually a low titer. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation and diagnosis'.)

●Systemic lupus erythematosus – Patients with SLE may experience alopecia, Raynaud phenomenon, cutaneous lupus, and glomerulonephritis. Labs will almost always show a positive antinuclear antibody (ANA) and other autoantibodies such as anti-double stranded deoxyribonucleic acid (DNA) and/or anti-Smith antibodies. By contrast, ANA is positive in less than 10 percent of patients with AOSD and is usually a low titer. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation'.)

●Dermatomyositis and polymyositis – Patients with 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. 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 "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Diagnostic approach' and 'Tissue biopsy in selected patients' above.)

●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, kidney disease, and skin lesions of PAN, if present, differ from AOSD. Diagnosis of PAN can often be established with a biopsy of an affected organ, and/or vascular imaging studies, in conjunction with antineutrophil cytoplasmic antibody testing. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

Other differential diagnoses

●Autoinflammatory diseases – Hereditary autoinflammatory 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). In periodic fever syndromes, the fever typically recurs periodically and in self-limited episodes, which is unlike the fever pattern of AOSD. Other features that distinguish TRAPS include eye and periorbital involvement, which is not seen in AOSD, and focal myalgia, unlike the more diffuse myalgia of AOSD. The diagnosis of these syndromes can be confirmed by commercially available genetic testing, which is described elsewhere. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

●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".)

●Schnitzler syndrome – Schnitzler syndrome, like AOSD, may present with arthralgia, intermittent fever, and lymphadenopathy; but unlike AOSD, Schnitzler 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'.)

●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 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 – Hemophagocytic lymphohistiocytosis (HLH) is classically defined as a disease of perforin-/granzyme-mediated cytotoxicity, and macrophage activation syndrome (MAS) as a disease of cytokine activation. However, increasingly sophisticated studies suggest that HLH and MAS are clinically overlapping conditions with final "convergent pathways" [90]. Patients with HLH unrelated to AOSD may have similar degrees of hyperferritinemia to AOSD. Both marked hyperferritinemia and a low fraction of glycosylated serum ferritin also occur in MAS as well as in various syndromes associated with HLH, such as those lymphoma and severe drug reactions [37,91,92]. The presence of cytopenia in multiple lineages is more characteristic of HLH or AOSD with MAS as opposed to AOSD alone, including leukopenia, granulocytopenia, lymphopenia, and thrombocytopenia. Interleukin 18 (IL-18) levels, reflecting a "cytokine storm," may be higher in AOSD/MAS compared with HLH [93]. The diagnosis of HLH/MAS can be confirmed by bone marrow biopsy, which can be used to direct therapy; however, the pathogenesis of HLH/MAS will depend on the clinical context. (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 [20,79,86,94-97]. 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 'Evaluation 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 [79], have the highest sensitivity in patients with a definite diagnosis of AOSD [98].

The Yamaguchi criteria require the presence of five features, with at least two being major diagnostic criteria [79]. 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

●Overview – Adult-onset Still's disease (AOSD) is an autoinflammatory disorder characterized by quotidian (daily) fevers, arthritis, and an evanescent rash. Diagnosing AOSD is challenging as patients may have a variety of nonspecific symptoms and laboratory abnormalities. (See 'Introduction' above and 'Nomenclature' above.)

●Etiology – Although the specific etiology of AOSD remains unknown, it is likely the manifestation of a pathologic autoinflammatory cascade due to innate immune cell activation (also called "cytokine storm"), possibly in the setting of infectious or genetic triggers. (See 'Etiology' above.)

●Clinical presentation

•Clinical symptoms – The major clinical features of AOSD include fever, rash, and arthritis or arthralgia, with each occurring in over 75 percent of patients. In addition, a majority of patients also have other symptoms or findings, including myalgia, pharyngitis, lymphadenopathy, and splenomegaly. (See 'Clinical symptoms' above.)

Macrophage activation syndrome (MAS) is a rare and serious manifestation of AOSD, characterized by fever, hepatosplenomegaly, and multiple laboratory abnormalities including high levels of inflammation, high ferritin, cytopenias, and transaminitis. (See 'Macrophage activation syndrome' above.)

•Laboratory findings – Common laboratory findings are not specific to AOSD but include signs of a systemic inflammatory response such as elevated acute phase reactants, leukocytosis with neutrophilia, thrombocytosis, anemia, and elevated hepatic aminotransferases. Elevations in serum ferritin can be striking (especially >3000 ng/mL) and are typically above levels seen in other disorders. (See 'Laboratory findings' above.)

●Evaluation and diagnosis

•When to suspect AOSD – The diagnosis of AOSD should be suspected in any patient who presents with persistent fever without a clear cause plus any of the following clinical features: rash, arthralgia and/or arthritis, markedly elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), markedly elevated serum ferritin, or features concerning for MAS. (See 'When to suspect adult-onset Still's disease' above.)

•Initial evaluation – For all patients suspected of having AOSD, we perform a thorough history and physical examination as well as laboratory and imaging studies to help identify typical features and to exclude other possible diagnoses. In selected patients, tissue biopsy may also be indicated to evaluate for complications from AOSD or to exclude alternative possible diagnoses if the diagnosis is unclear. (See 'Initial evaluation' above.)

•Establishing the diagnosis – AOSD is a diagnosis of exclusion that can generally be made based upon the presence of the characteristic clinical and laboratory features and the absence of another condition that may cause similar symptoms and findings. (See 'Establishing the diagnosis' above.)

●Differential diagnosis – The differential diagnosis of AOSD is extensive. The important categories of disease to exclude are infection, malignancy, drug reactions, systemic autoimmune rheumatic diseases, autoinflammatory diseases, and neutrophilic dermatoses. (See 'Differential diagnosis' above.)