Approach

Introduction

Diagnosis of adult-onset Still disease (AOSD) is often difficult because it has a variable course and the clinical features overlap with those seen in a wide range of other inflammatory conditions.[2] As there is no definitive diagnostic test for AOSD, it is often a diagnosis of exclusion.[5][22]​​​ Due to this difficulty, diagnosis is frequently delayed.[23][24]​​​[25][26][27]

  • Consider the diagnosis of AOSD if a young adult presents with daily intermittent high fevers, arthralgia, and a salmon-pink skin rash.

  • Presentation varies and may include additional systemic features such as pharyngitis, pleuritis, or pericarditis. It may be a first episode, or one of intermittent or prolonged chronic symptoms.

  • Check CBC, CRP, ferritin, and, if available, glycosylated ferritin. These are key investigations alongside others to rule out differentials such as infection, malignancy, or autoimmune disease.

  • Consider the clinical findings and investigation results alongside diagnostic classification criteria to help identify the condition.

History

Take a thorough history. Ask about the following most common features:[1][2][5]​​

  • Intermittent high-spiking fever ≥102.2°F (≥39.0°C)

  • Arthralgia or arthritis

  • Salmon-pink skin rash.

Fever

Almost all patients experience fever, which is typically high spiking (≥102.2°F [≥39.0°C]), occurring daily or occasionally twice daily over a period of at least 1 week, and resolving each time within a few hours.[5]​ Larger, more recent studies report fever in 91% to 100% of people with AOSD.[5][7][25][28][29][30][31]​​​​​

Arthralgia and arthritis

Arthralgia is reported in 47% to 95% in different studies of people with AOSD.[2][5][7][25]​​[28][29]​​[30][31]​​​​​​ Arthritis (seen in 51% to 66% of patients) typically begins as mild and localized, but it can become increasingly severe and polyarticular over the course of the disease.[2][5]​​

  • Joints that are commonly affected include the proximal interphalangeal joints, wrists, elbows, knees, and ankles.[23][25][32][33][34]​​​[35]

  • The distal interphalangeal joints and shoulder joints are typically spared.[23][25][32]​​​[33][34][35]​​​

  • Polyarticular disease is more common (30% to 90%) than oligoarticular (2% to 42%) or monoarticular (2% to 12%).[2]

Skin rash

The typical skin rash in AOSD is salmon-pink, nonpruritic, and maculopapular. It is transient, occurring during fever. Larger, more recent studies report a frequency of 62% to 80%.[5][7][25]​​[28][29]​​​[30][31]​​ Other reported skin manifestations include urticaria and dermatographism (seen in 31% to 59% of patients).[5] These are pruritic hives that appear and resolve over minutes to hours, leaving normal skin behind. In the case of dermatographism, the hives typically arise from scratching or mild trauma of the skin. Neutrophilic urticarial dermatosis may also occur, consisting of urticarial lesions lasting 24-48 hours with dense neutrophilic infiltrates on biopsy.[5]

[Figure caption and citation for the preceding image starts]: Salmon-pink rash typical of AOSD on right arm of a 28-year-old woman of Nigerian heritageAkintayo RO et al. BMJ Case Reports 2015; 2015: bcr2015210789; used with permission [Citation ends].com.bmj.content.model.Caption@5061af2b[Figure caption and citation for the preceding image starts]: Salmon-pink rash on the chest and neck of a white man with AOSDFrom the collection of Dr Sinisa Savic; used with permission [Citation ends].com.bmj.content.model.Caption@1ab5b207

Other common symptoms

Ask about other common symptoms of AOSD including the following, which typically occur during fevers:

  • Sore throat/pharyngitis: seen in over half of patients and up to 92% in some studies, but less common in patients ages ≥65 years (54% compared with 86% in one study).[32][36][37]​​​

  • Myalgia: frequency: 26% to 53%[5]

  • Pleuritis: different studies report variable incidence, with some reporting it in over half of patients with AOSD.[5]

In practice, patients sometimes have a history of unverified reports of high temperatures, repeated courses of antibiotics for sore throats, and a rash that can settle with the fever, leaving little to see for an attending physician.

Other less common features include symptoms associated with pericarditis and myocarditis.[2]

Older patients ages ≥65 years present similarly, although they are less likely than younger patients to develop pharyngitis and more likely to develop pleuritis (46% vs. 17%).[37][38] 

Risk factors

When taking a history, consider the presence of risk factors for AOSD, such as age and sex:

  • Multiple studies have found that women account for between 60% and 80% of people with AOSD.[8][11][12]​​[16]​​[17]​​

  • Most cases of AOSD occur in young adults, with a bimodal pattern showing two peaks of onset at ages 16-25 years and 36-46 years.[1][5]​​ However, there is now increasing evidence of a further peak between the ages of 60 and 65 years.​[7][8][9][10]​​​[16] Case series suggest that around 7% to 10% of cases are first diagnosed in patients older than 60 years of age although delayed diagnosis may be a contributory factor.[5]

Ask about any preceding infection

  • It is likely AOSD is the manifestation of a dysregulated immune system, precipitated by a preceding viral or bacterial illness.[18][19]​​​[20][21]

  • AOSD is thought to have a polygenic basis, whereby genetic factors predispose the patient to aberrant and sustained inflammatory responses in the context of an environmental or infectious trigger (e.g., cytomegalovirus, Epstein-Barr virus, rubella, Mycoplasma).[1][39][40][41]

Clinical course

When taking a history, be aware that the duration of symptoms and clinical course may vary between individual patients due to the different patterns of AOSD.

There are traditionally three broad patterns of disease:[5][42]​​

  • Monocyclic systemic (21% to 64% of cases): typically consists of one episode lasting a few months followed by remission.

  • Polycyclic systemic (9% to 50%): intermittent episodes or flares.

  • Chronic articular (12% to 56%): persisting symptoms, particularly affecting the joints.

More recently, a dichotomous classification system has been used, categorizing clinical AOSD subtypes as:[5]

  • Systemic (e.g., high fever, rash, multiorgan involvement) or

  • Articular (joint disease most prominent).

With future research, it is likely that these patterns will be further refined to incorporate clinical features, genetic analysis, cytokine profiles, and responses to treatment, as well as the manner in which the disease subtypes may evolve into separate autoinflammatory phenotypes as a consequence of prolonged immune dysregulation.[43]

Physical exam

Perform a full physical exam to identify the physical findings of AOSD and to exclude other conditions. This is particularly important as AOSD is typically a diagnosis of exclusion.

Common physical findings of AOSD include:[1][5][44]

  • A high-spiking fever (as described above)

  • Inflammatory arthritis (as described above)

  • A characteristic skin rash (as described above)

  • Lymphadenopathy (often cervical) (frequency: 28% to 51%)

  • Splenomegaly (frequency: 25% to 43%).

Perform a targeted exam of symptomatic joints to identify inflammatory disease.

Less common findings include:[2]

  • Hepatomegaly: studies vary on how frequently this occurs (7% to 71%).[5]

  • Signs of pericarditis (present in 3% to 17%) and myocarditis (in up to 7%).[7][25]​​[29]​​​​​​[30][45]​​ These are associated with treatment resistance and a less favorable prognosis.[2]

Keep in mind important differentials to exclude, such as:

  • Vasculitis

  • Malignancy

  • Systemic lupus erythematosus

  • Rheumatoid arthritis

  • Mononeuritis multiplex (perform a thorough neurologic exam)

  • The sequelae of infectious endocarditis (perform a thorough cardiac exam).

See Differentials.

Complications of AOSD as presenting features

Consider the possibility that a patient may present with one or more complications of AOSD. Macrophage activation syndrome (MAS) is the most common and significant of these complications. Reports of its frequency vary widely, ranging from 1.7% to 23.0% of AOSD patients, and patients with an older onset (≥65 years) are three to five times more likely to develop it.[1][4][5]​​[6]

This highlights the need to consider the diagnosis of AOSD in those presenting with MAS and conversely to consider MAS in any acutely unwell patient with a preexisting diagnosis of AOSD.[2][7][11][16]​​[28]​ 

  • Evaluation for MAS is advised if risk factors are present (e.g., high clinical disease activity and/or laboratory markers such as high serum ferritin and cytopenia [particularly leukopenia]).[2]

  • In practice, it is not uncommon for a patient who has needed intensive care for MAS to be later managed for underlying AOSD. Seek an expert opinion where other rheumatologic and infectious causes have been ruled out.

Initial investigations

Exclude other more common causes of inflammation, as these can be fatal if left untreated or inappropriately treated. Investigations commonly start with those for a patient with a fever of unknown origin.[5]

Request the following initial investigations:

  • Routine bloods such as CBC, renal panel, liver function tests, and C-reactive protein and/or erythrocyte sedimentation rate.

  • A septic screen, including carefully taken blood cultures and, where available, a procalcitonin to identify any underlying bacterial infections.

  • Radiologic investigations, such as a chest x-ray and renal/liver ultrasound scan as part of an initial septic screen. More extensive imaging may be done as differentials are increasingly ruled out.

  • If pericarditis is suspected, confirm with an ECG and echocardiogram.

  • If myocarditis is suspected, investigate with an ECG, cardiac enzymes, echocardiogram, and cardiac MRI.

Typical biochemical and hematologic findings include:[1][4][5][46][47]​​

  • Elevated CRP

  • Elevated ESR

  • Leukocytosis

  • Neutrophilia

  • Anemia

  • Thrombocytosis or thrombocytopenia.

There may be elevated serum creatinine and/or abnormal LFTs, particularly elevations in aspartate and alanine aminotransferase.

Further investigations

Once AOSD is suspected, a large number of further investigations may be required to exclude the differential diagnoses and establish AOSD as the primary diagnosis. This may include extensive infectious screens including targeted cultures, interferon-gamma release assays (IGRAs) serology, and polymerase chain reaction (PCR) tests for specific infections; echocardiograms; lymph node biopsy; bone marrow biopsy; CT scans; and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans as more deep-seated infections, various malignancies, and MAS as a presenting complication need to be excluded.

Perform further tests to screen for autoimmune/rheumatologic conditions. These investigations include but are not limited to:

  • Rheumatoid factor (RF)

  • Anticitrullinated peptide (ACPA)

  • Antineutrophil cytoplasmic autoantibodies (ANCA)

  • Antinuclear antibodies (ANA)

  • HLA-B27

  • Muscle MRI/biopsy.

Check the ferritin level in any patient who has had differentials such as rheumatoid arthritis ruled out and who has or has had characteristic features of AOSD (e.g., persistent high temperatures and arthralgia, especially if supported by the characteristic rash or pharyngitis).[2]

  • Hyperferritinemia is common (89%) in people with AOSD, though in isolation is poorly predictive of the disease.[47] ​However, the combination of a markedly elevated serum ferritin (≥5 × ULN) together with low fraction of glycosylated ferritin (<20%) can act as a sensitive and specific marker for AOSD.[1][2]​​[47]

Diagnostic classification criteria

If ferritin is elevated, use diagnostic classification criteria for AOSD to help confirm the diagnosis.

  • A clinical diagnosis of AOSD is supported by fulfillment of the Yamaguchi criteria, developed in 1992.[2]

    • These are the most widely used and validated criteria for confirming a clinical diagnosis of AOSD, with a sensitivity of 96.2% and specificity of 92.1%.​[2][4][48]​​ Yamaguchi criteria require the exclusion of infections, other rheumatic diseases, and malignancies.[47]

  • If AOSD is suspected, check the glycosylated serum ferritin level if available as the Fautrel criteria can provide an invaluable tool in identifying the condition, ensuring early specialist care and management.[4][6]​​​​​​

    • The Fautrel criteria were developed in 2002 and allow the process to be streamlined as they do not require any exclusion criteria.[49]

    • The Fautrel criteria include serum glycosylated ferritin (<20%) measurements, although this test may not be available in all locations.[2][39][49]​​

    • The Fautrel criteria have been validated to give a sensitivity of 96.3%, specificity of 98.9%, and positive and negative predictive values of 94.5% and 99.3%, respectively.[50]

  • See Criteria for full details of the two classification criteria mentioned above.

Empirical corticosteroids

In practice, once infection, malignancy, and rheumatologic diseases are ruled out, a common form of investigation is "treat to test" with corticosteroids. A prompt response to corticosteroids would be seen in a person with AOSD and may guide the clinician when considering further investigations and more targeted therapies.

Genetic testing

Once initial testing is complete and an autoinflammatory condition is suspected, genetic analysis is increasingly playing a role in the identification of the specific underlying condition. Though there is no genetic test for AOSD, it is important to exclude known inherited and acquired monogenic disorders.[6] A useful database of these conditions is available. Infevers: The registry of hereditary auto-inflammatory disorders mutations Opens in new window

In young adults, primary hemophagocytic lymphohistiocytosis should be excluded, while in adults, genetic analysis can reveal either inherited mutations or those acquired by chance in later life, known as genetic somatic mosaicism. An example of both can be found in the group of conditions known as NLRP3-autoinflammatory diseases (NLRP3-AID), where mutations in the NLRP3 gene lead to a spectrum of autoinflammatory diseases.[6] 

In older adults presenting with autoinflammatory symptoms and cytopenias, acquired pathogenic mutations in the UBA1 gene should be sought to rule out VEXAS syndrome, which in the past has been commonly misdiagnosed as AOSD and has different treatment options.[6]

Emerging investigations

Each subtype of AOSD may have a characteristic cytokine profile, with interleukin (IL)-18/1β being predominant in the systemic subtype and IL-6 in the articular subtype.[43][51][52] Cytokine testing may have a future role in risk stratification and identifying the most appropriate therapies. Risk of complications may also be predicted (e.g., increased likelihood of MAS with elevated IL-18).[51][52]​​[53]

The proteins S100A12 and the S100A8/S100A9 dimer (calprotectin) are elevated in people with AOSD and have shown superiority over standard approaches in differentiating systemic juvenile idiopathic arthritis (sJIA) from other inflammatory conditions. They may, in the future, offer a more accurate biomarker for AOSD diagnosis and disease activity.​[54][55][56]​​[57][58]​​​[59]

There is an association of certain HLA subtypes with AOSD. HLA-DQB1*06:02 (OR 2.70), HLA-DRB1*15:01 (OR 2.44), HLA-DRB1*11(OR 2.3), and HLA-DQA1*01:02 (OR 1.97) have all demonstrated an association with AOSD compared with healthy controls and may have a potential role in diagnosis in the future although further research is required.[60][61]

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