AOSD is a rare autoinflammatory condition that usually affects young adults and typically presents with intermittent high-spiking fevers, arthralgias/arthritis, a transient salmon-pink rash, and sore throat among other symptoms.[1] [2] [3] [4][5] It is a clinical diagnosis based on the presence of typical symptoms, signs, and investigation results after exclusion of other rheumatologic conditions, infections, and malignancy.[2] [4] [5] Its clinical course is variable with some patients having one or intermittent flares of systemic symptoms followed by periods of remission and others having chronic symptoms that predominantly affect the joints.[2] [4] [5] Some patients present with life-threatening complications, the most common of which is macrophage activation syndrome (MAS).[2] AOSD is commonly understood to be the adult form of systemic juvenile idiopathic arthritis (sJIA).[3] [5] [6]
Highlights & Basics
Key Highlights
- Adult-onset Still disease (AOSD) is a rare multisystem autoinflammatory disorder that typically affects young adults. The clinical course varies and can be monocyclic, polycyclic, or chronic with either systemic or articular symptoms predominant.
- The diagnosis is challenging as there is no definitive test and the clinical features overlap with those of many other conditions. The classic presenting symptoms are daily intermittent high fevers, arthralgia, and a salmon-pink skin rash, although other symptoms such as pharyngitis are also common. Occasionally, the first presentation may be a life-threatening complication such as macrophage activation syndrome.
- It is vital to order a wide range of tests to rule out infection, malignancy, and other rheumatic disorders that can mimic AOSD. If AOSD is then suspected, the key investigations are serum ferritin (hyperferritinemia is a highly sensitive but poorly specific marker) and, if available, glycosylated ferritin (which is more specific).
- Treatment is stepwise, starting with systemic corticosteroids. If the patient does not respond or responds but then relapses when the corticosteroid is tapered, conventional synthetic disease-modifying antirheumatic drugs and/or biologic agents can be used as corticosteroid-sparing agents.
Quick Reference
History & Exam
Key Factors
fever ≥102.2°F (≥39.0°C)
arthralgia
arthritis
salmon-colored maculopapular skin rash
Other Factors
dermatographic urticaria
sore throat
myalgia
lymphadenopathy
pleuritis
splenomegaly
hepatomegaly
pericarditis
myocarditis
signs of macrophage activation syndrome (MAS)
Diagnostics Tests
1st Tests to Order
CBC
renal panel
C-reactive protein (CRP)
erythrocyte sedimentation rate (ESR)
liver function tests
procalcitonin
blood cultures
chest x-ray
renal and liver ultrasound scan
echocardiogram
ECG
Other Tests to consider
cardiac enzymes
cardiac MRI
serum ferritin
glycosylated ferritin
further tests as part of full septic screen
further tests as part of autoimmune/rheumatologic screen
fluorodeoxyglucose (FDG)-positron emission tomography (PET) whole-body scan
whole-body CT scan
bone marrow biopsy
lymph node biopsy
empirical corticosteroid trial
autoinflammatory gene profiling
Emerging Tests
cytokine profiles
serum S100A12; serum calprotectin (S100A8/S100A9 dimer)
HLA genotyping
Treatment Options
acute
severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome
specialist management
intravenous corticosteroid
biologic agent
nonsteroidal anti-inflammatory drug (NSAID)
ongoing
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
oral corticosteroid
nonsteroidal anti-inflammatory drug (NSAID)
conventional synthetic disease-modifying antirheumatic drug (DMARD)
oral corticosteroid
nonsteroidal anti-inflammatory drug (NSAID)
biologic agent
oral corticosteroid
conventional synthetic disease-modifying antirheumatic drug (DMARD)
nonsteroidal anti-inflammatory drug (NSAID)
Definition
Classifications
Categorization based on clinical course
Conventionally, the clinical course of AOSD has been observed to follow one of three patterns:[1] [4] [5]
- Monocyclic systemic: typically one systemic episode lasting a few months followed by remission
- Polycyclic systemic: intermittent episodes or flares with remissions lasting from weeks to several years
- Chronic articular: persisting symptoms, usually affecting multiple joints and with the potential to develop to joint destruction.
More recently, two subtypes of AOSD with distinct serologic profiles have been proposed based on the predominant symptoms:[3] [4] [5]
- Systemic manifestation - predominant symptoms of fever and skin rash, with possible multiorgan involvement
- Chronic articular manifestation - predominant joint symptoms.
Vignette
Common Vignette 1
A 26-year-old woman attends the emergency department with an 8-week history of daily fevers accompanied by an associated and short-lasting sore throat and nonpruritic rash. In the past 3 weeks, she has also developed painful, stiff, and swollen wrists and knees. She has had two courses of antibiotics for tonsillitis in the community with no benefit. Her only recent illness was a flu-like illness 2 months prior, requiring 4 days off work, though she recovered fully. On exam she has a temperature of 39.2°C, a salmon-pink, maculopapular rash on her trunk and shoulders and there are palpable tender cervical lymph nodes. Her wrist joints are mildly swollen and tender. Bloods show a raised WBC count (17 x 10⁹/L), raised neutrophils (12.5 x 10⁹/L), hyperferritinemia (1200 ng/ml), and raised C-reactive protein (265 mg/mL). Rheumatoid factor, anticitrullinated protein antibody, and an antinuclear antibody screen are negative.
Common Vignette 2
A 72-year-old man reports a 2-week history of daily high temperatures, arthralgia in both wrists, cervical lymphadenopathy, and pleurisy. In the past 2 days he has developed a central chest pain worse on deep inspiration and lying down. On exam he has a high temperature, cervical lymphadenopathy, a macular erythematous rash on his trunk and a pericardial rub heard on auscultation. ECG shows widespread ST elevation. Bloods show markedly raised WBC count (23 x 10⁹/L), raised neutrophils (18 x 10⁹/L), raised CRP (195 mg/mL), hyperferritinemia (4600 ng/mL), and raised troponin (24 ng/L). Echocardiogram shows pericardial effusion.
Epidemiology
There is a paucity of robust epidemiologic data on adult-onset Still disease (AOSD), with very few prospectively collected data. It is a rare disease with an annual incidence that varies in different studies between 0.16 per 100,000 and 0.4 per 100,000 and is associated with a clearly increased mortality.[1] [2] [4] The estimated point prevalence was reported by one review at 0.73-6.77 per 100,000 and by another at between 1 and 34 cases per million.[1] [5] Incidence and prevalence are higher in recent studies compared with older studies, likely because of increased awareness.[5]
Most cases occur in young adults, with a bimodal pattern showing two peaks of onset at ages 16-25 years and 36-46 years.[1] [4] [5] However, there is growing evidence of a further peak at ages 60-65 years, although delayed diagnosis may be a contributory factor.[5] [7] [8][9] [10]
Most studies have noted a female predominance, with women accounting for 60% to 80% of cases, although a minority have reported an equal distribution between men and women.[7] [8] [10] [11] [12]
In one of the largest nationwide studies of AOSD epidemiology in the US, analysis of 5-year retrospective data between 2009 and 2013 revealed an inpatient mortality of 2.6%.[12]
Etiology
Adult-onset Still disease (AOSD) is a multisystem autoinflammatory disorder with a presumed polygenic basis but the precise etiology remains unclear.[1] [5] [6] It is postulated that an external - in most cases infectious - trigger is required to provoke an aberrant inflammatory response in genetically susceptible individuals, leading to the development of the disease.[1] [4] [5] AOSD and systemic juvenile idiopathic arthritis (sJIA) are commonly considered to represent a continuum of the same disease entity, distinguished by their differing age of onset.[3] [5] [6]
Genetic factors are believed to predispose the individual to an aberrant and sustained inflammatory response to the trigger, although there is no clear evidence of a familial pattern to AOSD.[1] [4] [5] Research has found a link between human leukocyte antigen (HLA) gene polymorphisms and susceptibility to AOSD, suggesting an important role for the adaptive immune system.[6] The reported associations between AOSD and HLA antigens include HLA-B17, HLA-B18, HLA-B35, HLA-DR2, and HLA-DR4 and, in addition, an association has been noted with both HLA-DRB1*12 and HLA-DRB1*15.[1] [4] [5] Other genetic factors postulated to predispose individuals to AOSD include polymorphisms affecting the genes for interleukin (IL)-18 and macrophage migration inhibitory factor (MIF).[1] Furthermore, a proportion of patients with AOSD carry at least one genetic variant associated with certain of the prototypic monogenic autoinflammatory conditions.[6]
No single pathogenic trigger for the aberrant immune response has been defined, suggesting the possibility that multiple environmental triggers may be relevant.[1] Suggested infectious triggers include:[1] [4]
- Viruses: for example, adenovirus, human immunodeficiency virus (HIV), parvovirus B19, Epstein-Barr virus (EBV), rubella virus, measles virus, hepatitis virus, cytomegalovirus, and influenza virus
- Bacteria: for example, Mycoplasma pneumoniae, Chlamydia pneumoniae, Yersinia enterocolitica.
Pathophysiology
The pathophysiology of AOSD remains poorly understood, although recent advances indicate the importance of a systemic inflammatory process involving dysregulated activation of both the innate and adaptive immune system, leading to the production of proinflammatory cytokines.[1] [6] Neutrophils and macrophages are the main effector cells of this dysregulated immune response; neutrophil activation is a characteristic feature of the disease with over 80% of patients having neutrophilic leukocytosis during acute flares of the condition.[4] [5][6]
Cytokines associated with driving the proinflammatory cascade in AOSD include interleukin(IL)-1, IL-6, IL-8, IL-18, and IL-37; interferon-gamma; and tumor necrosis factor (TNF)-alpha.[1] [3] [5] [6] It is postulated that IL-1-beta and IL-18 are primarily responsible for systemic symptoms such as fever, rash, and multiorgan involvement, whereas TNF-alpha and IL-6 are more closely associated with joint symptoms.[4] [6] IL-1 and IL-6 inhibition have become important management strategies via the development of biologic therapies.[1] [4]
Images
Diagnostic Approach
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
- Intermittent high-spiking fever ≥102.2°F (≥39.0°C)
- Arthralgia or arthritis
- Salmon-pink skin rash.
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 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]
- Polyarticular disease is more common (30% to 90%) than oligoarticular (2% to 42%) or monoarticular (2% to 12%).[2]
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]
Ask about other common symptoms of AOSD including the following, which typically occur during fevers:
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]
When taking a history, consider the presence of risk factors for AOSD, such as age and sex:
- 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
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.
- 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.
- 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]
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).
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.
- 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]
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]
- 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 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 .
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
- 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)-18/1beta being predominant in the systemic subtype and interleukin (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]
Risk Factors
History & Exam
- There can be other skin manifestations of the disease, such as urticarial dermatographism.
Tests
Differential Diagnosis
Sepsis
Infectious endocarditis
Differentiating Signs/Symptoms
- New heart murmur may be detected. Peripheral signs including splinter hemorrhages, Janeway lesions, Osler nodes, and Roth spots may be present.
Differentiating Tests
- Echocardiogram may reveal valvular, mobile vegetations.
- Hematuria may be detected on urine dipstick and urine microscopy.
Biliary infection
Differentiating Signs/Symptoms
- Preceding symptoms and signs of localized biliary infection such as abdominal pain and tenderness in the right upper quadrant. A positive Murphy sign is often present.
Differentiating Tests
- Abdominal ultrasound shows signs of acute cholecystitis including pericholecystic fluid, distended gallbladder, thickened gallbladder wall. Gallstones may be visualized.
- CT scan may show signs of cholecystitis including irregular thickening of the gallbladder wall, poor contract-enhancement of the gallbladder wall, increased density of fatty tissue around the gallbladder, gas in the gallbladder lumen or wall, membranous structures in the lumen, perigallbladder abscess.Targeted cultures: may be positive for a specific infective organism.[6]
Urinary tract infection
Differentiating Signs/Symptoms
- Preceding symptoms and signs of upper or lower urinary tract infection such as dysuria, urinary frequency, cloudy-looking urine.
Differentiating Tests
- Dipstick urine analysis is positive for leukocyte esterase and/or nitrite.
- Urine microscopy shows leukocytes and/or bacteria.
- Urine culture is positive for one or more infective organisms.
- Ultrasound scan of renal tract may demonstrate signs of obstruction associated with urinary infection.
- CT scan of the renal tract may demonstrate signs of acute pyelonephritis, or signs of obstruction associated with urinary infection.
Tuberculosis (TB)
Differentiating Signs/Symptoms
- Risk factors for TB may be present such as residence in/travel from TB-endemic region, silicosis, HIV, or immunosuppression. Cough may be present with pulmonary TB.
Differentiating Tests
- Chest x-ray may show fibronodular opacities in upper lobes with or without cavitation, may show other atypical signs, or may be normal.
- Specimen from the site of infection may be positive for Mycobacterium tuberculosis in sputum testing; for example, acid-fast bacilli smear, sputum culture, nucleic acid amplification testing (NAAT).
- There may be a positive result from a tuberculin skin test (TST) or an interferon-gamma release assay (IGRAs) for M tuberculosis, although a negative result does not exclude TB.[69]
- CT scan chest may show the same patterns of disease as seen with the chest x-ray.
Differentiating Signs/Symptoms
- Specific features of each infection can help differentiate clinically. Examples include viral hepatitis, parvovirus B19, measles, and rubella.
Differentiating Tests
- Serology, PCR: positive for the specific infection.[47]
Parasitic infection
Differentiating Signs/Symptoms
- Specific features of each infection can help differentiate clinically. Examples include toxoplasmosis and abscessed parasitosis.
Differentiating Tests
- Serology, PCR: positive for the specific infection.[47]
Drug-related hypersensitivity
Differentiating Signs/Symptoms
- This may include a wide array of mucosal and skin manifestations typically 1-3 weeks after exposure to a new drug. A review of the drug history may suggest a possible association between a new drug starting and the development of clinical signs.
- Generalized macular or papular rash.
- Drug rash with eosinophilia and systemic systems (DRESS) involves a rash that is more widespread than that in AOSD.
- Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) involves mucosal lesions and erythematous cutaneous macules progressing to blisters following a fever and sore throat.[70]
Differentiating Tests
- A blood (whole blood, plasma, or serum) concentration of the suspect drug above the usual target range. Skin testing (via skin prick tests, intradermal tests, or patch tests) may help to identify a causative drug. If DRESS is present there may be liver function test abnormalities associated with hepatitis and eosinophilia detected on CBC.
Hodgkin lymphoma
Differentiating Signs/Symptoms
- Dyspnea; cough; generalized pruritus; nonsymmetric, fixed and indurated lymph node enlargement; superior vena cava syndrome.
Differentiating Tests
- Lymph node biopsy shows typical histologic features.
Non-Hodgkin lymphoma
Differentiating Signs/Symptoms
- May be asymptomatic in low-grade presentations.More aggressive lymphoma may present with peripheral lymph node enlargement; splenomegaly; weight loss; fever; dyspnea; cough.
Differentiating Tests
- Lymph node biopsy shows typical histologic features and is the preferred diagnostic test for most patients. Rarely, bone marrow aspirate and biopsy is the only available site to make the diagnosis.
Differentiating Signs/Symptoms
- Examples include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
- Erythromelalgia, arterial and venous thrombosis, evidence of bleeding, livedo reticularis.
Differentiating Tests
- Bone marrow biopsy showing abnormal cells according to the type of myeloproliferative disorder.
- In chronic myeloid leukemia, peripheral blood smear shows most white blood cells are neutrophils with a left shift (mature or maturing myeloid cells).
- Abnormal hematocrit in polycythemia vera.
Differentiating Signs/Symptoms
- Includes kidney, colon, and lung cancer. Symptoms and signs predominantly associated with the affected organ (e.g., cough with lung cancer).
Differentiating Tests
- Imaging (e.g., CT scan, PET/CT scan) showing one or more masses consistent with tumor.
- Biopsies from the site, which may be obtained endoscopically, confirming malignancy.
Rheumatoid arthritis
Systemic lupus erythematosus (SLE)
Differentiating Signs/Symptoms
- Malar (butterfly) rash, photosensitive skin, discoid skin rash.
- Raynaud phenomenon.
- There may be evidence of venous or arterial thrombosis.
Differentiating Tests
- Antinuclear autoantibodies typically positive, but may also be positive in other connective tissue diseases. Anti-dsDNA and anti-Smith antibodies are highly specific for SLE.
Idiopathic inflammatory myopathies/dermatomyositis
Differentiating Signs/Symptoms
- Muscle weakness and atrophy.
- Heliotrope rash (violaceous to dusky-red rash) with eyelid edema - highly suggestive of dermatomyositis.
- Gottron papules (violaceous to dusty-red flat-topped papules and plaques over the dorsal surface of knuckles and more rarely the wrists, elbows, knees, and malleoli) with dermatomyositis.
Differentiating Tests
- Muscle MRI may show increased edema with dermatomyositis and polymyositis.
- Muscle biopsy may show perivascular or interfascicular inflammation, endothelial hyperplasia in the intramuscular blood vessels, perifascicular atrophy with dermatomyositis; endomysial inflammatory infiltrates, muscle necrosis, atrophy, muscle fiber regeneration with polymyositis.
- Skin biopsy may show vacuolar alteration of the basal layer of the epidermis, necrotic keratinocytes, vascular dilation, perivascular lymphocytic infiltrate with dermatomyositis.
Polyarteritis nodosa or other vasculitis
Differentiating Signs/Symptoms
- Signs of mononeuritis multiplex, paresthesia, diastolic blood pressure >90 mmHg.
Differentiating Tests
- Antineutrophil cytoplasmic antibodies (ANCA): positive in ANCA-associated vasculitis but negative in polyarteritis nodosa.
- Arteriography shows evidence of vasculitis, such as beading, aneurysm, or smooth tapering vessel stenosis. May test positive for hepatitis B virus infection.
- Biopsy of affected tissue, if feasible, can help establish the diagnosis.
- In polyarteritis nodosa, renal angiogram may show the classical feature of aneurysms.
Differentiating Signs/Symptoms
- No obvious differentiating symptoms or signs
Differentiating Tests
- Antistreptolysin O: titers showing recent streptococcal infection.
Reactive arthritis
Differentiating Signs/Symptoms
- Conjunctivitis, symptoms of urethritis, and arthritis occurring after an infection.
Differentiating Tests
- HLA-B27 may be positive (although a negative test does not exclude reactive arthritis).
- MRI of affected joints: sacroiliitis or enthesopathy/enthesitis
Sarcoidosis
Differentiating Signs/Symptoms
- Cough, dyspnea, wheeze, signs of uveitis.
Differentiating Tests
- Chest x-ray: bilateral hilar adenopathy
- Serum angiotensin converting enzyme (ACE) elevated in about half of patients.
- Biopsy of lesion - histology showing noncaseating granulomatosis.
Familial Mediterranean fever
Differentiating Signs/Symptoms
- Positive family history.
- More likely to have Italian, Greek, Turkish, Armenian, Sephardi Jewish, or Japanese ethnicity.
- Erysipeloid erythema may be present (7% to 40% of patients).[71]
- Peritonitis may be present.
Differentiating Tests
- Mediterranean fever (MEFV) gene analysis: mutation present
Differentiating Signs/Symptoms
- May be triggered by vaccination, although a provoking trigger is not always present.
Differentiating Tests
- Elevated serum IgD >100 mg/dL.
- Urinary mevalonic acid elevated during an attack.
- Mevalonate kinase analysis showing deficiency in enzyme activity
Differentiating Signs/Symptoms
- Positive family history.
- Urticaria-like neutrophilic rash (neutrophilic urticarial dermatosis).
- Sensorineural hearing loss.
- Conjunctivitis/uveitis
Differentiating Tests
- NLRP3 (formerly CIAS1) gene analysis: pathogenic variant identified.
Differentiating Signs/Symptoms
- Urticarial-like neutrophilic rash (neutrophilic urticarial dermatosis).
- Deep bone pain.
Differentiating Tests
- Serum electrophoresis/immune fixation shows monoclonal gammopathy of undetermined significance (MGUS): monoclonal IgM gammopathy present in majority of patients (IgG in a minority)
Differentiating Signs/Symptoms
- Generally has onset at an older age.
- May be associated with a myelodysplastic syndrome and, in rare cases, can present as such.
- Periorbital edema.
- History of relapsing polychondritis and thrombotic events.
Differentiating Tests
- CBC: cytopenia.
- UBA1 gene analysis: pathogenic variant identified.
Differentiating Signs/Symptoms
- Characteristic tender eruptions.
Differentiating Tests
- Biopsy of skin lesion: infiltrate of neutrophils in the dermis.
Criteria
Yamaguchi classification criteria for AOSD[48]
At least five criteria are required to confirm a clinical diagnosis of AOSD, two or more of which must be major criteria AND any infection, malignancy, or other rheumatic disorder known to mimic AOSD must be excluded.
Major criteria
- Fever of at least 102.2°F (39.0°C) lasting at least 1 week
- Arthralgias or arthritis lasting 2 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/microliter or greater), with at least 80% granulocytes
Minor criteria
- 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).
Fautrel classification criteria for AOSD[49]
The Fautrel criteria were developed to avoid the need for exclusion criteria but require testing of glycosylated ferritin, which is not available in many healthcare facilities. A confirmation of an AOSD diagnosis requires:
- ≥4 major criteria OR
- three major criteria AND two minor criteria
Major criteria
- Spiking fever ≥ 102.2°F (≥39.0°C)
- Arthralgias
- Transient erythematous rash
- Pharyngitis
- Polymorphonuclear neutrophils ≥80%
- Glycosylated ferritin ≤20%
Minor criteria
- Maculopapular rash
- Leukocytes ≥10,000/microliter (10 × 10⁹/L)
Treatment Approach
There are currently no internationally agreed guidelines for the treatment of adult-onset Still disease (AOSD). The German Society of Rheumatology published a guideline for diagnosis and treatment of AOSD in 2022.[2] Both this guideline and published expert recommendations suggest a stepwise approach, depending on the disease course and response to treatment. The overall aims of treatment are to:[4]
- Achieve clinical and biochemical remission of the disease. This should include resolution of symptoms (e.g., fevers, rash, and joint pains) in addition to normalization of the markers of disease activity (e.g., C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], and ferritin).
- Prevent organ damage and serious complications such as macrophage activation syndrome (MAS).
Treatment depends on clinical context.
- For patients with AOSD who are being investigated and managed in the outpatient setting, take a stepwise approach from corticosteroids to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and newer biologic agents depending on response.[6] If the patient responds well to corticosteroids but symptoms persist or recur when corticosteroid therapy is tapered, aim to add a second therapy as a corticosteroid-sparing agent.[73]
Initial management
Nonsteroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief
- Even in patients who benefit, avoid prolonged use of NSAIDs due to the risk of gastrointestinal bleeding and renal impairment, particularly in older patients.[74]
- NSAIDs may increase the risk of cardiovascular thrombotic events and serious gastrointestinal events.
Note that NSAIDs can be used for short-term symptomatic relief at any stage of treatment for AOSD.[2]
Assess disease activity to determine the need for additional treatment. Base your assessment on a combination of:[2]
- Clinical symptoms and signs (e.g., arthritis, fever, organ involvement)
- Laboratory results (serum ferritin, CRP, ESR).
Systemic corticosteroids
Treat patients who are diagnosed with AOSD and experiencing active disease with systemic corticosteroids as the first-line therapy.[2] Coprescribe gastrointestinal protection (proton-pump inhibitor) and bone protection (calcium and vitamin D) according to your local protocols.
Though corticosteroids provide rapid and sustained improvement in both articular and systemic AOSD, aim to avoid prolonged therapy due to the risk of adverse effects. These include diabetes, hypertension, osteoporosis, weight gain, and Cushing syndrome.[74]
- If resolution of symptoms and biochemical markers is achieved, aim to slowly taper the corticosteroid dose after 4-6 weeks.[1] It is important to taper the dose slowly as quick reductions can lead to disease relapse.
- For successfully treated patients, aim to slowly taper the corticosteroid dose to cessation before eventually trialing a period off other therapies to assess for clinical remission.
- If inflammation persists despite corticosteroid therapy or relapse occurs following the corticosteroid taper, add a corticosteroid-sparing agent (see Second-line therapies below for more details).
AOSD can be monophasic and therefore treatment with corticosteroids may be all that is required to manage patients with the disease.
Second-line therapies
Conventional synthetic disease-modifying antirheumatic drugs (DMARDs)
In patients who are corticosteroid dependent or who relapse when the corticosteroid dose is tapered, conventional synthetic DMARDs are the usual second-line treatment used as corticosteroid-sparing therapy, enabling a tapering of the corticosteroid dose.[2] [4] [73]
Start patients on methotrexate.[4]
- In one study of 26 patients with AOSD, methotrexate allowed 69% of participants to attain complete remission and 39% to discontinue corticosteroids.[76]
- Although patients with AOSD can often have deranged liver enzymes, methotrexate can still be prescribed in these instances but ensure close monitoring of transaminases.[77]
Biologic agents for refractory AOSD
Around 17% to 32% of patients do not respond to high-dose corticosteroids and conventional synthetic DMARDs, a condition termed refractory AOSD.[4] [78] [80] Biologic agents are the next step in management for this group.
Consider the use of interleukin (IL)-1 inhibitors (e.g., anakinra, canakinumab) or IL-6 inhibitors (e.g., tocilizumab) in patients with refractory AOSD.[1] [4] [78]
- Anakinra, canakinumab, and tocilizumab have generally been shown to be highly effective for refractory AOSD, often with rapid and sustained clinical and biochemical responses. These drugs have favorable safety profiles and significant numbers of patients achieve clinical remission and/or significant corticosteroid dose reductions.[81] [82] [83] [84] [85]
- The choice between anakinra, canakinumab, and tocilizumab depends on local experience and availability and it is possible to switch from one to another if the first option chosen does not work well. Check your local guidelines.
Tumor necrosis factor (TNF)-alpha inhibitors (e.g., infliximab or adalimumab) have been shown to achieve clinical remission, though at a lower rate than the alternatives.[4] Consider these only after at least one interleukin inhibitor has been tried without success, particularly if the patient has a chronic articular pattern of disease.[80] [83] [86]
Anakinra and canakinumab are licensed in Europe for people with AOSD, whereas only canakinumab is currently licensed for AOSD in the US. Other biologics are used off-label.
The conventional synthetic DMARD is usually continued alongside the biologic agent, although occasionally it may need to be stopped owing to adverse effects.
Request rapid specialist input for any patient in extremis (e.g., those in ICU or experiencing the serious complication of MAS).
- Intravenous systemic corticosteroids and immediate use of biologic agents may be required to achieve disease control.
Early use of biologic agents for high disease activity
Consider using a biologic, particularly an IL-1 inhibitor, as the preferred initial corticosteroid-sparing therapy for any patient whose clinical symptoms/signs and laboratory results show high disease activity.[2] [4] [6]
- Assess disease activity based on a combination of:[2]
- Clinical symptoms and signs (e.g., arthritis, fever, organ involvement)
- Laboratory results (serum ferritin, CRP, ESR)
- Anakinra and canakinumab are increasingly preferred to conventional synthetic DMARDs as second-line therapy (after corticosteroids) in patients with moderately or highly active disease. It is likely this approach will become standard in future, depending on availability and local protocols. Check your local guidelines.
- Most evidence for the use of biologic agents in AOSD has come from studies in patients who are resistant to conventional synthetic DMARDs although cohort studies have shown that anakinra is also effective as a treatment option prior to the use of conventional immunosuppressants.[2]
It is likely that over time biologic agents will replace conventional synthetic DMARDs as the preferred second-line agents for all patients with AOSD.[74]
Complications of AOSD
Serious and potentially life-threatening complications of AOSD can occur as a first presentation or at a later stage in management. Macrophage activation syndrome (MAS) is the most significant of these although patients can also present with life-threatening or organ-threatening visceral involvement without MAS.[1] [4] [5] [6]
Be aware that MAS and other complications of AOSD have their own treatment protocols and require specialist management.[4]
Always evaluate the possibility of MAS if the patient has risk factors for this serious complication.[2]
Other serious complications of AOSD include:[2]
- Perimyocardial disease such as pericarditis, pericardial effusion, and cardiomyopathy
- Interstitial lung disease
- AA amyloidosis. This is a rare complication but important to exclude in patients with persistently active AOSD.
Intravenous pulse-dose corticosteroid treatment (e.g., methylprednisolone) is often administered to patients who have significant organ dysfunction or MAS, transitioning to an oral corticosteroid after a few days.[1] [4] [5] [36] The clinical response is usually very rapid.[4]
Early use of biological agents may also be needed.[2] [4] [6] An IL-1 inhibitor is recommended as an add-on to corticosteroid therapy in AOSD-related MAS that fails to respond to corticosteroid therapy alone, with the strongest evidence supporting the use of anakinra.[87] [88] [89] [90]
In patients who have organ involvement without MAS, an IL-1 inhibitor or an IL-6 inhibitor is often used, with the choice between anakinra, canakinumab, and tocilizumab depending on local experience and availability.[3] [4] It is possible to switch from one to another if the first option chosen does not work well. Check your local guidelines.
Monitoring on therapy
Ensure ongoing monitoring under specialist care, which should include regular clinical assessment of bloods including CBC, CRP, ESR, eGFR, transaminases, ferritin, and coagulation tests.[91]
There are a number of scoring systems that are in clinical use and that can help with disease monitoring. Examples include Pouchot score, adapted American College of Rheumatology (ACR) response criteria, and the more recently proposed Still activity score.[92] [93] The choice of scoring system depends on local preference and expertise. With further research, it is hoped that one universal scoring system for disease activity will be adopted.
Specific monitoring is required for drugs used to manage AOSD; consult your local drug information source for more information.
Discontinuing therapy
AOSD can be monocyclic (19% to 44%), recurrent/polycyclic (10% to 41%), or chronic and progressive (35% to 67%).[91]
- Both monocyclic and polycyclic courses involve flares of symptoms and possibly years of subsequent clinical remission.
- Therefore, once good clinical control is achieved, tapering and discontinuation of treatment is an appropriate aim although there is not yet any standardized protocol or consensus on how this should be done.[91]
- Ensure patients are managed under specialist care if possible and aim to slowly taper corticosteroids to cessation, followed thereafter by trials of conventional synthetic DMARDs and biologic agents.
Treatment Options
severe disease: with severe organ dysfunction with or without signs of macrophage activation syndrome
specialist management
Comments
- In some patients, the first presentation of adult-onset Still disease (AOSD) is with a serious and potentially life-threatening complication. Macrophage activation syndrome (MAS) is the most significant of these although patients can also present with life-threatening or organ-threatening visceral involvement without MAS.[1] [4] [5][6]
- Be aware that MAS and other complications of AOSD have their own treatment protocols and require specialist management, including for consideration of the need for escalation to critical care. This is regardless of whether they occur as a first presentation or a later complication.
- Always evaluate the possibility of MAS if the patient has risk factors for this serious complication.[2] Key risk factors for MAS include high clinical disease activity and laboratory markers such as high serum ferritin and cytopenia (particularly leukopenia).[2] MAS has been reported to affect up to 15% of people with AOSD and it has a high mortality rate.[4]
- Other serious complications of AOSD include: perimyocardial disease (such as pericarditis, pericardial effusion, and cardiomyopathy); interstitial lung disease; and AA amyloidosis.[2] AA amyloidosis is a rare complication, but it is important to exclude in patients with persistently active AOSD.
intravenous corticosteroid
Primary Options
- methylprednisolone sodium succinate
0.5 to 1 g intravenously once daily for 3 days, followed by oral prednisone course
and
- prednisone
40-60 mg orally once daily, following the completion of 3-day methylprednisolone course
- methylprednisolone sodium succinate
Comments
biologic agent
Primary Options
- anakinra
consult specialist for guidance on dose
- anakinra
- canakinumab
consult specialist for guidance on dose
- canakinumab
- tocilizumab
consult specialist for guidance on dose
- tocilizumab
Comments
- An interleukin (IL)-1 inhibitor is recommended as an add-on therapy in AOSD-related MAS that fails to respond to corticosteroid therapy alone, with the strongest evidence supporting the use of anakinra.[87] [88] [89] [90] Be aware that MAS has a specific treatment protocol and requires specialist management, including potential need for escalation to critical care.
- In patients who have organ involvement without MAS, an IL-1 inhibitor or an IL-6 inhibitor (e.g., tocilizumab) is often used, with the choice between anakinra, canakinumab, and tocilizumab depending on local experience and availability.[3] [4] It is possible to switch from one to another if the first option chosen does not work well. Check your local guidelines.
- Anakinra, canakinumab, and tocilizumab have generally been shown to be highly effective for refractory AOSD, often with rapid and sustained clinical and biochemical responses. These drugs have favorable safety profiles and significant numbers of patients achieve clinical remission and/or significant corticosteroid dose reductions.[81] [82][83] [84][85]
- Anakinra and canakinumab are licensed in Europe for people with AOSD, whereas only canakinumab is currently licensed for AOSD in the US. Other biologics are used off-label. The doses used for these patients may be higher than the licensed dose for this indication, and a specialist should be consulted for guidance on the most appropriate dose.
- Most evidence for the use of biologic agents in people with AOSD has come from studies in patients who are resistant to conventional synthetic DMARDs although cohort studies have shown that anakinra is also effective as a treatment option prior to use of conventional immunosuppressants.[2]
- Biologic agents are associated with serious infections and malignancy. They are contraindicated in patients with active infections. Use caution in patients at risk of chronic or recurrent infections or malignancy. Screen for tuberculosis before treatment.
nonsteroidal anti-inflammatory drug (NSAID)
Primary Options
- indomethacin
25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day
- indomethacin
- ibuprofen
300-800 mg orally three to four times daily, maximum 3200 mg/day
- ibuprofen
Comments
- Even in patients who benefit, avoid prolonged use of NSAIDs due to the risk of gastrointestinal bleeding and renal impairment, particularly in older patients.[74]
- NSAIDs may increase the risk of cardiovascular thrombotic events and serious gastrointestinal events.
- Use the lowest effective dose for the shortest effective treatment duration.
- Note that NSAIDs can be used for short-term symptomatic relief at any stage of treatment for AOSD.[2]
mild or moderate disease: no severe organ dysfunction or signs of macrophage activation syndrome
oral corticosteroid
Primary Options
- prednisone
0.5 to 1 mg/kg/day orally initially, adjust dose according to response and gradually taper after 4-6 weeks
- prednisone
Comments
- Treat patients who are diagnosed with AOSD and experiencing active disease with systemic corticosteroids as the first-line therapy.[2]
- The condition should be highly responsive to corticosteroids, with significant clinical and biochemical improvement typically occurring within a few days.[1] [36] The rate of effectiveness for corticosteroids has been reported at between 38% and 95% in different studies.[2] Studies have shown that higher initial doses of prednisone provide quicker clinical resolution and reduce the risk of disease relapse.[36] [75]
- Though corticosteroids provide rapid and sustained improvement in both articular and systemic AOSD, aim to avoid prolonged therapy due to the risk of adverse effects. These include diabetes, hypertension, osteoporosis, weight gain, and Cushing syndrome.[74]
- If resolution of symptoms and biochemical markers is achieved, aim to slowly taper the corticosteroid dose after 4 to 6 weeks.[1] It is important to taper the dose slowly as quick reductions can lead to disease relapse. For successfully treated patients, aim to slowly taper the corticosteroid dose to cessation before eventually trialing a period off other therapies to assess for clinical remission.
- If inflammation persists despite corticosteroid therapy or relapse occurs following the corticosteroid taper, add a corticosteroid-sparing agent.
- AOSD can be monophasic and therefore treatment with corticosteroids may be all that is required to manage patients with the disease. However, up to 45% of patients become corticosteroid dependent and require second-line therapy with corticosteroid-sparing agents (i.e., conventional synthetic disease-modifying antirheumatic drugs and/or biologic agents).[24] [36]
- Coprescribe gastrointestinal protection (proton-pump inhibitor) and bone protection (calcium and vitamin D) according to your local protocols.
nonsteroidal anti-inflammatory drug (NSAID)
Primary Options
- indomethacin
25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day
- indomethacin
- ibuprofen
300-800 mg orally three to four times daily, maximum 3200 mg/day
- ibuprofen
Comments
- Even in patients who benefit, avoid prolonged use of NSAIDs due to the risk of gastrointestinal bleeding and renal impairment, particularly in older patients.[74]
- NSAIDs may increase the risk of cardiovascular thrombotic events and serious gastrointestinal events.
- Use the lowest effective dose for the shortest effective treatment duration.
- Note that NSAIDs can be used for short-term symptomatic relief at any stage of treatment for AOSD.[2]
conventional synthetic disease-modifying antirheumatic drug (DMARD)
Primary Options
- methotrexate
7.5 to 25 mg orally/subcutaneously/intramuscularly once weekly on the same day of each week
- methotrexate
Secondary Options
- cyclosporine modified
consult specialist for guidance on dose
- cyclosporine modified
Tertiary Options
- azathioprine
consult specialist for guidance on dose
- azathioprine
- leflunomide
consult specialist for guidance on dose
- leflunomide
- hydroxychloroquine sulfate
consult specialist for guidance on dos
- hydroxychloroquine sulfate
Comments
- Start patients on methotrexate.[4] Although patients with AOSD can often have deranged liver enzymes, methotrexate can still be prescribed in these instances but ensure close monitoring of transaminases.[77] In one study of 26 patients with AOSD, methotrexate allowed 69% of participants to attain complete remission and 39% to discontinue corticosteroids.[76] Methotrexate can cause hepatotoxicity, pulmonary toxicity, gastrointestinal toxicity, and malignancy. Myelosuppression, aplastic anemia, and gastrointestinal toxicity have been reported when methotrexate is used in combination with some NSAIDs (particularly at high doses).
oral corticosteroid
Primary Options
- prednisone
0.5 to 1 mg/kg/day orally, gradually taper according to response
- prednisone
Comments
- It is important to taper the dose slowly as quick reductions can lead to disease relapse.
nonsteroidal anti-inflammatory drug (NSAID)
Primary Options
- indomethacin
25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day
- indomethacin
- ibuprofen
300-800 mg orally three to four times daily, maximum 3200 mg/day
- ibuprofen
Comments
- Even in patients who benefit, avoid prolonged use of NSAIDs due to the risk of gastrointestinal bleeding and renal impairment, particularly in older patients.[74]
- NSAIDs may increase the risk of cardiovascular thrombotic events and serious gastrointestinal events.
- Use the lowest effective dose for the shortest effective treatment duration.
- Note that NSAIDs can be used for short-term symptomatic relief at any stage of treatment for AOSD.[2]
biologic agent
Primary Options
- anakinra
100 mg subcutaneously once daily
- anakinra
- canakinumab
4 mg/kg subcutaneously every 4 weeks, maximum 300 mg/dose
- canakinumab
- tocilizumab
consult specialist for guidance on dose
- tocilizumab
Secondary Options
- adalimumab
consult specialist for guidance on dose
- adalimumab
- infliximab
consult specialist for guidance on dose
- infliximab
Comments
- Consider the use of interleukin (IL)-1 inhibitors (e.g., anakinra, canakinumab) or IL-6 inhibitors (e.g., tocilizumab) in patients with refractory AOSD.[1][4] [78] Anakinra, canakinumab, and tocilizumab have generally been shown to be highly effective for refractory AOSD, often with rapid and sustained clinical and biochemical responses. These drugs have favorable safety profiles and significant numbers of patients achieve clinical remission and/or significant corticosteroid dose reductions.[81] [82][83] [84] [85] The choice between anakinra, canakinumab, and tocilizumab depends on local experience and availability and it is possible to switch from one to another if the first option chosen does not work well. Check your local guidelines.
- Tumor necrosis factor (TNF)-alpha inhibitors (e.g., infliximab, adalimumab) have been shown to achieve clinical remission in patients with AOSD, though at a lower rate than IL inhibitors. Consider these only after at least one interleukin inhibitor has been tried without success, particularly if the patient has a chronic articular pattern of disease.[80] [83] [86]
- Anakinra and canakinumab are licensed in Europe for people with AOSD, whereas only canakinumab is currently licensed for AOSD in the US. Other biologics are used off-label.
- Biologic agents are associated with serious infections and malignancy. They are contraindicated in patients with active infections. Use caution in patients at risk of chronic or recurrent infections or malignancy. Screen for tuberculosis before treatment.
- Note that anakinra and canakinumab are increasingly preferred to conventional synthetic DMARDs as second-line options (after corticosteroids) in patients whose clinical symptoms/signs and laboratory results show highly active disease.[2] [6] It is likely this approach will become standard in future, depending on availability and local protocol. Check local guidelines.
oral corticosteroid
Primary Options
- prednisone
0.5 to 1 mg/kg/day orally, gradually taper according to response
- prednisone
Comments
- It is important to taper the dose slowly as quick reductions can lead to disease relapse.
conventional synthetic disease-modifying antirheumatic drug (DMARD)
Primary Options
- methotrexate
7.5 to 25 mg orally/subcutaneously/intramuscularly once weekly on the same day of each week
- methotrexate
Secondary Options
- cyclosporine modified
consult specialist for guidance on dose
- cyclosporine modified
Tertiary Options
- azathioprine
consult specialist for guidance on dose
- azathioprine
- leflunomide
consult specialist for guidance on dose
- leflunomide
- hydroxychloroquine sulfate
consult specialist for guidance on dose
- hydroxychloroquine sulfate
Comments
- The conventional synthetic DMARD is usually continued alongside the biologic agent, although sometimes it may need to be stopped due to adverse effects.
nonsteroidal anti-inflammatory drug (NSAID)
Primary Options
- indomethacin
25 mg orally (immediate-release) two to three times daily initially, increase gradually according to response, maximum 200 mg/day
- indomethacin
- ibuprofen
300-800 mg orally three to four times daily, maximum 3200 mg/day
- ibuprofen
Comments
- Even in patients who benefit, avoid prolonged use of NSAIDs due to the risk of gastrointestinal bleeding and renal impairment, particularly in older patients.[74]
- NSAIDs may increase the risk of cardiovascular thrombotic events and serious gastrointestinal events.
- Use the lowest effective dose for the shortest effective treatment duration.
- Note that NSAIDs can be used for short-term symptomatic relief at any stage of treatment for AOSD.[2]
Emerging Tx
Janus kinase (JAK) inhibitors
JAK inhibitors are increasingly used under specialist management in people with refractory AOSD, although this depends on local expertise. There is as yet limited evidence for their efficacy with trials currently planned or underway.[4] [74] In one observational study of 14 patients with refractory AOSD, tofacitinib achieved complete remission in 50% and significantly reduced the average daily dose of corticosteroid required.[94] Baricitinib has been found to induce clinical remission in patients with AOSD who had been refractory to interleukin (IL)-1 and IL-6 inhibitors.[95] JAK inhibitors are associated with an increased risk of malignancy, major cardiovascular events, venous thromboembolism, infections, and mortality.[96] [97][98]
Interleukin (IL)-18 inhibitors
IL-18 inhibitors such as tadekinig alfa (a recombinant IL-18 binding protein with a high affinity for IL-18) have been found to have a favorable safety profile and produced a positive response in 50% of participants in a phase 2 trial.[99] There is as yet limited evidence for their efficacy with trials currently planned or underway.[4] [74]
Rituximab
Rituximab, an anti-CD20 monoclonal antibody, has been shown in a few case studies to have potential effectiveness for refractory AOSD. It blocks T-cell activation and the generation of proinflammatory cytokines.[4]
Follow-Up Overview
Prognosis
Clinical course
- 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 and progressive symptoms, particularly affecting the joints.
The advent of targeted and biologic agents is likely to have a significant impact on the distribution of these clinical courses. Though chronic and progressive AOSD is the most frequent pattern, more prompt recognition and induction of therapy will allow a large number of these patients to achieve rapid and sustained disease control, bringing parity with the other disease patterns.[91] With all patterns of AOSD there is a high likelihood of rapid response to corticosteroids as well as biologic agents.[74] Nonetheless, observational studies report that many patients require drug treatment for symptom control for months and years, highlighting the heterogeneity of the disease course and the need to take an individual approach with each patient.[5] [91]
Mortality
Mortality data for AOSD is scarce and varies widely between studies.[5] One 5-year retrospective study of 5820 people hospitalized for ASOD in the US found an inpatient mortality rate of 2.6%.[12] The specific mortality rate has been estimated at 1% to 3%.[4]
- Comprehensive analysis of risk factors, comorbidities, and the burden of disease in patients remains an unmet research need.
Evidence suggests that a delay in diagnosis of more than 6 months is associated with an increased likelihood of patients developing relapses or chronic articular patterns of disease.[5]
Citations
Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult onset Still's disease. J Autoimmun. 2018 Sep;93:24-36.[Abstract][Full Text]
Vordenbäumen S, Feist E, Rech J, et al. Diagnosis and treatment of adult-onset Still's disease: a concise summary of the German society of rheumatology S2 guideline. Z Rheumatol. 2023 Feb;82(suppl 2):81-92.[Abstract][Full Text]
Macovei LA, Burlui A, Bratoiu I, et al. Adult-onset Still's disease-a complex disease, a challenging treatment. Int J Mol Sci. 2022 Oct 24;23(21):12810.[Abstract][Full Text]
Efthimiou P, Kontzias A, Hur P, et al. Adult-onset Still's disease in focus: clinical manifestations, diagnosis, treatment, and unmet needs in the era of targeted therapies. Semin Arthritis Rheum. 2021 Aug;51(4):858-74.[Abstract][Full Text]
Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992 Mar;19(3):424-30.[Abstract]
1. Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult onset Still's disease. J Autoimmun. 2018 Sep;93:24-36.[Abstract][Full Text]
2. Vordenbäumen S, Feist E, Rech J, et al. Diagnosis and treatment of adult-onset Still's disease: a concise summary of the German society of rheumatology S2 guideline. Z Rheumatol. 2023 Feb;82(suppl 2):81-92.[Abstract][Full Text]
3. Colafrancesco S, Manara M, Bortoluzzi A, et al. Management of adult-onset Still's disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts. Arthritis Res Ther. 2019 Dec 11;21(1):275.[Abstract][Full Text]
4. Macovei LA, Burlui A, Bratoiu I, et al. Adult-onset Still's disease-a complex disease, a challenging treatment. Int J Mol Sci. 2022 Oct 24;23(21):12810.[Abstract][Full Text]
5. Efthimiou P, Kontzias A, Hur P, et al. Adult-onset Still's disease in focus: clinical manifestations, diagnosis, treatment, and unmet needs in the era of targeted therapies. Semin Arthritis Rheum. 2021 Aug;51(4):858-74.[Abstract][Full Text]
6. Al-Hakim A, Mistry A, Savic S. Improving diagnosis and clinical management of acquired systemic autoinflammatory diseases. J Inflamm Res. 2022;15:5739-55.[Abstract][Full Text]
7. Sfriso P, Priori R, Valesini G, et al. Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients. Clin Rheumatol. 2016 Jul;35(7):1683-9.[Abstract][Full Text]
8. Bogdan M, Nitsch-Osuch A, Samel-Kowalik P, et al. Adult-onset Still's disease in Poland - a nationwide population-based study. Ann Agric Environ Med. 2021 Jun 14;28(2):250-4.[Abstract][Full Text]
9. Magadur-Joly G, Billaud E, Barrier JH, et al. Epidemiology of adult Still's disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis. 1995 Jul;54(7):587-90.[Abstract][Full Text]
10. Evensen KJ, Nossent HC. Epidemiology and outcome of adult-onset Still's disease in Northern Norway. Scand J Rheumatol. 2006 Jan-Feb;35(1):48-51.[Abstract][Full Text]
11. Lenert A, Oh G, Ombrello MJ, et al. Clinical characteristics and comorbidities in adult-onset Still's disease using a large US administrative claims database. Rheumatology (Oxford). 2020 Jul 1;59(7):1725-33.[Abstract][Full Text]
12. Mehta BY, Ibrahim S, Briggs W, et al. Racial/ethnic variations in morbidity and mortality in adult onset Still's disease: an analysis of national dataset. Semin Arthritis Rheum. 2019 Dec;49(3):469-73.[Abstract][Full Text]
13. Magliulo D, Narayan S, Ue F, et al. Adult-onset Still's disease after mRNA COVID-19 vaccine. Lancet Rheumatol. 2021 Oct;3(10):e680-2.[Abstract][Full Text]
14. Palassin P, Bres V, Hassan S, et al. Comprehensive description of adult-onset Still's disease after COVID-19 vaccination. J Autoimmun. 2023 Jan;134:102980.[Abstract][Full Text]
15. Matsuda M, Funakubo Asanuma Y, Yokota K, et al. New-onset adult-onset Still's disease following COVID-19 vaccination: three case reports and a literature review. Intern Med. 2023 Jan 15;62(2):299-305.[Abstract][Full Text]
16. Balci MA, Pamuk ON, Pamuk GE, et al. AB1142 epidemiology and outcome of adult-onset Still's disease in Northwestern Thrace region in Turkey. Ann Rheum Dis. 2015;74(suppl 2):1284.
17. Hocevar A, Rotar Z, Krosel M, et al. SAT0524 the incidence rate of adult onset Still's disease in Slovenia.Ann Rheum Dis. 2020;79 (suppl 1):1218-9.[Full Text]
18. Wouters JM, van der Veen J, van de Putte LB, et al. Adult onset Still's disease and viral infections. Ann Rheum Dis. 1988 Sep;47(9):764-7.[Abstract][Full Text]
19. Escudero FJ, Len O, Falcó V, et al. Rubella infection in adult onset Still's disease. Ann Rheum Dis. 2000 Jun;59(6):493.[Abstract][Full Text]
20. Jia J, Shi H, Liu M, et al. Cytomegalovirus infection may trigger adult-onset Still's disease onset or relapses. Front Immunol. 2019;10:898.[Abstract][Full Text]
21. Perez C, Artola V. Adult Still's disease associated with Mycoplasma pneumoniae infection. Clin Infect Dis. 2001 Mar 15;32(6):E105-6.[Abstract][Full Text]
22. National Health Service. Clinical Commissioning Policy: tocilizumab for the treatment of adult-onset Still's disease refractory to second-line therapy (adults) [210801P] (URN: 1609). 2021 [internet publication].[Full Text]
23. Franchini S, Dagna L, Salvo F, et al. Adult onset Still's disease: clinical presentation in a large cohort of Italian patients. Clin Exp Rheumatol. 2010 Jan-Feb;28(1):41-8.[Abstract][Full Text]
24. Gerfaud-Valentin M, Jamilloux Y, Iwaz J, et al. Adult-onset Still's disease. Autoimmun Rev. 2014 Jul;13(7):708-22.[Abstract][Full Text]
25. Hu QY, Zeng T, Sun CY, et al. Clinical features and current treatments of adult-onset Still's disease: a multicentre survey of 517 patients in China. Clin Exp Rheumatol. 2019 Nov-Dec;37(6 suppl 121):52-7.[Abstract][Full Text]
26. Kim YJ, Koo BS, Kim YG, et al. Clinical features and prognosis in 82 patients with adult-onset Still's disease. Clin Exp Rheumatol. 2014 Jan-Feb;32(1):28-33.[Abstract]
27. Pay S, Türkçapar N, Kalyoncu M, et al. A multicenter study of patients with adult-onset Still's disease compared with systemic juvenile idiopathic arthritis. Clin Rheumatol. 2006 Sep;25(5):639-44.[Abstract][Full Text]
28. Zhang Y, Yang Y, Bai Y, et al. Clinical characteristics and follow-up analysis of adult-onset Still's disease complicated by hemophagocytic lymphohistiocytosis. Clin Rheumatol. 2016 May;35(5):1145-51.[Abstract][Full Text]
29. Asanuma YF, Mimura T, Tsuboi H, et al. Nationwide epidemiological survey of 169 patients with adult Still's disease in Japan. Mod Rheumatol. 2015 May;25(3):393-400.[Abstract][Full Text]
30. Kalyoncu U, Solmaz D, Emmungil H, et al. Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: data from a large multicenter cohort. J Autoimmun. 2016 May;69:59-63.[Abstract][Full Text]
31. Nakamura H, Fujieda Y, Tarumi M, et al. Calcineurin inhibitors for adult-onset Still's disease: a multicentre retrospective cohort study. Clin Exp Rheumatol. 2020 Sep-Oct;38(5 suppl 127):11-6.[Abstract]
32. Liu Z, Lv X, Tang G. Clinical features and prognosis of adult-onset Still's disease: 75 cases from China. Int J Clin Exp Med. 2015;8(9):16634-9.[Abstract][Full Text]
33. Riera E, Olivé A, Narváez J, et al. Adult onset Still's disease: review of 41 cases. Clin Exp Rheumatol. 2011 Mar-Apr;29(2):331-6.[Abstract]
34. Zeng T, Zou YQ, Wu MF, et al. Clinical features and prognosis of adult-onset still's disease: 61 cases from China. J Rheumatol. 2009 May;36(5):1026-31.[Abstract][Full Text]
35. Chen DY, Lan JL, Hsieh TY, et al. Clinical manifestations, disease course, and complications of adult-onset Still's disease in Taiwan. J Formos Med Assoc. 2004 Nov;103(11):844-52.[Abstract]
36. Kong XD, Xu D, Zhang W, et al. Clinical features and prognosis in adult-onset Still's disease: a study of 104 cases. Clin Rheumatol. 2010 Sep;29(9):1015-9.[Abstract]
37. Kishida D, Ichikawa T, Takamatsu R, et al. Clinical characteristics and treatment of elderly onset adult-onset Still's disease. Sci Rep. 2022 Apr 26;12(1):6787.[Abstract][Full Text]
38. Di Cola I, Di Muzio C, Conforti A, et al. Adult-onset Still's disease with elderly onset: results from a multicentre study. Clin Exp Rheumatol. 2022 Sep;40(8):1517-25.[Abstract][Full Text]
39. Hofheinz K, Schett G, Manger B. Adult onset Still's disease associated with malignancy - cause or coincidence? Semin Arthritis Rheum. 2016 Apr;45(5):621-6.[Abstract][Full Text]
40. Liozon E, Ly KH, Vidal-Cathala E, et al. Adult-onset Still's disease as a manifestation of malignancy: report of a patient with melanoma and literature review [in French]. Rev Med Interne. 2014 Jan;35(1):60-4.[Abstract][Full Text]
41. Gaggiano C, Rigante D, Vitale A, et al. Hints for genetic and clinical differentiation of adult-onset monogenic autoinflammatory diseases. Mediators Inflamm. 2019;2019:3293145.[Abstract][Full Text]
42. Cush JJ, Medsger TA Jr, Christy WC, et al. Adult-onset Still's disease. Clinical course and outcome. Arthritis Rheum. 1987 Feb;30(2):186-94.[Abstract][Full Text]
43. Mitrovic S, Fautrel B. Clinical phenotypes of adult-onset Still's disease: new insights from pathophysiology and literature findings. J Clin Med. 2021 Jun 15;10(12):2633.[Abstract][Full Text]
44. Nigrovic PA, Schneider R. Systemic juvenile idiopathic arthritis and adult onset still disease. In: Hashkes PJ, Laxer RM, Simon, A, eds. Textbook of autoinflammation. Cham, Switzerland: Springer Nature Switzerland AG; 2019, 587-616.
45. Gracia-Ramos AE, Contreras-Ortíz JA. Myocarditis in adult-onset Still's disease: case-based review. Clin Rheumatol. 2020 Mar;39(3):933-47.[Abstract]
46. Colafrancesco S, Priori R, Valesini G. Presentation and diagnosis of adult-onset Still's disease: the implications of current and emerging markers in overcoming the diagnostic challenge. Expert Rev Clin Immunol. 2015 Jun;11(6):749-61.[Abstract][Full Text]
47. Mitrovic S, Fautrel B. New markers for adult-onset Still's disease. Joint Bone Spine. 2018 May;85(3):285-93.[Abstract][Full Text]
48. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992 Mar;19(3):424-30.[Abstract]
49. Fautrel B, Zing E, Golmard JL, et al. Proposal for a new set of classification criteria for adult-onset still disease. Medicine (Baltimore). 2002 May;81(3):194-200.[Abstract][Full Text]
50. Lebrun D, Mestrallet S, Dehoux M, et al. Validation of the Fautrel classification criteria for adult-onset Still's disease. Semin Arthritis Rheum. 2018 Feb;47(4):578-85.[Abstract][Full Text]
51. Inoue N, Shimizu M, Tsunoda S, et al. Cytokine profile in adult-onset Still's disease: comparison with systemic juvenile idiopathic arthritis. Clin Immunol. 2016 Aug;169:8-13.[Abstract][Full Text]
52. Jamilloux Y, Gerfaud-Valentin M, Martinon F, et al. Pathogenesis of adult-onset Still's disease: new insights from the juvenile counterpart. Immunol Res. 2015 Feb;61(1-2):53-62.[Abstract][Full Text]
53. Ahmed MG. Clinical significance of interleukin-18 and interleukin-6 on disease course of adult-onset still's disease. Ann Rheum Dis, 2018;77(suppl 2):1162.
54. Holzinger D, Frosch M, Kastrup A, et al. The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis. Ann Rheum Dis. 2012 Jun;71(6):974-80.[Abstract][Full Text]
55. Aljaberi N, Tronconi E, Schulert G, et al. The use of S100 proteins testing in juvenile idiopathic arthritis and autoinflammatory diseases in a pediatric clinical setting: a retrospective analysis. Pediatr Rheumatol Online J. 2020 Jan 16;18(1):7.[Abstract][Full Text]
56. Kim HA, An JM, Nam JY, et al. Serum S100A8/A9, but not follistatin-like protein 1 and interleukin 18, may be a useful biomarker of disease activity in adult-onset Still's disease. J Rheumatol. 2012 Jul;39(7):1399-406.[Abstract][Full Text]
57. Kim HA, Han JH, Kim WJ, et al. TLR4 endogenous ligand S100A8/A9 levels in adult-onset Still's disease and their association with disease activity and clinical manifestations. Int J Mol Sci. 2016 Aug 16;17(8):1342.[Abstract][Full Text]
58. Wittkowski H, et al. S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin. Arthritis Rheum. 2008 Dec;58(12):3924-31.
59. Bae CB, Suh CH, An JM, et al. Serum S100A12 may be a useful biomarker of disease activity in adult-onset Still's disease. J Rheumatol. 2014 Dec;41(12):2403-8.[Abstract][Full Text]
60. Ombrello MJ, Remmers EF, Tachmazidou I, et al. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15970-5.[Abstract][Full Text]
61. Teng JL, Chen X, Chen J, et al. The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population. J Autoimmun. 2021 Jan;116:102562.[Abstract][Full Text]
62. Bojan A, Parvu A, Zsoldos IA, et al. Macrophage activation syndrome: a diagnostic challenge (review). Exp Ther Med. 2021 Aug;22(2):904.[Abstract][Full Text]
63. Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis is key. Open Access Rheumatol. 2018;10:117-28.[Abstract][Full Text]
64. National Institute for Health and Care Excellence. Procalcitonin testing for diagnosing and monitoring sepsis (ADVIA Centaur BRAHMS PCT assay, BRAHMS PCT Sensitive Kryptor assay, Elecsys BRAHMS PCT assay, LIAISON BRAHMS PCT assay and VIDAS BRAHMS PCT assay) [DG18]. Oct 2015 [internet publication].[Full Text]
65. Aho K, Palusuo T, Kurki P. Marker antibodies of rheumatoid arthritis: diagnostic and pathogenetic implications. Semin Arthritis Rheum. 1994 Jun;23(6):379-87.[Abstract]
66. Goldbach-Mansky R, Lee J, McCoy A, et al. Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res. 2000;2(3):236-43.[Abstract][Full Text]
67. Zhou X, Li Y, Wang Q. FDG PET/CT used in identifying adult-onset Still's disease in connective tissue diseases. Clin Rheumatol. 2020 Sep;39(9):2735-2742.[Abstract][Full Text]
68. Holzinger D, Foell D, Kessel C. The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases. Mol Cell Pediatr. 2018 Sep 25;5(1):7.[Abstract][Full Text]
69. Metcalfe JZ, Everett CK, Steingart KR, et al. Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis. J Infect Dis. 2011 Nov 15;204(suppl 4):S1120-9.[Abstract][Full Text]
70. Hamm RL. Drug-hypersensitivity syndrome: diagnosis and treatment. J Am Coll Clin Wound Spec. 2011 Dec;3(4):77-81.[Abstract][Full Text]
71. Barzilai A, Langevitz P, Goldberg I, et al. Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic correlation. J Am Acad Dermatol. 2000 May;42(5 pt 1):791-5.[Abstract][Full Text]
72. Japanese Ministry of Health, Labour and Welfare Clinical Practice Guidelines Committee. Evidence-based clinical practice guideline for adult Still's disease. 2018 [internet publication].[Full Text]
73. Fautrel B, Patterson J, Bowe C, et al. Systematic review on the use of biologics in adult-onset still's disease. Semin Arthritis Rheum. 2023 Feb;58:152139.[Abstract][Full Text]
74. Galozzi P, Bindoli S, Doria A, et al. Progress in biological therapies for adult-onset Still's disease. Biologics. 2022;16:21-34.[Abstract][Full Text]
75. Colina M, Zucchini W, Ciancio G, et al. The evolution of adult-onset Still disease: an observational and comparative study in a cohort of 76 Italian patients. Semin Arthritis Rheum. 2011 Oct;41(2):279-85.[Abstract][Full Text]
76. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. J Rheumatol. 1999 Feb;26(2):373-8.[Abstract]
77. Cipriani P, Ruscitti P, Carubbi F, et al. Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. Clin Ther. 2014 Mar 1;36(3):427-35.[Abstract]
78. Sfriso P, Bindoli S, Galozzi P. Adult-onset Still's disease: molecular pathophysiology and therapeutic advances. Drugs. 2018 Aug;78(12):1187-95.[Abstract]
79. Mitamura M, Tada Y, Koarada S, et al. Cyclosporin A treatment for Japanese patients with severe adult-onset Still's disease. Mod Rheumatol. 2009;19(1):57-63.[Abstract][Full Text]
80. Jamilloux Y, Gerfaud-Valentin M, Henry T, et al. Treatment of adult-onset Still's disease: a review. Ther Clin Risk Manag. 2015;11:33-43.[Abstract][Full Text]
81. Kaneko Y. Interluekin-6 inhibitors for the treatment of adult-onset Still's disease. Mod Rheumatol. 2022 Jan 5;32(1):12-5.[Abstract][Full Text]
82. Colafrancesco S, Priori R, Valesini G, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still's disease: a multicentre retrospective observational study. Front Pharmacol. 2017;8:369.[Abstract][Full Text]
83. Zhou S, Qiao J, Bai J, et al. Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review. Ther Clin Risk Manag. 2018;14:167-71.[Abstract][Full Text]
84. Laskari K, Tektonidou MG, Katsiari C, et al. Outcome of refractory to conventional and/or biologic treatment adult Still's disease following canakinumab treatment: countrywide data in 50 patients. Semin Arthritis Rheum. 2021 Feb;51(1):137-43.[Abstract][Full Text]
85. Ruscitti P, Ursini F, Sota J, et al. The reduction of concomitant glucocorticoids dosage following treatment with IL-1 receptor antagonist in adult onset Still's disease. A systematic review and meta-analysis of observational studies. Ther Adv Musculoskelet Dis. 2020;12:1759720X20933133.[Abstract][Full Text]
86. Fautrel B, Sibilia J, Mariette X, et al. Tumour necrosis factor alpha blocking agents in refractory adult Still's disease: an observational study of 20 cases. Ann Rheum Dis. 2005 Feb;64(2):262-6.[Abstract][Full Text]
87. Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology (Oxford). 2019 Jan 1;58(1):5-17.[Abstract][Full Text]
88. Hines MR, von Bahr Greenwood T, Beutel G, et al. Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. Crit Care Med. 2022 May 1;50(5):860-72.[Abstract]
89. Mehta P, Cron RQ, Hartwell J, et al. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol. 2020 Jun;2(6):e358-67.[Abstract][Full Text]
90. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019 Jun 6;133(23):2465-77.[Abstract][Full Text]
91. Feist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still's disease. Nat Rev Rheumatol. 2018 Oct;14(10):603-18.[Abstract][Full Text]
92. Pouchot J, Sampalis JS, Beaudet F, et al. Adult Still's disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore). 1991 Mar;70(2):118-36.[Abstract]
93. Kalyoncu U, Kasifoglu T, Omma A, et al. Derivation and validation of adult Still Activity Score (SAS). Joint Bone Spine. 2023 Jan;90(1):105499.[Abstract][Full Text]
94. Hu Q, Wang M, Jia J, et al. Tofacitinib in refractory adult-onset Still's disease: 14 cases from a single centre in China. Ann Rheum Dis. 2020 Jun;79(6):842-4.[Abstract][Full Text]
95. Kacar M, Fitton J, Gough AK, et al. Mixed results with baricitinib in biological-resistant adult-onset Still's disease and undifferentiated systemic autoinflammatory disease. RMD Open. 2020 Jul;6(2):e001246.[Abstract][Full Text]
96. US Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots and death for JAK inhibitors that treat certain chronic inflammatory conditions. 2021 [internet publication].[Full Text]
97. European Medicines Agency. EMA confirms measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders. 2023 [internet publication].[Full Text]
98. Medicines and Healthcare Products Regulatory Agency. Janus kinase (JAK) inhibitors: new measures to reduce risks of major cardiovascular events, malignancy, venous thromboembolism, serious infections and increased mortality. 2023 [internet publication].[Full Text]
99. Gabay C, Fautrel B, Rech J, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis. 2018 Jun;77(6):840-7.[Abstract][Full Text]
Key Articles
Other Online Resources
Referenced Articles
Guidelines
Diagnostic
Summary
Guideline based on 26 clinical questions aimed at helping rheumatologists, nonspecialist physicians, other healthcare professionals and patients to understand and treat AOSD.Published by
Japanese Ministry of Health, Labour and Welfare Clinical Practice Guidelines committee
Published
2018
Summary
Recommendations on the two key questions of "how should AOSD be diagnosed?" and "how should AOSD be treated?", structured using the PICO scheme.Published by
German Society of Rheumatology
Published
2022