Adult-onset Still's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Adult-onset Still’s disease (AOSD) is an inflammatory condition characterized by high spiking fever, rash, sore throat, and joint pain. In 1896, an English doctor named George Frederick Still, described the condition in children and the disease is named after him. In 1971, EG Bywaters described the term “adult Still’s disease” which was later used for adults who had a condition similar to systemic onset JRA. Adult-onset Stiil’s disease (AOSD) may be classified based on the predominant clinical picture with which the patient presents into systemic sub-type and chronic arthritis sub-type. The sub-types differ based on the cytokine profile, clinical course and response to treatment. It is an autoimmune inflammatory arthritis that typically affects adolescents and adults ranging from age 16-40 years. Major etiological mechanisms behind cause a dysfunction of the innate and cellular immunity (limited) leading to activation of effector cells of the disease. Although the pathogenesis of adult-onset Still’s disease is largely knwon to be idiopathic. Triggers of AOSD lead to activation of toll-like receptors (TLR) and activation of immune system. Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) play an important role in the etiopathogenesis of AOSD. They lead to release of various cytokines in the body such as interleukin-1 beta (IL-1), interleukin-6 (IL-6), interleukin-17, interleukin-18, interferon-alpha (IFN-alpha) and tumor necrosis factor (TNF-alpha). On gross examination, the involved joints may exhibit soft tissue swelling, cartilage loss, jointerosions and carpal ankylosis (late during the disease process). On microscopic examination of the joint fluid, typical features associated with inflammatory joint disease may be observed. There is a dearth of data regarding the incidence and prevalence of adult-onset Still’s disease (AOSD). In the Japanese and the European populations, the reported prevalence rates range from 10 to 340 cases per 100,000 individuals. The disease occurs worldwide and usually affects young adults (age 16-35 years). If left untreated, adult-onset Still’s disease (AOSD) follows a relapsing and remitting course. Initial presentation of AOSD may be between 16 to 35 years of age. Symptoms usually evolve over weeks to months. Life-threatening complications known to be associated with AOSD include, macrophage activating syndrome (MAS), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), diffuse alveolar hemorrhage, pulmonary arterial hypertension (PAH), pericardial tamponade and myocarditis. The prognosis of adult-onset Still’s disease depends upon the clinical course of the disease. The chronic articular form of the disease is associated with worse prognosis. The diagnosis of adult-onset Still’s disease (AOSD) is made clinically along with supporting laboratory abnormalities and exclusion of other rheumatologic disorders, malignancy and infections. Three diagnostic criteria have been established in order to aid in the diagnosis of AOSD. Yamaguchi criteria is widely adopted. A patient suffering from AOSD may present with a fever greater than equal to 39 degrees celcius (102.2 degrees Fahrenheit) for greater than equal to 1 week along with associated arthralgia/arthritis for greater than equal to 2 weeks. There may be a maculopapular non-pruritic rash on the trunk or limbs. Patients may also complain of sore throat and lymphadenopathy. The symptoms of AOSD evolve over a period of weeks. On x-ray of the affected joints, soft tissue swelling and joint effusions may be seen during early course of the disease. Intercarpal and carpometacarpal joint space narrowing (JSN) and ankylosis may be observed. MRI is more sensitive than x-ray in detecting bony erosions. It can detect synovitis, inflammation of the lining of the joints and tendon abnormalities. Medical therapy in adult-onset Still’s disease (AOSD) is guided by disease activity and severity. Corticosteroids are the first line therapy; Disease modifying anti-rheumatic drugs (DMARDs) as monotherapy or in combination with other agents may be used in refractory or complicated cases.

Adult-onset Still’s disease (AOSD) is an inflammatory condition characterized by high spiking fever, rash, sore throat, and joint pain. In 1896, an English doctor named George Frederick Still, described the condition in children and the disease is named after him. In 1971, EG Bywaters described the term “adult Still’s disease” which was later used for adults who had a condition similar to systemic onset JRA. There’s no cure for adult-onset Still’s disease; however, symptomatic treatment using corticosteroids, anti-interleukinagents and disease modifying anti-rheumatic drugs (DMARDs) may provide relief, and aid in remission.

Adult-onset Stiil’s disease (AOSD) may be classified based on the predominant clinical picture with which the patient presents into systemic sub-type and chronic arthritis sub-type. The sub-types differ based on the cytokine profile, clinical course and response to treatment.

Adult-onset Still’s disease (AOSD) is an autoimmune inflammatory arthritis that typically affects adolescents and adults ranging from age 16-40 years. Major etiological mechanisms behind cause a dysfunction of the innate and cellular immunity (limited) leading to activation of effector cells of the disease. Although the pathogenesis of adult-onset Still’s disease is largely knwon to be idiopathic. Triggers of AOSD lead to activation of toll-like receptors (TLR) and activation of immune system. Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) play an important role in the etiopathogenesis of AOSD. They lead to release of various cytokines in the body such as interleukin-1 beta (IL-1), interleukin-6 (IL-6), interleukin-17, interleukin-18, interferon-alpha (IFN-alpha) and tumor necrosis factor (TNF-alpha) . These cytokines play major roles in modifying the normal working of the body and produce the typical clinical pictiure associated with AOSD. Some distinct HLA alleles have been shown to be associated with AOSD such as HLA-DR4, HLA-Bw35 (associated with good prognosis), HLA-DRB1, HLA-DRw6 (joint root involvement), HLA-B17, HLA-B35 and HLA-DR2. On gross examination, the involved joints may exhibit soft tissue swelling, cartilage loss, jointerosions and carpal ankylosis (late during the disease process). On microscopic examination of the joint fluid, typical features associated with inflammatory joint disease may be observed.

The cause of adult-onset Still’s disease (AOSD) is unknown.

Adult-onset Still’s disease (AOSD) is a diagnosis of exclusion and other conditions presenting with fever, fatigue, arthralgia, myalgia, rash and soft tissue swelling should be excluded if a diagnosis of AOSD is suspected clinically.

There is a dearth of data regarding the incidence and prevalence of adult-onset Still’s disease (AOSD). In the Japanese and the European populations, the reported prevalence rates range from 10 to 340 cases per 100,000 individuals. The disease occurs worldwide and usually affects young adults (age 16-35 years). Adult-onset Still’s disease (AOSD) affects females more than males. Aging adults affected by adult-onset Still’s disease (AOSD) have a higher rate of development of complications related to AOSD and a higher mortality rate compared to younger individuals.

The cause of adult-onset Still’s disease (AOSD) remain unknown but stress are known to be associated with an increased risk of developing AOSD.

There is insufficient evidence to recommend routine screening of AOSD.

If left untreated, adult-onset Still’s disease (AOSD) follows a relapsing and remitting course. Initial presentation of AOSD may be between 16 to 35 years of age. Symptoms usually evolve over weeks to months. Life-threatening complications known to be associated with AOSD include, macrophage activating syndrome (MAS), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), diffuse alveolar hemorrhage, pulmonary arterial hypertension (PAH), pericardial tamponade and myocarditis. The prognosis of adult-onset Still’s disease depends upon the clinical course of the disease. The chronic articular form of the disease is associated with worse prognosis. Other indicators of poor prognosis of AOSD include, presence of polyarthritis, interestitial pneumonia, pleuritis, joint erosions, Still’s rash (salmon-colored maculopapular rash) and development of secondary complications.

The diagnosis of adult-onset Still’s disease (AOSD) is made clinically along with supporting laboratory abnormalities and exclusion of other rheumatologic disorders, malignancy and infections. Three diagnostic criteria have been established in order to aid in the diagnosis of AOSD. Yamaguchi criteria is widely adopted.

Obtaining a comprehensive history is an integral part of diagnosing adult-onset Still’s disease (AOSD). The typical age of onset of adult-onset Still’s disease (AOSD) is between 16 to 35 years of age. A patient suffering from AOSD may present with a fever greater than equal to 39 degrees celcius (102.2 degrees Fahrenheit) for greater than equal to 1 week along with associated arthralgia/arthritis for greater than equal to 2 weeks. There may be a maculopapular non-pruritic rash on the trunk or limbs. Patients may also complain of sore throat and lymphadenopathy. The symptoms of AOSD evolve over a period of weeks.

On physical examination, a patient suffering from adult-onset Still’s disease (AOSD) may appear fatigued, has a high grade fever (spiking fever), tachycardia, salmon colored maculopapular rash on trunk and/or extremities, lymphadenopathy, hepatosplenomegaly, pleural and pericardial friction rub (due to underlying pleuritis and pericarditis).

Adult-onset Still’s disease (AOSD) is diagnosed based on clinical presentation and history findings. However, due to underlying inflammatory process, inflammatory marker such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated. Complete blood count may show leukocytosis with a left shift (increased neutrophils), anemia, thrombocytosis or pancytopenia (in cases of hemophagocytic syndrome).

There are no specific EKG findings associated with adult-onset Still’s disease (AOSD), however, in cases complicated by pericarditis, cardiac tamponade or myocarditis EKG abnormalities may be observed.

On x-ray of the affected joints, soft tissue swelling and joint effusions may be seen during early course of the disease. Intercarpal and carpometacarpal joint space narrowing (JSN) and ankylosis may be observed.

On CT scan of the abdomen, patients suffering from Still’s disease may have hepatomegaly and splenomegaly.

MRI is more sensitive than x-ray in detecting bony erosions. It can detect synovitis, inflammation of the lining of the joints and tendon abnormalities.

Bone scan (bone scinitgraphy) may be used for early detection of articular erosions in adult-onset Still’s disease (AOSD).

There are no other diagnostic studies associated with adult-onset Still’s disease (AOSD).

Medical therapy in adult-onset Still’s disease (AOSD) is guided by disease activity and severity. Corticosteroids are the first line therapy; Disease modifying anti-rheumatic drugs (DMARDs) as monotherapy or in combination with other agents may be used in refractory or complicated cases.

Surgery is not the mainstay of treatment of adult-onset Stills’ disease (AOSD).

There is no primary prevention for adult-onset Still’s disease (AOSD)

Secondary prevention of adult-onset Still’s disease (AOSD) is aimed at preventing relapses of the disease. Tocilizumab may be used to prevent relapses associated with AOSD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Adult-onset Still’s disease (AOSD) is an inflammatory condition characterized by high spiking fever, rash, sore throat, and joint pain. In 1896, an English doctor named George Frederick Still, described the condition in children and the disease is named after him. In 1971, EG Bywaters described the term “adult Still’s disease” which was later used for adults who had a condition similar to systemic onset JRA. There’s no cure for adult-onset Still’s disease; however, symptomatic treatment using corticosteroids, anti-interleukin agents and disease modifying anti-rheumatic drugs (DMARDs) may provide relief, and aid in remission.

• Adult-onset Still’s disease is an inflammatory condition characterized by high spiking fever, rash, sore throat, and joint pain.^[1]
• As it progresses, adult-onset Still’s disease may lead to chronic arthritis and other complications.
• In 1896, an English doctor named George Frederick Still, described the condition in children and the disease is named after him.^[2]
• Still’s disease occurring in children < 16 years is now referred to as systemic onset juvenile rheumatoid arthritis (JRA).
• In 1971, EG Bywaters described the term “adult Still’s disease” which was later used for adults who had a condition similar to systemic onset JRA.^[3]
• The cause of adult-onset Still’s disease is unknown. Risk factors known to be associated with Still’s disease are stress and infections (pathogen-associated molecular patterns– PAMPs)
• There’s no cure for adult-onset Still’s disease; however, symptomatic treatment using corticosteroids, anti-interleukin agents and disease modifying anti-rheumatic drugs (DMARDs) may provide relief, and aid in remission.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Adult-onset Stiil’s disease (AOSD) may be classified based on the predominant clinical picture with which the patient presents into systemic sub-type and chronic arthritis sub-type. The sub-types differ based on the cytokine profile, clinical course and response to treatment.

Adult-onset Stiil’s disease (AOSD) may be classified based on the predominant clinical picture with which the patient presents. The following are the sub-types:^[1][2]

• ASOD with pre-dominant systemic symptoms
• ASOD with pre-dominant arthritis

Adult-onset Still’s disease sub-types	Systemic sub-type	Distinguishing features
		Pre-dominant cellular mechanism	Cytokine profile	Clinical presentation	Laboratory findings	Response to treatment	Miscellaneous
		Natural killer (NK) cell dysfunction (marked deficiency) CD8 type (cytotoxic) T cell dysfunction (marked deficiency) Neutrophil, monocyte and macrophage activation	Interleukin 1 beta Interleukin 18 Interferon alpha and beta Interleukin 4	Arthralgia Myalgia Hepatitis Spleenomegaly Spiking fever (evening spike) Orbital inflammation Cardiac dysfunction Pulmonary dysfucntion Weight loss Sore throat Lymphadenopathy	Thrombocytopenia Hyperferritinemia	Strong response to interleukin-1 inhibitors Weak response to interleukin 18 inhibitors and interferon gamma inhibitors	Upregulation of genes involved in granulocyte formation
	Arthritis sub-type	Natural killer (NK) cell dysfunction (deficiency) CD8 type (cytotoxic) T cell dysfunction (deficiency) Neutrophil, monocyte and macrophage activation	Interleukin 17 Interleukin 23 Interleukin 6 Tumor necrosis factor alpha (TNF-alpha)	Involvement of wrist, ankle, elbow joints, proximal interphalyngeal joints (PIP) Arthralgia Myalgia Spiking fever Salmon-colored maculopapular rash Less common systemic and organ involvement	Thrombocytosis Arthritis	Strong response to interleukin 6 inhibitors Good response to TNF-alpha inhibitors Weak reponse to interleukin 17 inhibitors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Adult-onset Still’s disease (AOSD) is an autoimmune inflammatory arthritis that typically affects adolescents and adults ranging from age 16-40 years. Major etiological mechanisms behind cause a dysfunction of the innate and cellular immunity (limited) leading to activation of effector cells of the disease. Although the pathogenesis of adult-onset Still’s disease is largely knwon to be idiopathic. Triggers of AOSD lead to activation of toll-like receptors (TLR) and activation of immune system. Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) play an important role in the etiopathogenesis of AOSD. They lead to release of various cytokines in the body such as interleukin-1 beta (IL-1), interleukin-6 (IL-6), interleukin-17, interleukin-18, interferon-alpha (IFN-alpha) and tumor necrosis factor (TNF-alpha). These cytokines play major roles in modifying the normal working of the body and produce the typical clinical pictiure associated with AOSD. Some distinct HLA alleles have been shown to be associated with AOSD such as HLA-DR4, HLA-Bw35 (associated with good prognosis), HLA-DRB1, HLA-DRw6 (joint root involvement), HLA-B17, HLA-B35 and HLA-DR2. On gross examination, the involved joints may exhibit soft tissue swelling, cartilage loss, joint erosions and carpal ankylosis (late during the disease process). On microscopic examination of the joint fluid, typical features associated with inflammatory joint disease may be observed.

Adult-onset Still’s disease is an autoimmune inflammatory arthritis that typically affects adolescents and adults ranging from age 16-40 years. Major etiological mechanisms behind cause a dysfunction of the innate and cellular immunity (limited) leading to activation of effector cells of the disease.

Although the pathogenesis of adult-onset Still’s disease is largely known to be idiopathic. Triggers of AOSD lead to activation of toll-like receptors (TLR) and activation of immune system. The following triggers may be implicated as factors responsible for generating key pathological processes occurring in adult-onset Still’s disease (AOSD):^{[1][2][3][4][5][6][7][8]}

Pathogen-associated molecular patterns (PAMPs)

• Bacteria
  • Yersinia enterocolitica
  • Chlamydophila pneumoniae
  • Brucella abortus
  • Borrelia burgdorferi
• Viruses
  • Rubella
  • Echovirus 7
  • Mumps
  • Cytomegalovirus (CMV)
• Fungi

Danger-associated molecular patterns (DAMPs)

• Chemicals
• Toxins
• Stress

Both innate and adaptive immunity play roles in the pathological evolution of adult-onset Still’s disease with the dysfunction occurring in the innate immunity predominating the picture. The following dysfunctions are involved:

Changes in the innate immunity

• Natural killer cells have been found to be decreased in patients with AOSD. The mechanism underlying dysfunctional NK cells is a defect in IL-18 receptor β phosphorylation.^[9]
• Neutrophil and macrophage activation lie at the heart of pathogenesis of AOSD due to the effects of the proinflammatory interleukin-18 (IL-18) signalling.
• CD64, a marker of neutrophil activation has been found to be upregulated in active AOSD.^[10]
• Macrophage colony stimulating factor (MCSF), intercellular adhesion molecule-1 (ICAM-1) and calprotectin are elevated and act as markers of active disease.^[11][12]

Changes in the adaptive immunity

• T cell activation has also been shown to play role in the pathogenesis of AOSD with Th1 (cytotoxic) subset prevailing over Th2 CD4+ T cells.
• Increased number of Th17 cells derived from the differentiation of naive CD4+ T cells due to to activation by interleukin-1 beta, transforming growth factor-beta and interleukin- 6 is also seen in active AOSD. ^[13][14]

Interleukin-1 beta plays a key role in producing major characteristic features of adult-onset Still’s disease. PAMPs and DAMPs lead to stimulation of protein complex nucleotide-binding oligomerization-domain-(NOD-) like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (expressed in myeloid cells). The consequence of all these trigger-stimulated NOD and NLRP increasing interactions is an increased production of interleukin-1 beta.^[15]The following processes are affected by an increased production of this key interleukin of AOSD:

(a) Hypothalamic-pituitary axis influence

Activation of the hypothalamic–pituitary axis by interleukin-1 beta lead to the following changes:

Hormonal

• An increased secretion of adrenocorticotrophic hormone (ACTH) and anti-diuretic hormone (ADH).
• A decreased secretion of growth hormone (GH) and somatostatin.^[16]

Systemic

• Disturbance of the thalamic temperature regulating centres leading to fever.^[17]
• Fatigue^[18]
• Anorexia^[19] 

(b) Liver synthesis and secretion of acute phase proteins

Both interleukin-1 beta, interleukin-6 and interferon-alpha (IFN-alpha) lead to increased production of acute phase reactants by the liver due to inflammatory and oxidative stress occurring during active AOSD. The following acute phase reactant proteins are elevated in AOSD as a result of increased liver production:^[20][21]

• C-reactive protein (CRP)
• Ferritin  
• Serum amyloid protein (SAA)

(c) Osteoclasts activation and matrix metalloproteinases (MMPs) synthesis

Interleukin-1 and TNF-alpha have been shown to inhibit chondrogenesis leading to decreased repair process of bone and cartilage in AOSD.^[22]

(d) Innate immune system cells activation

Effector cells of the innate immune system such as macrophages and neutrophils are activated mainly due to interleukin-1. The neutrophil to lymphocyte count ratio is increased due to elevated neutrophils.^[23]

(e) Increased gene transcription of proinflammatory molecules

The following proinflammatory factors are produced in an increased concentration in AOSD:

• Inducible nitric oxide synthase (iNOS)^[24]
• Interleukin 1, 6 and TNF-alpha induced cyclo-oxygenase 2 (COX2)^[25]
• Phospholipase A2^[26]
• Intracellular adhesion molecules^[27]
• Colony-stimulating factors (C-SF)^[28]

It is produced by macrophages and monocytes as a consequence of bacterial and viral infections (which are thought to be triggers of AOSD).^[29] A defective phosphorylation of IL-18 receptor is though to give rise to this dysfunction.^[30]

Th17 cells lead to an increased production of interleukin-17. The stimulaton of Th17 cells is drived by interleukin-1, transforming growth factor beta (TGF-beta) and interleukin-6.^[31][32]

Imblanced production of interferon-gamma is thought to be associated with AOSD.^[33]  Levels of the IFN-γ-induced chemokines, CXCL9, CXCL10 and CXCL11 are increased during active phase of AOSD.^[34]

Hemophagocytic lymphohistiocytosis (also known as macrophage activation syndrome– MAS) is a severe life-threatening complication that may develop in patients of Still’s disease.^[35][36] Interleukin 1-beta and interleukin 18 mediated activation of macrophages eventually leads to secretion of interferon-gamma by the NK and CD8+ T cells. There is increased activation of T cells leading to hypersecretion of proinflammatory cytokines, including interferon gamma, interleukin (IL)-1, IL-6, IL-18, and tumor necrosis factor alpha (TNF-alpha).^[37][38]

Some distinct HLA alleles have been shown to be associated with AOSD. The following are the major HLA alleles:^[39][40]

• HLA-DR4
• HLA-Bw35 (associated with good prognosis)
• HLA-DRB1 
• HLA-DRw6 (joint root involvement)
• HLA-B17
• HLA-B35
• HLA-DR2

Genetic polymorphisms in genes encoding the following factors are known to be asosicated with AOSDL:

• IL-6
• IL-1
• Macrophage inhibitory factor (MIF), or TNF i

On gross examination, the involved joints may exhibit the following features:^[41]

• Soft tissue swelling
• Cartilage loss
• Joint erosions
• Carpal ankylosis

On microscopic examination of the synovial fluid, typical findings of inflammatory arthritis may be observed. The following table outlines the typical findings on synovial fluid examination of joints affected by AOSD:

Test	Normal	Inflammatory arthritis (AOSD, RA, crystal arthritis, spondyloarthritis)
Appearance	Clear	Clear to opaque (yellow white)
White blood cell count/mm3	< 200	> 2000
Polymorphonuclear cells	< 25%	Greater than equal to 50%
Culture	Negative	Negative
Intracellular crystals	Negative	Positive only in crystal induced arthritis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The cause of adult-onset Still’s disease (AOSD) is unknown.

The cause of adult-onset Still’s disease (AOSD) is unknown.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Adult-onset Still’s disease (AOSD) is a diagnosis of exclusion and other conditions presenting with fever, fatigue, arthralgia, myalgia, rash and soft tissue swelling should be excluded if a diagnosis of AOSD is suspected clinically.

Adult-onset Still’s disease (AOSD) is a diagnosis of exclusion and other conditions presenting with fever, fatigue, arthralgia, myalgia, rash and soft tissue swelling should be excluded if a diagnosis of AOSD is suspected clinically. The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]}

Category of Disease	Diseases	Signs and symptoms										Laboratory findings
		Fever	Fatigue	Arthralgia	Myalgia	Soft tissue swelling/serositis	Skin rash	Weight loss	Dyspnea	Sore throat	Lymphadenopathy	Complete blood count (CBC)	Liver function tests (LFTs)	Inflammatory markers		Autoantibodies						Diagnostic tests
														Erythrocyte sedimentation rate (ESR)	C- reactive protein (CRP)	Anti-nuclear antibodies (ANA)	Rheumatoid factor (RF)	Anti- glomerular basement membrane (anti-GBM)	Anti-dsDNA	Anti-Jo1/ Anti Mi2	ANCA
Infections	HIV	+	+	+	+	+/-	–	+	+/-	+ /-	+	Leukopenia Anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Herpesviridae	+	+	+	+	+	Papular or vesicular Erythematous base Painful	–	–	+/-	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–
	Measles	+	+	+	+	–	3-5 days after fever Erythematous maculopapular rash starts on face spreads to trunk and extremities (centrifugal)	–	–	+	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–
	Viral hepatitis	+	+	–	+/-	–	–	+/-	–	–	+/-	Leukocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Parvovirus B19	+	+	+	+/-	–	Slapped cheek rash	–	–	–	+	Leukopenia Aplastic anemia (low reticulocyte count) Thrombocytopenia	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Infective endocarditis	+	+	+	+/-	–	Purpuric	+/-	+	–	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–	Blood cultures, ultrasonography
	Borreliosis, Brucellosis, Yersiniosis	+	+	+	+	–	Target rash (Borrelia) Diffuse maculopapular (Brucellosis) Erythema nodosum (Yersiniosis)	–	–	–	+	Leukocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–	Serology, PCR
	Syphilis and Jarisch-Herxheimer reaction	+	+	+	+	–	Non-pruritic Macular On palms and soles Round Seen in secondary syphilis Penile ulceration (painless)	–	–	+	+	Leukocytosis	ALT↑ (Uncommon) AST↑ (Uncommon)	↑	↑	–	–	–	–	–	–	Serology, PCR
	Toxoplasmosis	+	+	–	+	–	Maculopapular Palms and soles	–	–	+	+	Leukocytosis (eosinophilia)				–	–	–	–	–	–	Serology, PCR
Neoplasia	Malignant lymphoma	+	+	–	+/-	+/-	Purplish scaly rash in cases of cutaneous lymphoma	+	+	–	+	Anemia of chronic disease	In case of liver metastasis (Non-Hodgkin lymphoma): ALT↑ AST↑	↑	↑	–	–	–	–	–	–	CT, PET/CT, Bone marrow examination, lymph node biopsy
	Multicentric Castleman disease	+	+	–	–	+	–	+	+	–	+	Anemia Thrombocytopenia	–	↑	↑	–	–	–	–	–	–	Lymph node biopsy
	Angioimmunoblastic T cell lymphoma	+	+	–	–	–	Maculopapular eruption on the trunk mimicking toxic erythema	+	–	–	+	Lymphocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–	Lymph node biopsy
Drug hypersensitivity	Drug reaction with eosinophilia and systemic symptoms	+	+	+	+	+/-	Utricaria (Immediate type) Maculopapular (Delayed type)	–	+	–	–	Leukocytosis (eosinophilia)	–	↑	↑	–	–	–	–	–	–	Eosinophil count, skin biopsy
Autoimmune conditions	Systemic lupus erythematosus	+	+	+	+/-	+	Butter-fly shaped erythematous malar rash that spares the nasolabial folds Coin-shaped erythematous rash on extremities or trunk	+	+	–	+/-	Leukopenia Hemolytic anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	+	+	–	+	–	–	Antinuclear autoantibodies
	Inflammatory myositis	+	+	–	+ (weakness > pain)	–	Macular red rash over the back of the fingers, elbows or knees (Grotton’s sign) Macular purpish or reddish rash on the upper chest or back  (Shawl-like, heliotrope rash)	–	–	–	+/-	Leukocytosis	–	↑	↑	+/-	+/-	–	–	+	–	Idem, muscle biopsy
	Rheumatoid arthritis	+	+	+	–	+	Purpura Ulcers	–	+	–	+	Anemia of chronic disease Neutropenia (Felty’s syndrome)	–	↑	↑	+/-	+/-	–	–	–	–	Anti-citrullinated peptids autoantibodies, rheumatoid factor
	Systemic vasculitides	+	+	+	–	+	Nasopharyngeal ulceration (Wegner’s granulomatosis) Erythematous rash on palms and soles (Kawasaki disease)	–	+/-	–	+/-	Leukocytosis	–	↑	↑	–	–	+/-	–	–	+	ANCA, tissue biopsy, arteriography
	Familial Mediterranean fever	+	+	+	+	+	Red rash on lower extremities (ankles and knees)	+	+ (due to pain)	–	+/-	Leukocytosis (during acute flares)	–	↑	↑	–	–	–	–	–	–	Familial history, MEFV gene analysis
	Mevalonate kinase deficiency	+	+	+	+	–	Maculopapular rash Aphthous ulcers (or stomatitis)	+	–	+	+	Leukocytosis (during acute flares)	–	↑	↑	–	–	–	–	–	–	Urinary mevalonic acid, mevalonate kinase analysis
	Reactive arthritis	+	+	+	–	–	Keratoderma blennorrhagica (palms, soles, scrotum) Circinate balanitis (penile)	–	+ (Aortic insufficiency)	–	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–	HLA B27, magnetic resonance imaging
Miscellaneous	Sarcoidosis	+	+	+	–	+	Waxy skin plaques Violaceous facial lesions Erythema nodosum	+	+	–	+	Lymphopenia Eosinophilia	Normal ALT, AST ALP ↑ (infiltrative pattern)	↑	↑	–	–	–	–	–	–	Lymph node/Lung biopsy ACE levels FDG-PET
	Neutrophilic dermatosis
	Kikuchi–Fujimoto disease

Adult-onset Still’s disease (AOSD) should be differentiated from other causes of fever and polyarthralgia/arthritis of the peripheral skeleton. The differentials include the following:^{[26][27][28][29]}

Arthritis Type	Clinical Features							Body Distribution				Key Signs				Laboratory Abnormalities
	History of Psoriasis	Symmetric joint involvement	Asymmetric joint involvement	Enthesopathy	Dactylitis	Nail Dystrophy	Human immunodeficiency virus association	Upper extremity-hands	Lower extremity	Sacroiliac joints	Spine	Osteopenia	Joint Space	Ankylosis	Periostitis	Soft tissue swelling	ESR	Rheumatoid factor (RF)	HLA-B27
Psoriatic arthritis	+	+	++	+	+	+	+	+++ (DIP/PIP)	+++	++ (Unilateral)	++	–	++ (Widening)	++	+++ (Fluffy)	++	+	–	30-75%
Rheumatoid arthritis	–	++	+	–	–	–	–	+++ (MCP/wrist)	+++	+ (Unilateral)	++(Cervical)	+++	+++ (Narrowing)	+	+ (Linear)	+++	+++	+++	6-8%
Reactive arthritis (Reiter’s syndrome)	–	+++	–	+	+	–	–	++	+++	++ (Unilateral)	+	+	+ (Narrowing)	–	+++ (Fluffy)	++	++	–	75%

Key:+ : Infrequently present, ++ : Frequently present, +++ : Always present, – : Absent

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

There is a dearth of data regarding the incidence and prevalence of adult-onset Still’s disease (AOSD). In the Japanese and the European populations, the reported prevalence rates range from 10 to 340 cases per 100,000 individuals. The disease occurs worldwide and usually affects young adults (age 16-35 years). Adult-onset Still’s disease (AOSD) affects females more than males. Aging adults affected by adult-onset Still’s disease (AOSD) have a higher rate of development of complications related to AOSD and a higher mortality rate compared to younger individuals.

• There is a dearth of data regarding the incidence and prevalence of adult-onset Still’s disease (AOSD).
• In the Japanese and the European populations, the reported prevalence rates range from 10 to 340 cases per 100,000 individuals.^[1]
• The disease occurs worldwide and usually affects young adults (age 16-35 years).
• In France, the annual incidence of AOSD was estimated to be 0.16 per 100,000 individuals.^[2]
• In Japan, the annual incidence of AOSD was estimated to be 0.22 per 100,000 individuals.^[3]
• In Norway, the annual incidence of AOSD was estimated to be 0.4 per 100,000 individuals.^[4]

• Aging adults affected by adult-onset Still’s disease (AOSD) have a higher rate of development of complications related to AOSD and a higher mortality rate compared to younger individuals.^[5]

• Adult-onset Still’s disease (AOSD) affects females more than males.^[6][7]

• Adult-onset Still’s disease (AOSD) affects Caucasians more than other races.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

The cause of adult-onset Still’s disease (AOSD) remain unknown but stress are known to be associated with an increased risk of developing AOSD.^[1]

The cause of adult-onset Still’s disease (AOSD) remain unknown but stress are known to be associated with an increased risk of developing AOSD.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

There is insufficient evidence to recommend routine screening of AOSD.

There is insufficient evidence to recommenf routine screening of AOSD.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

If left untreated, adult-onset Still’s disease (AOSD) follows a relapsing and remitting course. Initial presentation of AOSD may be between 16 to 35 years of age. Symptoms usually evolve over weeks to months. Life-threatening complications known to be associated with AOSD include, macrophage activating syndrome (MAS), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), diffuse alveolar hemorrhage, pulmonary arterial hypertension (PAH), pericardial tamponade and myocarditis. The prognosis of adult-onset Still’s disease depends upon the clinical course of the disease. The chronic articular form of the disease is associated with worse prognosis. Other indicators of poor prognosis of AOSD include, presence of polyarthritis, interestitial pneumonia, pleuritis, joint erosions, Still’s rash (salmon-colored maculopapular rash) and development of secondary complications.

• If left untreated, adult-onset Still’s disease (AOSD) follows a relapsing and remitting course.
• Initial presentation of AOSD may be between 16 to 35 years of age.
• Symptoms usually can evolve over weeks to months.
• AOSD exhibits a variable clinical course:
  • 20% with long-term remission
  • 30% remit-relapse
  • 50% chronic arthritis
• May progress to develop macrophage activating syndrome (MAS), also known as hemophagocytic syndrome.

Adult-onset Still’s disease may lead to the development of the following life-threatening complications:^[1][2]

• Macrophage activation syndrome (MAS)
• Disseminated intravascular coagulation (DIC)
• Thrombotic thrombocytopenic purpura (TTP)
• Diffuse alveolar hemorrhage
• Pulmonary arterial hypertension (PAH)
• Pericardial tamponade
• Myocarditis

The prognosis of adult-onset Still’s disease depends upon the clinical course of the disease:^[3][4]

• The self-limited form of AOSD is characterized by systemic symptoms for example: fever, rash, serositis, and organomegaly.
• Most patients experience one episode and remit within 1 year of the initial presentation.

• Patients experience pre-dominantly systemic symptoms with or without joint symptoms.
• Patients typically follow a relapsing-remitting course with intermittent flares.
• Most episodes milder than the initial presentation.

• Patients have pre-dominant articular symptoms and joint destruction.
• The articular form is associated with a worse prognosis than the systemic form.
• Severe joint destruction may warrant joint replacement surgery in severely ill patients.

• The following findings may be associated with a poor prognosis in patients suffering from AOSD:
  • Polyarthritis
  • Interstitial pneumonia
  • Pleuritis
  • Joint erosions
  • Still’s rash
  • Development of secondary complications, for example:
    • Macrophage activation syndrome (MAS)
    • Disseminated intravascular coagulopathy (DIC)
    • Thrombotic thrombocytopenic purpura (TTP)
    • Diffuse alveolar hemorrhage
    • Pulmonary arterial hypertension

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