Adult-onset Still disease (AOSD), commonly referred in the literature as the adult form of systemic-onset juvenile idiopathic arthritis, is a disorder of unknown etiology [1] [2]. The clinical presentation might be quite different from patient to patient, but the following manifestations are included in the diagnostic criteria [1] [3] [4] [5]:

• Fever - Although not specific, the recurring appearance of very high fever (> 39°C) that lasts for a few hours and mainly happens in the late afternoon or early evening period, is a hallmark of AOSD [3] [6].
• Joint pain - The involvement of knees, wrists, or ankles is another important manifestation of AOSD [3] [4]. Arthritis usually accompanies fever and has a relatively short duration as well [3].
• Rash - A salmon-pink or erythematous nonpruritic maculopapular rash, developing together with fever and joint pain, is frequently observed, and is most commonly seen on the trunk and the proximal limbs [5].

Other common manifestations of AOSD are lymphadenopathy, hepatosplenomegaly, muscle aches, and pharyngitis [1] [7]. The clinical course of the disorder can be highly variable, ranging from mild and self-limiting to severely debilitating disease [3]. Furthermore, AOSD may cause a myriad of complications in affected individuals, such as pulmonary hypertension, thrombotic thrombocytopenic purpura (TTP), amyloidosis, and macrophage activation syndrome [1]. An early detection of this disorder could significantly aid in successful treatment and improvement of the overall quality of life.

• Fever

  We describe five patients less than 16 years of age who presented with an acute illness characterized by fever and a distinctive skin eruption. [ncbi.nlm.nih.gov]

  Fevers develop each day (usually in the afternoon or evening), and the rash comes and goes with the fever. Other signs and symptoms may include abdominal pain, pleurisy, swollen lymph nodes, and weight loss. [rarediseases.info.nih.gov]

• Lymphadenopathy

  Adult-onset Still disease (AOSD) is a systemic inflammatory disorder characterized clinically by high spiking fever, polyarthralgia/arthritis, a salmon-pink evanescent rash, predominantly neutrophilic leucocytosis, lymphadenopathy, liver dysfunction, [ncbi.nlm.nih.gov]

  Definition / general Rare systemic inflammatory disease accompanied by a triad of spiking fever, maculopapular exanthema and arthralgia, accompanied frequently by lymphadenopathy Essential features Fever, skin rash, joint pains, lymphadenopathy with paracortical [pathologyoutlines.com]

  Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, abnormal liver function tests, and negative rheumatoid factor and ANA. Elevated ferritin is often found and may assist in diagnosis. [orpha.net]

• High Fever

  A 48-year-old woman was admitted because of spiking high fever, sore throat, and jaundice. [ncbi.nlm.nih.gov]

  Major diagnostic criteria include arthralgia for more than 2 weeks, intermittent high fever for more than 1 week, characteristic rash, and white blood cell count above 10,000. [orpha.net]

• Anemia

  AOSD patients with RHS showed higher frequencies of leukopenia, anemia, thrombocytopenia, hypoalbuminemia, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia, and elevated lactate dehydrogenase levels than did those without RHS. [ncbi.nlm.nih.gov]

  Autoimmune hemolytic anemia. Nihon Rinsho 2008;66:520–523. 15. Pirofsky B. Clinical aspects of autoimmune hemolytic anemia. Semin Hematol 1976;13:251–265. [synapse.koreamed.org]

  METHODS: Previously we developed a method to measure the iron content of ferritin; we investigated the usefulness of this method to establish the iron status of patients with anemia of inflammation. [jrheum.org]

  CC: 6 days of fevers and URI symptoms ID: 67 yo female with pernicious anemia presents with 6 days of fevers and URI symptoms and 3 weeks of nonpruritic, round, scaly rash on her forearm. [uscmedicine.blog]

• Swinging Fever

  In hospital it was found that she had swollen joints, a high swinging fever and blood tests that were consistent with severe inflammation. The Rheumatology specialists were called and a diagnosis of Adult Onset Still’s Disease was made. [nras.org.uk]

• Splenomegaly

  Adult-onset Still disease (AOSD) is a systemic inflammatory disorder characterized clinically by high spiking fever, polyarthralgia/arthritis, a salmon-pink evanescent rash, predominantly neutrophilic leucocytosis, lymphadenopathy, liver dysfunction, and splenomegaly [ncbi.nlm.nih.gov]

• Generalized Lymphadenopathy

  lymphadenopathy Pathophysiology Pathophysiology is yet to be clearly defined Interleukins, macrophage colony stimulating factor, interferon gamma and tumor necrosis factor alpha may play a role May also be due to genetic factors, immune dysfunction and [pathologyoutlines.com]

  Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. [rheumnow.com]

  It differs from classical rheumatoid arthritis in that it is more often marked by acute febrile onset, and generalized lymphadenopathy and hepatosplenomegaly are more prominent. [icd10data.com]

  B (Minor criteria) comprises (i) TLC or 15000/mm 3 (ii) Still's rash (iii) Pleuritis or pericarditis (iv) Hepatomegaly or splenomegaly or generalized lymphadenopathy. Our patient qualified for all criteria from A and two criteria from B. [ijnm.in]

  On examination, she looked pale, febrile (temperature 39.2ºC), had non-suppurative pharyngitis and generalized lymphadenopathy. The lymph nodes were slightly tender, small and discrete. [pjms.com.pk]

• Pharyngitis

  Arthritis (OR, 8.6; 95% confidence interval [CI], 1.5-49.1; p 0.014), pharyngitis (OR, 6.9; 95% CI, 1.5-30.2; p 0.010), splenomegaly (OR, 5.4; 95% CI, 1.1-26.7; p 0.039), and neutrophilic leukocytosis (OR, 18.1; 95% CI, 3.5-93.6; p 0.001) were significantly [ncbi.nlm.nih.gov]

  Pharyngitis Pharyngitis, non-suppurative occurs in approximately 70% of the patients [ 6 ]. Hepatomegaly with or without elevation in liver aminotransferases frequently occurs. [oapublishinglondon.com]

  The presenting features are variable and may include high fever ( 39 C) with daily spikes, sore throat or pharyngitis, arthralgia or arthritis ( 65% of patients), transient maculopapular rash, and more rarely myalgia, lymphadenopathy, hepatosplenomegaly [orpha.net]

  Clinical features include quotidian fevers, arthralgias, arthritis, pharyngitis, lymphadenopathy and an evanescent rash. AOSD should be considered in the differential diagnosis of fever of unknown origin. [pagepress.org]

  2 Department of Internal Medicine, The University of Chicago Medical Center, Chicago, IL, USA Abstract: Adult-onset Still's disease (AOSD) – a multi-systemic inflammatory condition characterized by high fevers, polyarthritis, an evanescent rash, and pharyngitis [dovepress.com]

• Nausea

  Poor appetite, nausea, and weight loss may occur. Lymphadenopathy, splenomegaly, hepatomegaly, and sore throat are also common. Pericarditis, pleuritis, pericardial effusion and pleural effusion may occur but is less likely. [slideshare.net]

  Poor appetite, nausea, and weight loss are common. There is also commonly swelling of the lymph glands, enlargement of the spleen and liver, and sore throat. [rxlist.com]

• Hepatomegaly

  Liver involvement was observed in all cases, with hepatomegaly in 81.3%, increased liver enzymes in 50.0%, and hypergammaglobulinemia in 68.8%. Cardiac involvement was observed in 12.6%, pleuritis in 6.3%, and renal involvement in 25.0%. [ncbi.nlm.nih.gov]

  Physical examination revealed pallor, hepatomegaly. [ijnm.in]

  – Elevated acute-phase reactants: elevated ESR, CRP, white count, and hyperferritinemia (69-97% of patients) -Other findings that may be found include: myalgia, sore throat, hepatomegaly, splenomegaly, lymphadenopathy, serositis, abdominal pain, elevated [utswim.wordpress.com]

• Hepatosplenomegaly

  Adult onset Still's disease (AOSD) is a systemic inflammatory disease characterized by high-fevers, articular involvement, maculopapular rash, hepatosplenomegaly, lymphadenopathy, and a neutrophilic leukocytosis. [ncbi.nlm.nih.gov]

  […] interferon gamma and tumor necrosis factor alpha may play a role May also be due to genetic factors, immune dysfunction and infections Clinical features Systemic inflammatory disease manifesting with spiking fever, sore throat, arthralgia, skin rash and hepatosplenomegaly [pathologyoutlines.com]

  HLH is also characterized by fever, hepatosplenomegaly, increased ferritin levels all of which are also features of AOSD. [ijpmonline.org]

  The presenting features are variable and may include high fever ( 39 C) with daily spikes, sore throat or pharyngitis, arthralgia or arthritis ( 65% of patients), transient maculopapular rash, and more rarely myalgia, lymphadenopathy, hepatosplenomegaly [orpha.net]

  There was no hepatosplenomegaly or lymphadenopathy. [cureus.com]

• Periorbital Edema

  Periorbital edema/erythema and nonlinear urticarial lesions were also seen. Two children had splinter hemorrhages of the nail beds and one girl developed a fixed, scaling, pigmented, linear eruption. [ncbi.nlm.nih.gov]

  Da-Lim Yoon, Seohyun Lee, So Young Park, You Jae Kim, Bon San Koo, Min Wook So, Yong-Gil Kim, Chang-Keun Lee and Bin Yoo, A Case of Adult-Onset Still's Disease Presenting with Periorbital Edema, Journal of Rheumatic Diseases, 20, 4, (243), (2013). [doi.org]

• Retinal Hemorrhage

  Fundoscopic examination showed multiple areas of retinal whitening, discrete superficial retinal hemorrhages, and few characteristic Purtscher flecken in the left eye. The patient was diagnosed with adult-onset Still disease. [ncbi.nlm.nih.gov]

• Skin Rash

  Recently, a nonclassic, nonevanescent skin rash has been reported. We report a 27-year-old woman with AOSD showing persistent pruritic papular lesions. Histologically, dyskeratotic keratinocytes were seen in the upper epidermis. [ncbi.nlm.nih.gov]

  Abstract Adult onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology characterized by spiking fever, evanescent skin rash, arthralgia or arthritis, involvement of various organs, and predominantly neutrophilic leucocytosis [e-ijd.org]

• Eruptions

  We describe five patients less than 16 years of age who presented with an acute illness characterized by fever and a distinctive skin eruption. [ncbi.nlm.nih.gov]

• Koebner Phenomenon

  It commonly appears on the trunk, neck, or extremities and may be associated with dermatographism, Koebner phenomenon (lesions arising at sites of trauma/pressure), pruritus, or urticaria. Fixed dermal plaques have been rarely described. [rheumaknowledgy.com]

  In one-third of patients, the rash is mildly pruritic and develops at sites of pressure or trauma (Koebner’s phenomenon). Arthralgia/Arthritis and Myalgia Intense arthralgias are a universal finding. [stillsdisease.org]

  Look for the rash in areas subject to pressure like the beltline and under the breasts or it can be elicited by stroking the skin (Koebner’s phenomenon). The rash is frequently misdiagnosed as a drug reaction. Figure 1. [clinicaladvisor.com]

  This type of eruption often had a linear configuration, possibly because of the Koebner phenomenon, thus resembling a flagellate erythema. [journals.lww.com]

  Cutaneous manifestations of AOSD: The common ones are Still’s Rash, Koebner phenomenon, Dermatographism. Uncommon: It includes Pruritis, Urticaria, Dermal plaques, Facial Rash, Alopecia, Erythema nodosumd and Raynaud’s phenomenon. [pjms.com.pk]

• Eczema

  Allergic Eczema... Academy of Nutrition and Dietetics The food you eat determines the quality of your life. It affects your appearance, may prevent some diseases... [doi.org]

• Splinter Hemorrhage

  Two children had splinter hemorrhages of the nail beds and one girl developed a fixed, scaling, pigmented, linear eruption. Severe malaise, myalgia, arthralgia, and leukocytosis were present in every patient. [ncbi.nlm.nih.gov]

• Arthritis

  Specifically, a sustained arthritis for at least 6 weeks is required for a diagnosis of systemic juvenile idiopathic arthritis, whereas transient arthritis and arthralgia are accepted criteria in adult-onset Still disease. [ncbi.nlm.nih.gov]

  Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009;60:2102–12. PubMedCentral PubMed CrossRef Google Scholar 41. [doi.org]

• Arthralgia

  Severe malaise, myalgia, arthralgia, and leukocytosis were present in every patient. [ncbi.nlm.nih.gov]

  Arthralgia is usually correlated with fever spikes. [orpha.net]

  AOSD, although uncommon, has a characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of pyrexia of unknown origin associated with a rash and arthralgia. [e-ijd.org]

• Myalgia

  Since March 2017, he has had progressive fatigue, myalgias, rash, weight loss, diarrhea, and recurrent low-grade fever. Subsequent bone marrow biopsy and FDG PET/CT demonstrated no active lymphoma. [ncbi.nlm.nih.gov]

  Five weeks earlier, sore throat, fever, malaise, and myalgias had developed. Broad-spectrum antibiotic therapy was administered, without improvement. A diagnosis was made. [blogs.nejm.org]

  The presenting features are variable and may include high fever ( 39 C) with daily spikes, sore throat or pharyngitis, arthralgia or arthritis ( 65% of patients), transient maculopapular rash, and more rarely myalgia, lymphadenopathy, hepatosplenomegaly [orpha.net]

• Anuria

  Five days later, the patient presented with dyspnea, hypotension, and anuria. Anasarca developed with massive pleural effusion, ascites, and systemic edema, resulting in an increase of 47 kg in body weight. [ncbi.nlm.nih.gov]

The diagnosis of AOSD is primarily a one of exclusion, as numerous autoimmune, malignant, and infectious diseases induce the nonspecific signs and symptoms seen in this condition [1] [3] [7] [8]. Thus, a comprehensive clinical and laboratory workup is necessary. Firstly, during a history taking, patients should be asked about the course of the disease and the appearance of symptoms, whereas a thorough physical examination has an important role in identifying lymphadenopathy, cutaneous changes, joint inflammation, and hepatosplenomegaly.

A complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum ferritin should be evaluated in laboratory studies [1] [3] [4] [7] [8]. Additionally, rheumatoid factor (RF) and antinuclear antibodies (ANA), both performed to exclude conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are also recommended in the initial workup [3].

Current diagnostic criteria are divided into major (Fever ≥ 39°C, joint pain, skin rash, pharyngitis, granulocytosis of ≥ 80%, and glycosylated ferritin fraction of ≤ 20%) and minor (leukocytosis of > 10,000/mm3 and a typical skin rash) [3] [4] [7] [8]. AOSD is confirmed if ≥ 4 major criteria or 3 major and 2 minor criteria are met [1] [3] [4] [7].

• Bilirubin Increased

  Subsequently, the serum level of ferritin decreased, but serum total bilirubin increased to 17.3 mg/dL. Therefore, cyclosporin was administered orally. [ncbi.nlm.nih.gov]

• Thrombocytosis

  Both patients had marked leukocytosis with neutrophil predominance, thrombocytosis, elevated liver enzymes and elevated acute phase rectants. [ajol.info]

  A peripheral smear also showed neutrophilia and thrombocytosis. [ijdvl.com]

  Blood cell count for improvement in leukocytosis and thrombocytosis. [clinicaladvisor.com]

  Investigations revealed hemoglobin of 9.7 g/dL, polymorphonuclear leukocytosis total leukocyte count (TLC 17500/mm 3 with 92% neutrophils), thrombocytosis (platelet count 848000/mm 3 ), a markedly raised erythrocyte sedimentation rate (ESR) (45 mm in [ijnm.in]

  Neutrophilic leukocytosis (WBC 12.5), thrombocytosis, markedly elevated ESR (50% are 90 mm/hr and 90% are 50 mm/hr) or C-reactive protein levels ( 2.0 mg/dl). [rheumaknowledgy.com]

• Total Bilirubin Increased

  Subsequently, the serum level of ferritin decreased, but serum total bilirubin increased to 17.3 mg/dL. Therefore, cyclosporin was administered orally. [ncbi.nlm.nih.gov]

• Listeria Monocytogenes

  monocytogenes meningitis in a patient receiving etanercept for Still’s disease, Clin Exp Rheumatol, 2005, vol. 23 pg. 121 28 Adalimumab (anti-TNF-alpha) therapy to improve the clinical course of adult-onset Still’s disease: the first case report, Clin [doi.org]

• Human Papillomavirus

  Genital human papillomavirus (HPV) infection has been reported to induce or exacerbate AIIDs, such as systemic lupus erythematosus (SLE). No guidelines are available for the management of genital warts in AOSD. Case report and literature review. [ncbi.nlm.nih.gov]

Treatment failed in four cases (two with each anti-TNF-α) [ 15 ]. [doi.org]

Biologic drugs, TNF-α inhibitors, and IL-1 and IL-6 blockers have been used for the treatment of patients with AOSD refractory to conventional treatment or those with life-threatening manifestations aiming for better disease control. [ncbi.nlm.nih.gov]

Medications that block the action of interleukin-1, such as anakinra, can be effective treatments when standard steroid treatments are insufficient. [en.wikipedia.org]

Prognosis The overall prognosis is generally good, once acute life-threatening manifestations have been controlled. Some patients with chronic disease and major joint involvement may have significantly altered quality of life. [orpha.net]

Systemic manifestations, per se, did not contribute to poor functional prognosis. Chronic articular disease had the worst outcome: 27% evolved to functional class III status, compared with none in the cyclic systemic groups. [ncbi.nlm.nih.gov]

The disease is an entity with heterogeneous pathology; and diverse suggested etiologies, clinical manifestations and prognoses. [ncbi.nlm.nih.gov]

Etiology The etiology of AOSD and its underlying pathogenetic mechanisms are not known. No risk factors for the disease have been identified so far, but environmental factors are suspected. [orpha.net]

Our study aims to analyze different aspects of articular manifestations complicating adult onset Still disease to define epidemiological, clinical and evolving characteristics of these complications. [panafrican-med-journal.com]

Summary Epidemiology Prevalence and incidence data are difficult to determine given the broad, non-specific clinical presentation. The estimated prevalence of AOSD is more than 1/100,000 population. [orpha.net]

[…] disease accompanied by a triad of spiking fever, maculopapular exanthema and arthralgia, accompanied frequently by lymphadenopathy Essential features Fever, skin rash, joint pains, lymphadenopathy with paracortical hyperplasia and immunoblastic reaction Epidemiology [pathologyoutlines.com]

Magadur-Joly G et al (1995) Epidemiology of adult Still’s disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis 54(7):587–590 PubMed CrossRef Google Scholar 4. [doi.org]

References Magadur-Joly G, Billaud E, Barrier JH, Pennec YL, Masson C, et al. (1995) Epidemiology of adult Still's disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis 54: 587. [archivesofmedicine.com]

Recent accumulation of knowledge, mostly arising from hereditary autoinflammatory diseases and from the systemic-onset juvenile idiopathic arthritis (sJIA), has given raise to new hypotheses on the pathophysiology of AOSD. [ncbi.nlm.nih.gov]

More important, novel biologic therapies have offered important clues to AOSD's underlying pathophysiology. [dovepress.com]

Pathophysiology is yet to be clearly defined Interleukins, macrophage colony stimulating factor, interferon gamma and tumor necrosis factor alpha may play a role May also be due to genetic factors, immune dysfunction and infections Clinical features [pathologyoutlines.com]

Additional research into the pathophysiology of PNGD is also warranted, as this would optimize medical management. [archivesofmedicine.com]

Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives. Best Pract Res Clin Rheumatol. 2012;26:505–33. PubMed CrossRef Google Scholar 52. [doi.org]

Clinicians need to be aware of this condition so that they can correctly diagnose it and prevent its serious complications. [ncbi.nlm.nih.gov]

Treatment aims to control inflammation, and prevent joint damage and other complications. [rarediseases.info.nih.gov]

It is important to keep the inflammation under control to prevent more damage to the body. If prednisone is taken for a long time, a doctor may recommend taking calcium and vitamin D to prevent thinning of the bones. [arthritis.org]

When steroids are used they will often be given with other drugs to help to prevent side-effects. [nras.org.uk]

CTFPHC REFERENCE BOOK Screening for Colorectal Cancer CTFPHC REFERENCE BOOK Screening for Cognitive Impairment CTFPHC REFERENCE BOOK Screening for Depression CTFPHC REFERENCE BOOK Screening for Developmental Delay CTFPHC Review Canadian Task Force on Preventive [qxmd.com]

1. Kadavath S, Efthimiou P. Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options. Ann Med. 2015;47(1):6-14.
2. Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P. Adult-onset Still's disease. Autoimmun Rev. 2014;13(7):708-722.
3. Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still’s disease. Ann Rheum Dis. 2006;65(5):564-572.
4. Gopalarathinam R, Orlowsky E, Kesavalu R, Yelaminchili S. Adult Onset Still’s Disease: A Review on Diagnostic Workup and Treatment Options. Case Reports in Rheumatology. 2016;2016:6502373.
5. Mobini M, Ghasemian R, Zameni F. Adult Onset Still's Disease With Different Antibodies: A Case Report and Review of Literature. Acta Med Iran. 2016;54(10):683-685.
6. Larson EB. Adult Still's disease—recognition of a clinical syndrome and recent experience. West J Med. 1985;142:665–671.
7. Dudziec E, Pawlak-Buś K, Leszczyński P. Adult-onset Still’s disease as a mask of Hodgkin lymphoma. Reumatologia. 2015;53(2):106-110.
8. Meijvis SC, Endeman H, Geers AB, ter Borg EJ. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still's disease. Neth J Med. 2007;65(6):212-214.