AOSD – Adult-Onset Still Disease

Adult-Onset Still's Disease (AOSD) has not been linked to any specific gene at this time. Thus, diagnostic criteria are clinical and not verified by genetic testing.

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It has an estimated prevalence (independent of ethnicity) of 0.62 per 100,000 individuals worldwide. The number of cases in Japan and Turkey may be slightly higher based on recent research.

Symptoms are systemic and include: fevers, rash, splenomegaly, lymphadenopathy, myalgia, arthritis, hepatomegaly, pericarditis, pleuritis, severe anaemia, abdominal pain, renal dysfunction, fatigue, headache, sore throat, and weight loss (may be rapid).

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High daily fevers (≥39 °C/102.2 °F) usually spike during the evening at approximately the same time each day and return to normal in the morning. These fevers may be accompanied by a feeling of extreme fatigue with a rash.

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The cutaneous/skin manifestations include a salmon-pink rash (small, non-itchy spots or patches up to 5 cm in diameter) that disappears quickly and usually presents on the trunk, neck, and extremities, which appears in 95% of patients. Urticaria (hives) may also present and can be raised and itchy. Fever and skin symptoms may present months or even years before developing chronic arthritis. Muscles and joints, typically impacting the knees and wrists, may swell and cause limited mobility due to stiffening and aching. Arthritis may also affect the fingers, shoulders, elbows, and ankles.

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Triggers

The disease onset may be triggered by a variety of genetic, environmental, and infectious (bacterial and viral) factors. However, it is uncertain, and research of causation is ongoing.

AOSD is typically considered as a diagnosis of exclusion and a definitive diagnosis should be made based on the Yamaguchi or Fautrel criteria only after excluding infectious, malignant, and other connective tissue diseases. Timely diagnosis and treatment of the disease with corticosteroids, followed by maintenance therapy with disease modifying antirheumatic drugs (DMARDs) or biologics such as TNF-alpha agents or interleukin (IL-1) inhibitors.

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Patients with AOSD may experience macrophage activation syndrome (MAS), a severe and potentially life-threatening complication. Timely diagnosis and treatment of the disease may prevent symptoms, alleviate pain, and lead to a more favorable prognosis with improved quality of life.

The major and the minor criteria of the Fautrel criteria are:

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Major criteria:

• Spiking fever > 39 °C

• Arthralgias

• Transient erythematous rash

• Sore throat

• PMN > 80% (polymorphonuclear)

• Glycosylated ferritin < 20%

Minor criteria:

• Maculopapular rash

• Leucocytosis > 10,000/mm3

Diagnosis requires at least 4 or more major criteria or 3 major + 2 minor criteria.

NSAIDs and corticosteroids (prednisolone is the preferred choice for steroid use) represent the first line therapy, when there is limited systemic impact from the disease.

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DMARDs such as Methotrexate, Cyclosporine, Azathioprine or Leflunomide, also may be used.

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Patients who do not respond to these therapies, may benefit by taking biologics such as: IL-1 inhibitors anakinra, canakinumab and rilonacept, IL-6 inhibitor tocilizumab, anti-TNF agents such as infliximab, etanercept, and adalimumab. Research is ongoing in regard to using other types of biologics for AOSD patients.

Laboratory tests should include acute phase reactants (CRP, ESR, SAA), ferritin, liver enzymes, albumin, complete blood count (CBC), ANA & rheumatoid factor (to rule out other rheumatic diseases).

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Abnormalities may include extremely elevated neutrophils (leukocytosis within 15,000–30,000), high ferritin or liver enzymes, elevated erythrocyte sedimentation rate (ESR) & C-reactive protein (CRP), anemia, low albumin (hypoalbuminemia), and thrombocytopenia (> 400,000).

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Inflammatory cytokines such as interleukin IL-1, IL-6, IL-18, TNF, and S100 proteins may also be elevated.

AOSD female patients may have higher risk factors for successful pregnancy. Comorbidities may include hypertension, diabetes, and thyroid problems. Obstetrical complications may include: spontaneous abortion, prematurity, intrauterine growth restriction, premature rupture of membranes, and other issues, thus requiring a highly trained multidisciplinary team (rheumatologist and an obstetrician) before, during and post pregnancy.

Petros Efthimiou, Apostolos Kontzias, Peter Hur, Kavita Rodha, G S Ramakrishna, Priscila Nakasato. Adult-onset Still's disease in focus: Clinical manifestations, diagnosis, treatment, and unmet needs in the era of targeted therapies, Seminars in Arthritis and Rheumatism. Volume 51, Issue 4, 2021, Pages 858-874, ISSN 0049-0172. https://doi.org/10.1016/j.semarthrit.2021.06.004.

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Feist E., Quartier P., Fautrel B., Schneider R. et al. “Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups.” Clinical and Experimental Rheumatology, 02 Mar 2018, 36(4):668-675. https://europepmc.org/abstract/med/29533755

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Macovei LA, Burlui A, Bratoiu I, Rezus C, Cardoneanu A, Richter P, Szalontay A, Rezus E. Adult-Onset Still's Disease-A Complex Disease, a Challenging Treatment. Int J Mol Sci. 2022 Oct 24;23(21):12810. doi: 10.3390/ijms232112810. PMID: 36361602; PMCID: PMC9655522.

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Rajesh Gopalarathinam, Eric Orlowsky et al., “Adult Onset Still’s Disease: A Review on Diagnostic Workup and Treatment Options”. Case Reports in Rheumatology, Volume 2016, Article ID 6502373, 6 pages. http://dx.doi.org/10.1155/2016/6502373

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M. Yamaguchi, A. Ohta, T. Tsunematsu et al., “Preliminary criteria for classification of adult Still's disease,” Journal of Rheumatology, vol. 19, no. 3, pp. 424–430, 1992. https://europepmc.org/abstract/med/1578458

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A. Mert, R. Ozaras, F. Tabak et al., “Fever of unknown origin: a review of 20 patients with adult-onset Still's disease,” Clinical Rheumatology, vol. 22, no. 2, pp. 89–93, 2003. https://link.springer.com/article/10.1007%2Fs10067-002-0680-3

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John J. Cush, MD, Autoinflammatory Syndromes. Dermatol Clin. 2013 Jul; 31(3): 471–480.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489412

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E. G. Bywaters, “Still's disease in the adult,” Annals of the Rheumatic Diseases, vol. 30, no. 2, pp. 121–133, 1971. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1005739

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Helmut Wittkowski, Michael Frosch, Nico Wulffraat et al. “S100A12 is a novel molecular marker differentiating systemic‐onset juvenile idiopathic arthritis from other causes of fever of unknown origin.” Arthritis & Rheumatology, Volume58, Issue 12, December 2008, Pages 3924-3931. https://onlinelibrary.wiley.com/doi/full/10.1002/art.24137

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Gerfaud-Valentin M, Hot A, Huissoud C, Durieu I, Broussolle C, Seve P. Adult-onset Still's disease and pregnancy: about ten cases and review of the literature. Rheumatol Int. 2014 Jun;34(6):867-71. doi: 10.1007/s00296-013-2765-5. Epub 2013 Apr 27. PMID: 23624554.