NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Peter A. Nigrovic, MD, Harvard Medical School, Chief, Division of Immunology, Boston Children’s Hospital, Director, Center for Adults with Pediatric Rheumatic Illness (CAPRO), Brigham and Women’s Hospital, for assistance in the preparation of this report.
Summary
Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder that can affect the entire body (systemic disease). The cause of the disorder is unknown (idiopathic). Affected individuals may develop episodes of high, spiking fevers, a pink or salmon colored rash, joint pain, muscle pain, a sore throat and other symptoms associated with systemic inflammatory disease. The specific symptoms and frequency of episodes vary from one person to another and the progression of the disorder is difficult to predict. In some individuals, the disorder appears suddenly, disappears almost as quickly and may not return. In other people, AOSD is a chronic, potentially disabling condition. Various anti-inflammatory medications are used to treat individuals with AOSD, and affected individuals may respond to therapy differently.
Introduction
Adult-onset Still’s disease is the adult form of systemic juvenile idiopathic arthritis (juvenile Still’s disease). These disorders are named after Sir George Frederic Still, a British physician who first described a form of childhood arthritis associated with fever in the medical literature in 1896. Adults with “Still’s disease” were first reported in the medial literature in 1971, but cases that fit the description of the disorder appear as early as the late 1800s. AOSD might be difficult to diagnose given its rarity and the fact that symptoms may overlap with other diseases. Making a timely and accurate diagnosis is important for appropriate patient care and counseling. Although the symptoms of AOSD can affect quality of life, especially if they are chronic, the disease is not usually life -threatening.
The symptoms, progression, and severity of AOSD are highly variable from one person to another, but three main patterns have been identified:
Monophasic pattern: patients with monophasic AOSD have a single episode of symptoms that typically lasts weeks to months, but usually less than a year.
Polyphasic (intermittent) pattern: patients with polyphasic AOSD develop more than one episode of symptoms. Affected individuals are usually symptom-free for weeks to years between episodes. In general, subsequent episodes tend to be less severe and shorter in duration compared to the initial one.
Chronic pattern: patients with chronic AOSD have persistent symptoms over time.
Most individuals with AOSD develop some combination of the symptoms normally associated with systemic inflammatory disease. These include a spiking fever, a skin rash, muscle pain (myalgia), and joint pain (arthralgia) and inflammation (arthritis). The fever seen in AOSD is typically greater than 102.2oF (39oC). In some patients, fever spikes occur once or twice a day, usually in the late afternoon or early evening. The rash of AOSD, which usually but not always develops during a fever episode, is pink or salmon colored. It mostly affects the chest and thighs, but can also affect the arms, legs and face. It may or may not be itchy (pruritic) and tends to disappear quickly (evanescent). Affected joints may become swollen, stiff and inflamed. The knees, wrists, ankles, and hips are most commonly affected. Muscle and joint pain can be intense and is often worse during a fever episode. If AOSD goes untreated, chronic inflammation of the joints can potentially result in destruction of the affected joints. Chronic joint inflammation leading to these complications is more common in chronic AOSD and can potentially cause long-term, severe and disabling complications. Other symptoms that can be seen in AOSD include a sore throat, abdominal pain, nausea, loss of appetite (anorexia), weight loss and enlargement of the spleen (splenomegaly), liver (hepatomegaly) and lymph nodes (lymphadenopathy).
More rarely, AOSD can cause inflammation of internal organs. In some patients, the thin, sac-like membrane that surrounds the heart (pericardium) or the heart muscle (myocardium) may become inflamed (pericarditis or myocarditis, respectively). The membrane lining the lungs may also become inflamed (pleuritis) and may cause fluid to accumulate around the lungs (pleural effusion). Heart and lung involvement can cause difficulty breathing and chest pain, but in most patients it is usually not severe enough to be readily apparent and is often only detected by imaging. Another rare but potentially dangerous complication of AOSD is macrophage activation syndrome (MAS), also called secondary hemophagocytic lymphohystiocytosis (HLH), a condition characterized by an overactive and abnormal response of the immune system (for more information on this disorder, choose “HLH” as your search term in the Rare Disease Database).
The cause of AOSD is unknown (idiopathic). Researchers believe that the disorder might be caused by a combination of genetic factors and an abnormal or exaggerated response to infections or other environmental exposures. AOSD is not a hereditary disease and usually does not run in families.
Some researchers believe that AOSD is an autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system, which is the first line of defense of the immune system. They are not the same as autoimmune disorders, in which the adaptive immune system (the second line of defense of the immune system) malfunctions and mistakenly attacks healthy tissue.
Researchers also believe that specialized proteins that modulate the immune system (cytokines) may also play a role in the development of AOSD. Interleukin-1 (IL-1), a cytokine that is known to mediate cell response to inflammation, may play a role in the development of the disease, as abnormal clinical findings involving IL-1 have been found in some individuals with AOSD. For this reason, therapy with a drug to block the activity of IL-1 is being explored (see Investigational Therapies below). Additional cytokines including interleukin-6 (IL-6), IL-18, and tumor necrosis factor-alpha (TNF-alpha) are also believed to play a role in the development of AOSD and could therefore potentially be targeted for treatment.
The exact incidence of AOSD is unknown, but it is thought to affect between 1 and 34 people per million, depending on the population studied. Because of the highly variable symptoms and rarity of the disorder, it often goes undiagnosed or misdiagnosed, making it difficult to determine its true frequency in the general population. AOSD seems to affect men and women in equal numbers, although some reports state that the disorder affects women slightly more often than men. It primarily affects young adults between the ages of 16-35 but can also occur in older individuals.
The diagnosis of AOSD is difficult to make because there is no specific test or distinguishing laboratory finding that clearly differentiates the disorder from similar disorders. A diagnosis of AOSD is usually made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and the exclusion of other possible disorders (diagnosis of exclusion). A variety of tests may be performed to aid in a diagnosis including blood tests as well as imaging studies that might reveal changes in the bones or joints or enlargement of the spleen or liver. An echocardiogram, which uses sound waves to create a picture of the heart, may reveal inflammation of the pericardium or myocardium.
Blood tests may reveal characteristic changes to blood cell levels normally associated with AOSD. Affected individuals often have elevated levels of white blood cells (leukocytosis) and/or platelets (thrombocytosis) or low levels of red blood cells (anemia). However, this pattern of laboratory abnormalities is seen in many inflammatory disorders. Another common laboratory finding for individuals suspected of having an inflammatory disorder, including AOSD, is elevated inflammatory markers, namely the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Another blood test commonly used is serum ferritin, which is frequently disproportionally elevated in AOSD. Additionally, some patients have high blood levels of enzymes that are released by the liver, namely alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). To exclude other disorders, levels of certain antibodies such as antinuclear antibodies (ANA) and rheumatoid factor (RF) are usually measured. However, these antibodies are typically absent in patients with AOSD.
Although they are not perfect, certain sets of criteria can also help with the diagnosis of AOSD. The most commonly used set of criteria are the Yamaguchi criteria. To be considered for a diagnosis of AOSD, affected individuals need to fulfil at least 5 criteria, including at least 2 major criteria. Conditions that can mimic AOSD also need to be excluded to make a diagnosis. The Yamaguchi criteria are the following:
Major criteria
Minor criteria
Treatment
Many different therapies have been tried for individuals with AOSD. No one treatment has proven consistently effective in all patients. In addition to symptomatic and supportive treatment, a variety of different drugs taken alone or in combination may be used to treat affected individuals.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat symptoms of inflammation. Fever, joint pain and bone pain have responded to treatment with these drugs. Examples of NSAIDs include ibuprofen, naproxen, indomethacin and diclofenac. Other painkillers (analgesics) such as acetaminophen (Tylenol) may also be used. Corticosteroid drugs such as prednisone may be used to treat systemic symptoms. Corticosteroids have powerful anti-inflammatory properties. However, long-term use of corticosteroids is associated with many side effects. Affected individuals may therefore receive high doses of corticosteroids that will be progressively reduced over time. Researchers are also exploring medications that can replace corticosteroids or permit lower doses to be used (see Investigational Therapies below). One approved drug sometimes used in conjunction with corticosteroids to treat individuals with AOSD is the immunosuppressive drug methotrexate. Methotrexate is commonly used to treat arthritis and other conditions that affect joints (rheumatic diseases). When used for individuals with AOSD, methotrexate may be known as a “steroid-sparing agent” because it permits lower doses of corticosteroids to be used, thereby lowering the associated risk of side effects.
In 2020, the U.S. Food and Drug Administration (FDA) approved canakinumab (Ilaris) to treat patients with active Still’s disease, including AOSD. Canakinumab blocks the cytokine IL-1. This medication is typically used if corticosteroids and methotrexate have not been successful.
In recent years, some promising therapies have been studied for AOSD including drugs known as biological response modifiers. These drugs block the activity of cytokines that are believed to play a role in the development of the disorder. Although these medications might be used by experts or in clinical trials, their efficacy for AOSD has not been fully demonstrated yet.
Anakinra blocks the activity of IL-1, which some researchers believe plays a key role in the development of AOSD. Anakinra is now increasingly used in individuals with AOSD, and many of those who have received the therapy have rapidly and markedly improved. More research is necessary to determine the long-term safety and effectiveness of this promising therapy for individuals with AOSD.
Individuals with AOSD have also been treated with TNF-alpha antagonists, which block the activity of TNF-alpha. These medications are often used to treat individuals with rheumatoid arthritis and notably include infliximab and etanercept. They have shown promise in small studies involving individuals with AOSD, in particular patients with chronic arthritis, but more research is necessary to evaluate their long-term safety and effectiveness.
Tocilizumab (Actemra) is a medication that blocks IL-6. It was approved by the FDA in 2011 as a treatment for systemic juvenile idiopathic arthritis. This disease is very closely related to AOSD and most experts consider it the same disease. Tocilizumab was also approved by the FDA in 2010 for the treatment of adult patients with moderately to severely active rheumatoid arthritis.
Additional drugs that have been studied or used to treat individuals with AOSD include intravenous immunoglobulin, cyclosporin A, azathioprine, leflunomide, cyclophosphamide and thalidomide.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Ryan JG, Goldbach-Mansky R. The spectrum of autoinflammatory diseases: recent bench to bedside observations. Curr Opin Rheumatol. 2008;20:66-75.
Kalliolias GD, Liossis SN. The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still’s disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs. 2008;17:349-359.
Efthimiou P, Kontzias A, Ward CM, Ogden NS. Adult-onset Still’s disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy? Nat Clin Pract Rheumatol. 2007;3:328-335.
Kalliolias GD, Georgiou PE, Antonopoulos IA, Andonopoulos AP, Liossis SN. Anakinra treatment in patients with adult-onset Still’s disease is fast, effective, safe and steroid-sparing: experience from an uncontrolled trial. Ann Rheum Dis. 2007;66:842-843.
Efthimiou P, Georgy S. Pathogenesis and management of adult-onset Still’s disease. Semin Arthritis Rheum. 2006;36:144-152.
Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still’s disease. Ann Rheum Dis. 2006;65:564-572.
Ding C, Jones G. Anti-interleukin-6 receptor antibody treatment in inflammatory autoimmune diseases. Rev Recent Clin Trials. 2006;1:193-200.
Fitzgerald AA, Leclercq SA, Yan A, et al. Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum. 2005;52:1794-1803.
INTERNET
Mandl LA. Clinical manifestations and diagnosis of adult Still’s disease. UpToDate. Last updated: Jan 02, 2020. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-adult-stills-disease. Accessed April 20, 2021
Mandl LA. Treatment of adult Still’s disease. UpToDate. Last updated: Dec 21, 2020. https://www.uptodate.com/contents/treatment-of-adult-stills-disease. Accessed April 20, 2021
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