Adult-onset Still's disease | |
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Specialty | Rheumatology |
Named after | Sir George Frederic Still |
Adult-onset Still's disease (AOSD) is a form of Still's disease, a rare systemic autoinflammatory disease characterized by the classic triad of fevers, joint pain, and a distinctive salmon-colored bumpy rash. The disease is considered a diagnosis of exclusion. [1] Levels of the iron-binding protein ferritin may be extremely elevated with this disorder. AOSD may present in a similar manner to other inflammatory diseases and to autoimmune diseases, which must be ruled out before making the diagnosis.
Prognosis is usually favorable but manifestations of the disease affecting the lungs, heart, or kidneys may occasionally cause severe life-threatening complications. [2] It is treated first with corticosteroids such as prednisone. Medications that block the action of interleukin-1, such as anakinra, can be effective treatments when standard steroid treatments are insufficient. [3]
Obvious similarities exist with juvenile rheumatoid arthritis (also known as "juvenile-onset Still's disease"), [4] and there is some evidence that the two conditions are closely related. [5] [6]
The disease typically presents with joint pain, high fevers, a salmon-pink macular or maculopapular rash, enlargement of the liver and spleen, swollen lymph nodes, and a neutrophil-predominant increased white blood cell count in the blood. [1] Tests for rheumatoid factor and anti-nuclear antibodies are usually negative and serum ferritin is markedly elevated. Patients experiencing a flare-up from adult-onset Still's disease usually report extreme fatigue, swelling of the lymph nodes and, less commonly, fluid accumulation in the lungs and heart. In rare cases, AOSD can cause life-threatening complications, including hemophagocytic lymphohistiocytosis, intervertebral disc calcification (IVDC), fulminant hepatitis, or disabling conditions such as aseptic meningitis and sensorineural hearing loss. [7] [8] [9] [1]
The cause of adult-onset Still's disease is unknown and it is not heritable, but it presumably involves interleukin-1 (IL-1), since medications that block the action of IL-1β are effective treatments. Interleukin-18 is expressed at high levels. [2] [10] [11]
The diagnosis is clinical, not based upon serology. [12] At least seven sets of diagnostic criteria have been devised; however, the Yamaguchi criteria have the highest sensitivity. Diagnosis requires at least five features, with at least two of these being major diagnostic criteria. [13]
Major criteria | Minor criteria |
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Fever of at least 39 °C for at least one week | Sore throat |
Arthralgias or arthritis for at least two weeks | Lymphadenopathy |
Nonpruritic salmon-colored rash (usually over trunk or extremities while febrile) | Hepatomegaly or splenomegaly |
Leukocytosis (10,000/microL or greater), with granulocyte predominance | Abnormal liver function tests |
Negative tests for antinuclear antibody and rheumatoid factor |
People with AOSD generally experience one of two patterns in the disease:
One set of 21 adult-onset Still's disease patients were divided into four types, according to clinical course patterns. These included monocyclic systemic disease, polycyclic systemic disease, chronic articular monocyclic systemic disease, and chronic articular polycyclic systemic disease. People with chronic articular and polyarticular disease were at higher risk to develop disabling arthritis. [14]
Adult-onset Still's disease is treated with anti-inflammatory medications. Steroids such as prednisone are used to treat severe symptoms of Still's. Other commonly used medications include hydroxychloroquine, penicillamine, azathioprine, methotrexate, etanercept, anakinra, tocilizumab, cyclophosphamide, adalimumab, rituximab, and infliximab. [15]
Newer medications target interleukin-1 (IL-1), particularly IL-1β. [16] A randomized, multicenter trial reported better outcomes in a group of 12 patients treated with anakinra than in a group of 10 patients taking other disease-modifying antirheumatic drugs. [17] In June 2020 FDA approved Ilaris (canakinumab) for the treatment of AOSD, this is the first FDA approved treatment for AOSD. [18] Canakinumab is another anti-IL1 drug which selectively binds IL-1β and rilonacept which blocks both IL-1A and IL-1β. [19] The monoclonal anti-IL6 antibody tocilizumab is another treatment option as effective as anakinra. [20]
The condition "juvenile-onset Still's disease" is now usually grouped under juvenile rheumatoid arthritis. However, there are obvious similarities between the two conditions, [4] and there is some evidence that they may be closely related. [5] [6]
Adult-onset Still's disease is rare and has been described all over the world. The number of new cases per year is estimated to be 1.6 per 1,000,000 population. [1] The number of people currently affected is estimated at 1.5 cases per 100,000–1,000,000 population. [21] Onset is most common in two age ranges, between ages 16–25 and between ages of 36–46 years. [22]
Still's disease is named after English physician Sir George Frederic Still (1861–1941). [23] [24] The adult-onset version was characterized by E. G. Bywaters in 1971. [1]
Researchers are investigating whether levels of a protein named calprotectin could be used to improve diagnosis and monitoring. [25]
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some types of arthritis, other organs are also affected. Onset can be gradual or sudden.
Gout is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.
Sjögren syndrome or Sjögren's syndrome is a long-term autoimmune disease that primarily affects the body's exocrine glands, particularly the lacrimal and salivary glands. Common symptoms include dry mouth, dry eyes and often seriously affects other organ systems, such as the lungs, kidneys, and nervous system.
Rheumatology is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatology covers more than 100 different complex diseases, collectively known as rheumatic diseases, which includes many forms of arthritis as well as lupus and Sjögren's syndrome. Doctors who have undergone formal training in rheumatology are called rheumatologists.
Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.
Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bowel problems—as well as back pain—may occur. Joint mobility in the affected areas sometimes worsens over time. Ankylosing spondylitis is believed to involve a combination of genetic and environmental factors. More than 90% of people affected in the UK have a specific human leukocyte antigen known as the HLA-B27 antigen. The underlying mechanism is believed to be autoimmune or autoinflammatory. Diagnosis is based on symptoms with support from medical imaging and blood tests. AS is a type of seronegative spondyloarthropathy, meaning that tests show no presence of rheumatoid factor (RF) antibodies.
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a slightly modified recombinant version of the human interleukin 1 receptor antagonist protein. It is marketed by Swedish Orphan Biovitrum. Anakinra is administered by subcutaneous injection.
Macrophage activation syndrome is a severe, potentially life-threatening, complication of several chronic rheumatic diseases of childhood. It occurs most commonly with systemic-onset juvenile idiopathic arthritis (SoJIA). In addition, MAS has been described in association with systemic lupus erythematosus (SLE), Kawasaki disease, and adult-onset Still's disease. It is thought to be closely related and pathophysiologically very similar to reactive (secondary) hemophagocytic lymphohistiocytosis (HLH). The incidence of MAS is unknown as there is a wide spectrum of clinical manifestations, and episodes may remain unrecognized.
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of the adaptive immune system, people with autoinflammatory diseases do not produce autoantibodies or antigen-specific T or B cells. Instead, the autoinflammatory diseases are characterized by errors in the innate immune system.
In hematology, hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis, and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes. There are inherited and non-inherited (acquired) causes of HLH.
Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a rare genetic disorder, but a high frequency is observed in Northern European regions.
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.
Childhood arthritis is an umbrella term used to describe any rheumatic disease or chronic arthritis-related condition which affects individuals under the age of 16. There are several subtypes that differentiate themselves via prognosis, complications, and treatments. Most types are autoimmune disorders, where an individual's immune system may attack its own healthy tissues and cells.
Canakinumab, sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis, active Still's disease, including adult-onset Still's disease, gout flares. It is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.
Schnitzler syndrome or Schnitzler's syndrome is a rare disease characterised by onset around middle age of chronic hives (urticaria) and periodic fever, bone pain and joint pain, weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver.
Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye.
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Systemic-onset juvenile idiopathic arthritis (sJIA), also known as Still disease, Still's disease, and systemic juvenile idiopathic arthritis, is a subtype of juvenile idiopathic arthritis (JIA) that is distinguished by arthritis, a characteristic erythematous skin rash, and remitting fever. Fever is a common symptom in patients with sJIA, characterized by sudden temperature rise above 39°C and then a sudden drop. Over 80% of patients have a salmon-colored macular or maculopapular rash, which can be migratory and nonpruritic. Arthritis can develop weeks, months, or even years after onset and can affect various joints. SJIA is characterized by splenic and lymph node enlargements, with prominent symmetrical lymphadenopathy. Pericardial involvement is common, with 81% of children with active systemic symptoms having abnormal echocardiographic findings and 36% having an effusion or pericardial thickening. Around one-third of children with sJIA have occult macrophage activation syndrome (MAS), a potentially fatal illness causing T cells and macrophages to rapidly multiply and activate, resulting in a "cytokine storm."
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