Definition, Etiology, PathogenesisTop
Adult-onset Still disease (AOSD) is a systemic form of juvenile idiopathic arthritis associated with fever, rash, lymphadenopathy, splenomegaly, serositis, and inflammation of multiple organs. The condition was first described in 1971 by Eric George Bywaters, in a case series of adult patients with symptoms reminiscent of children with Still disease (now known as systemic juvenile idiopathic arthritis). It is classically characterized by spiking fevers, arthritis, and an evanescent salmon-colored rash. AOSD is a rare condition, with incidence rates ranging from 0.16 to 0.4/100,000 patient-years. The condition typically affects young adults, with a median age of onset of 36 years, and predominantly women. The exact etiology of AOSD is still unknown. It has been associated with a number of different human leukocyte antigens (HLAs), including HLA-Bw35, HLA-DR4, and HLA-DrW6; however, the strengths of these associations remain unclear. It is also proposed that a preceding infection may play a role in the etiology of AOSD, leading to an epigenetic effect.
Clinical Features and Natural HistoryTop
AOSD develops after the age of 16. In adults, the symptoms may be due to the first occurrence of the disease or a relapse. The course of AOSD may be self-limiting (lasting <1 year), relapsing (relapses may be very frequent), or chronic (symptoms are continuously present throughout the year). In some patients, significant joint destruction occurs.
Symptoms (Table 1):
1) Most frequent:
a) Fever (>80% of cases; usually >39 degrees Celsius, most commonly in the evening or twice during a 24-hour period).
b) Sore throat with features of inflammation (>50%; frequently develops several days or weeks prior to other symptoms).
c) Salmon-pink macular or maculopapular rash (>80%; often transient, develops only during episodes of fever, rarely pruritic, most frequently located on the trunk and proximal limbs, less often on the face; it may be triggered by heat [eg, following a hot bath] or skin abrasion [eg, scratchy clothing]).
d) Arthralgia (>90%; worsens during febrile periods; occasionally arthritis, most commonly affecting the knees and wrists; approximately one-fourth of patients develop ankyloses of the involved joints).
e) Myalgia (>80%).
f) Lymphadenopathy (>50%; most frequently affecting the cervical lymph nodes; the lymph nodes may be tender; retroperitoneal lymphadenopathy may cause abdominal pain that is difficult to diagnose).
g) Splenomegaly, hepatomegaly (50%).
2) Less frequent: Symptoms of pleuritis or pericarditis, weight loss.
3) Rare: Pulmonary fibrosis, myocarditis or cardiac tamponade, hair loss, Sjögren syndrome, aseptic meningitis, peripheral neuropathy, amyloidosis, subacute glomerulonephritis and interstitial nephritis, hemolytic anemia, disseminated intravascular coagulation, macrophage activation syndrome, cataract, hearing impairment.
1. Laboratory tests: In the periods of increased disease activity, the following features are observed:
1) Elevated erythrocyte sedimentation rate (ESR) and plasma C-reactive protein (CRP) levels.
2) Leukocytosis (often >20,000/microL) with >80% of neutrophils in the differential counts.
6) Very high serum ferritin levels (levels >3000 ng/mL are suggestive of AOSD [in adults, this is the second most frequent cause of ferritin levels >1000 ng/mL next to hemophagocytic syndrome: Hemophagocytic Lymphohistiocytosis]; the increase correlates with the disease activity).
7) Elevated serum aminotransferase and lactate dehydrogenase (LDH) levels.
8) IgM rheumatoid factor (RF) and antinuclear antibodies (ANAs) (very rarely observed; in diagnostic workup, negative RF and ANAs are suggestive of Still disease; <10% of patients).
2. Synovial fluid: Synovial aspirate in AOSD is nonspecific, and features are consistent with inflammatory arthritis.
3. Imaging studies: Radiographs of the hands are usually nonspecific and not very helpful in establishing the diagnosis of AOSD. Radiographs of the involved joints may reveal periarticular osteopenia, narrowing of the joint space, erosions, as well as early development of ankylosis. In some patients, rapid destruction of 1 or both hip joints, less often of a knee joint, is observed. Computed tomography (CT) may demonstrate retroperitoneal lymphadenopathy.
Most frequently, diagnosis is based on the Yamaguchi diagnostic criteria (Table 1).
The key categories of conditions in the differential diagnosis for AOSD are infections, malignancies, and autoimmune diseases. Potential infections to rule out include human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, hepatitis B, hepatitis C, parvovirus B19, rubella, infective endocarditis, syphilis, and toxoplasmosis. Malignancies to exclude are primarily malignant lymphomas or any other metastatic disease. Potential autoimmune diseases, which may mimic AOSD, include systemic lupus erythematous, rheumatoid arthritis, systemic vasculitis, familial Mediterranean fever, hemophagocytic syndrome, and sarcoidosis.
1. Nonsteroidal anti-inflammatory drugs (NSAIDs): Retrospective cohort studies have shown NSAIDs to be ineffective in controlling symptoms of AOSD, with >80% of patients failing to respond. In addition, up to 20% of patients experienced an adverse event. Therefore, NSAIDs are not an effective agent in controlling disease activity. They may be used as adjunctive therapy for arthritic symptoms, but high-quality evidence for their use in this role is lacking. NSAIDs could be tried alone in a mild form of the disease for a limited period of time.
2. Glucocorticoids: Retrospective cohort studies have shown that glucocorticoids at an oral dose of 0.5 to 1 mg/kg daily of prednisone (or an equivalent dose of methylprednisolone) may be used, as they were effective in controlling AOSD symptoms in up to 65% of patients.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational and retrospective character of the study. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. J Rheumatol. 1999 Feb;26(2):373-8. PubMed PMID: 9972972. Clinical improvement may be evident within hours of initiating therapy. Tapering usually begins within 4 to 6 weeks after initiating treatment. However, a large proportion of patients (40%-45%) become steroid-dependent and unable to completely taper off prednisone, which subjects them to many potential adverse effects, such as glucocorticoid-induced osteoporosis and avascular necrosis, among many others.
3. Disease modifying antirheumatic drugs (DMARDs): Adding a DMARD is critical, given the high percentage of patients who become steroid-dependent. Methotrexate is the drug suggested when selecting a steroid-sparing agent. Doses of oral methotrexate range from 7.5 mg/wk to 25 mg/wk. Although methotrexate is the most studied DMARD in the treatment of AOSD, the evidence for its use is still lacking, coming only from small retrospective cohorts. These small studies have shown that addition of methotrexate may achieve a partial or complete remission of AOSD and allows at least a majority of patients to either reduce their glucocorticoid dose, or to taper it off completely.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational and retrospective character of the study. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. J Rheumatol. 1999 Feb;26(2):373-8. PubMed PMID: 9972972. Methotrexate has been shown to have similar efficacy in patients with AOSD and primarily systemic or articular manifestations.
4. Interleukin-1 (IL-1) antagonists:
1) Anakinra is a recombinant IL-1 beta-receptor antagonist given as a daily subcutaneous injection that might be considered in those resistant to the therapies described above. A number of case series have reported on the potential role that anakinra may play in patients with AOSD refractory to steroids, DMARDs, and in 1 case series, refractory to tumor necrosis factor (TNF)-alpha inhibitors. In addition, a small open randomized trial assessed the efficacy of anakinra as a steroid-sparing agent in patients with AOSD with active disease despite treatment with prednisolone ≥10 mg per day, with or without concomitant DMARD use.Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the small sample size, open design, and relatively short duration of the intervention. Nordström D, Knight A, Luukkainen R, et al. Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still's disease. An open, randomized, multicenter study. J Rheumatol. 2012 Oct;39(10):2008-11. doi: 10.3899/jrheum.111549. Epub 2012 Aug 1. PubMed PMID: 22859346. Ortiz-Sanjuán F, Blanco R, Riancho-Zarrabeitia L, et al. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review. Medicine (Baltimore). 2015 Sep;94(39):e1554. doi: 10.1097/MD.0000000000001554. PubMed PMID: 26426623; PubMed Central PMCID: PMC4616841. Anakinra therapy typically has quick noticeable clinical improvements within days of initiating therapy. However, a number of cases of disease relapse have been reported several days after discontinuing anakinra.
2) Canakinumab is another fully humanized monoclonal antibody against IL-1. Unlike anakinra, canakinumab has a much longer half-life (26 days vs 6 hours). The evidence for the drug is limited to a single case report of 2 patients successfully treated with canakinumab after failing to respond to glucocorticoids, methotrexate, and anakinra. Its cost for many is prohibitively expensive.
5. TNF-alpha inhibitors: Three available TNF-alpha inhibitors—infliximab, etanercept, and adalimumab—have been tried in patients with AOSD.
1) Infliximab is a chimeric monoclonal antibody against TNF-alpha. There are a number of small case series in which treatment with infliximab improved systemic and articular symptoms of AOSD, while also improving inflammatory markers (ESR, CRP) and ferritin levels. There are also case series suggesting infliximab may be used as a steroid-sparing agent in patients treated with prednisone and methotrexate. However, the evidence for infliximab in AOSD is limited to small retrospective case series and 1 prospective open-label trial consisting of only 4 patients.
2) Adalimumab is a fully human monoclonal antibody against TNF-alpha. Case reports and case series suggest that adalimumab may be effective in patients with AOSD and can be used as a steroid-sparing agent. The quality of evidence regarding the role of adalimumab role in the treatment of AOSD is limited to case reports and case series.
3) Etanercept is a recombinant molecule of fragments of soluble TNF-alpha receptor linked to the Fc portion of human IgG. A small prospective cohort study of 12 patients with AOSD with severe arthritic symptoms refractory to DMARDs who were treated with etanercept suggested a modest improvement in the arthritic symptoms, but most patients did not have a complete response. A number of other case reports and case series have reported that etanercept was able to achieve a partial response in patients with AOSD and primary chronic arthritic symptoms, but few were able to achieve disease remission. Like with the other TNF-alpha inhibitors, the quality of evidence for the role of etanercept role in the treatment of AOSD is poor, limited primarily to case reports, case series, and 1 small prospective open-label study. TNF-alpha inhibitors might be considered in those who do not respond to a more standard treatment with glucocorticoids and methotrexate.
6. Interleukin-6 (IL-6) inhibitor: Tocilizumab is a fully humanized monoclonal antibody against IL-6 receptors, which was used in 1 prospective open-label trial of 14 patients with AOSD (who previously failed anakinra and at least 1 TNF-alpha inhibitor). After 6 months of therapy with tocilizumab, 57% of patients had remission of joint symptoms and 86% had resolution of the systemic symptoms. Another retrospective review consisted of 16 AOSD patients treated previously with at least 1 biologic before switching to tocilizumab.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Ortiz-Sanjuán F, Blanco R, Calvo-Rio V, et al. Efficacy of tocilizumab in conventional treatment-refractory adult-onset Still's disease: multicenter retrospective open-label study of thirty-four patients. Arthritis Rheumatol. 2014 Jun;66(6):1659-65. doi: 10.1002/art.38398. PubMed PMID: 24515813. All but one patient responded well after treatment with tocilizumab, and 2 patients were able to completely withdraw their glucocorticoid therapy. The effects were quite rapid, with a normalization of CRP levels by 7.1 weeks (mean), and ferritin levels by 5.8 weeks (mean). Overall, tocilizumab remains a promising option for patients with refractory AOSD with both systemic and articular manifestations. However, the quality of evidence is limited to case reports, case series, and 1 prospective open-label cohort study. As such, tocilizumab may be considered in patients failing therapy with glucocorticoids and methotrexate.
7. Intravenous immunoglobulins: Limited evidence from case reports and case series supports some benefit of IV immunoglobulins infusions in patients resistant to or unable to tolerate other forms of therapy.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data involving a small number of patients. Vignes S, Wechsler B, Amoura Z, et al. Intravenous immunoglobulin in adult Still's disease refractory to non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol. 1998 May-Jun;16(3):295-8. PubMed PMID: 9631752.
The natural history of AOSD can be quite variable. Some patients have a single systemic self-limited episode with symptoms improving within a few months and resolving by 1 year. Other patients have a polycyclic form of the disease, with multiple flares of the systemic and arthritic symptoms and clear periods of remission between the flares. Finally, the remaining patients have a form associated with chronic disease, where inflammatory arthritis is the predominant manifestation. These patients are prone to develop secondary osteoarthritis, with associated impact on health-related quality of life and disability.
Polyarthritis and arthritis affecting the large joints (shoulder, hip) at the onset of the disease are associated with an increased risk of developing chronic disease. AA amyloidosis is a rare complication of AOSD, which is attributed to chronic uncontrolled systemic inflammation. The incidence of AA amyloidosis is low, especially with appropriate therapies to decrease the level of inflammation. Death may occur due to infection, liver failure, amyloidosis (occurs in approximately a third of patients), respiratory failure, heart failure, or disseminated intravascular coagulation.
1) Fever ≥39 degrees Celsius persisting for ≥1 week
2) Arthralgia persisting for ≥2 weeks
3) Typical rash
4) White blood cell count ≥10,000/microL (>80% neutrophils)
1) Sore throat
2) Lymphadenopathy and/or splenomegaly
3) Increased serum aminotransferase or lactate dehydrogenase levels (after other causes have been excluded)
4) Negative IgM rheumatoid factor and antinuclear antibodies (immunofluorescence assay)
1) Infections, in particular sepsis and infectious mononucleosis
2) Malignancy, in particular lymphoma
3) Other rheumatic diseases, in particular polyarteritis nodosa and vasculitis in the course of rheumatoid arthritis
For the diagnosis of adult-onset Still disease, ≥5 criteria must be met, including ≥2 major. In patients with any of the exclusion criteria, the diagnosis is excluded.
Sensitivity of the criteria is 80.6%, and specificity is 98.5%.