Adult-onset Still disease (AOSD)

Essentials of Diagnosis

•    Fever that spikes in "rabbit ears" pattern with daily return to normal.

•    Salmon-colored macular rash only occurring with fever.

•    Arthritis, splenomegaly, pleuritis, pericarditis, and marked leukocytosis common.

•    Pharyngitis often the initial symptom.

General Considerations

Adult-onset Still disease (AOSD) is a multisystem inflammatory disease that typically begins with a sore throat. Nonsuppurative pharyngitis may develop days to weeks before the typical quotidian fever, evanescent rash, and joint pains begin. Other constitutional symptoms soon follow, including profound fatigue, weight loss, and anorexia. Malignancy and infectious causes of these symptoms must be excluded because AOSD is diagnosed mainly on clinical grounds.

Etiology

The cause of AOSD has yet to be identified. The presence of daily spiking fevers has focused research efforts on the possibility that the cause of AOSD is infection-related. To date, however, there has not been any infectious agent or genetic predisposition identified in patients with this disease.

Incidence

Fortunately, AOSD is rare. One series reported an incidence of 0.16 cases per 100,000 population. Women and men are equally affected. The peak onset is between ages 20 and 45, although cases have been reported in all age groups. Pediatric patients with systemic-onset juvenile idiopathic arthritis can have a recurrence of active Still disease at any age into adulthood.

Clinical Findings

There is no definitive lab test for AOSD, but a high serum ferritin and marked leukocytosis with fever, rash, and arthritis in the absence of other possible causes is highly suggestive of this diagnosis.

Symptoms and Signs

The fever of AOSD is relentless, often lasting weeks at a time before the diagnosis can be established. Temperature spikes occur daily in these patients, often in the afternoon or evening. These elevations in temperature can be associated with shaking chills and sweating. The daily return to baseline or normal temperature is a distinguishing feature that separates patients with AOSD from those with chronic infection. Typically, in patients with chronic infection the temperature remains elevated between fever spikes.

The rash of AOSD is salmon-colored, macular, and can occur anywhere on the trunk and extremities. It is evanescent, and manifests during the febrile episodes but clears completely when the temperature returns to normal. It may be mildly pruritic and extend to areas that are scratched (Koebner phenomenon). Biopsy of involved skin, even with immunofluorescence, is usually not diagnostic. The presence of this particular rash in association with a daily fever is diagnostic of AOSD, even though the rash itself is nondescript, and can easily be mistaken for a drug reaction or viral exanthem. In some patients, the rash may reappear in the identical location during subsequent flares of active disease. Usually the face, palms, and soles are spared.

Joint pain is a common feature of AOSD, but true arthritis may be slow to develop. Initially, patients often have significant joint and muscle pain without true synovitis. Marked arthralgias and myalgias may be present initially and can develop into frank arthritis over time. Arthritis develops in large joints such as the hip, knee, ankle, shoulder and wrist more often than the small joints of the hands and feet. Persistent synovitis and restricted range of motion in affected joints can occur even after the fever has resolved. Destructive arthritis occurs in 20% of patients with AOSD. Carpal and cervical ankylosis can occur as a result of arthritis in both the adult and childhood-onset forms of the disease. Avascular necrosis is a significant risk for those patients with AOSD who require glucocorticoids for control of their systemic symptoms or persistent arthritis or both. Hip involvement and persistent synovitis are poor prognostic signs and justify an aggressive treatment approach.

Pleuritis, pericarditis, lymphadenopathy, hepatomegaly, and splenomegaly are common in AOSD (Table). Biopsy specimens of lymph nodes show reactive changes due to polyclonal B-cell hyperplasia.

Table - Clinical Manifestations of Adult-Onset Still Disease

Fever

Acute pharyngitis

Arthritis/arthralgia

Severe myalgias

Lymphadenopathy

Splenomegaly

Hepatic dysfunction

Pleuritis

Pericarditis

Laboratory

There is no definitive lab test for AOSD; however, marked leukocytosis (>15,000/ L) with a predominance of neutrophils
(>80%) and a markedly elevated ESR (>90 mm/h) is seen in almost all patients with this disorder. The lab findings in AOSD suggest both acute and chronic inflammation with a low serum albumin, anemia of chronic disease, elevated C-reactive protein, and elevated complement levels. Marked elevation of the serum ferritin (above 3000 mg/mL) is seen in over 70% of AOSD patients. A high ferritin can be seen in hematologic malignancies but does not occur in other rheumatic disease syndromes. There is a low percentage (<20%) of serum ferritin that is glycosylated in patients with AOSD which may be even more specific for this disease. However, this test is not routinely clinically available. Recent studies have documented elevated levels of interleukin-18 that correlate with clinical activity of AOSD. This may help to explain the unusual pattern of inflammatory markers specific to this disease.

The antinuclear antibody test and rheumatoid factor are negative in almost all cases (Table2). Mild elevation of liver function tests are a frequent but nonspecific finding. There is no threat to renal function associated with AOSD, and the creatinine and urinalysis typically remain normal.

Table. Common Laboratory Test Abnormalities in AOSD

Elevated erythrocyte sedimentation rate

Elevated white blood cell counta

Elevated platelet count

Anemia

Elevated liver enzymes

Elevated ferritin

Negative antinuclear antibodies

Negative rheumatoid factor

TLC >15,000/ L with >80% PMN leukocytes.

 
Differential Diagnosis

Diagnostic criteria in AOSD using major and minor criteria from clinical and laboratory findings listed in Tables 1 and 2. These proposed classification systems rely on different combinations of major and minor criteria once infection, malignancy, and other rheumatic disorders have been excluded.

When patients present with sore throat, daily fever, rash, arthritis, and muscle pain, infection tops the list of possible causes. The most common causes of rash, fever, and arthritis are infectious, including viral infections (such as rubella, parvovirus, Epstein-Barr virus, cytomegalovirus, hepatitis B and C, and HIV) and bacterial infections (Borrelia burgdorferi [Lyme disease], Borrelia hermsii [relapsing fever], streptococcal-associated arthritis and rheumatic fever recurrence, and subacute bacterial endocarditis, among others). It is vitally important to exclude infection before beginning treatment for AOSD.

Malignancy can cause fever, rash, arthralgias, and also many of the nonspecific lab abnormalities seen in AOSD. Patients with hematologic malignancies often have enlarged lymph nodes, elevated ferritin levels, splenomegaly, abnormal liver function, and fever that can be difficult to distinguish from AOSD.

Other rheumatic disease syndromes can also mimic the signs and symptoms of AOSD. Sarcoidosis, polyarteritis nodosa, antineutrophilic cytoplasmic anti-body–associated vasculitis, inflammatory bowel disease, and recurrent fever syndromes such as familial Mediterranean fever, autoimmune neutropenia, hemophagocytic syndromes, and systemic lupus erythematosus must all be ruled out to establish a diagnosis of AOSD.

Treatment

Treatment of this condition can be challenging. Early in the disease course, treatment with nonsteroidal anti-inflammatory drugs can help reduce fever, joint pain, and muscle aches, but can lead to markedly elevated liver function tests. Aspirin was previously considered to be the mainstay of therapy, but frequently caused significant hepatitis. Nonsteroidal anti-inflammatory drugs are less likely to cause similar problems but the potential remains. Systemic glucocorticoids are indicated to control persistent synovitis and to treat life-threatening manifestations and constitutional symptoms that interfere with the activities of daily living. If arthritis persists, treatment with a disease-modifying agent, such as methotrexate or cyclosporine, or an anti-cytokine agent, such as anakinra (an interleukin-1 inhibitor) or etanercept (a tumor necrosis factor inhibitor), can induce remission and minimize glucocorticoid exposure. There are remarkable responses to anakinra reported in the literature. Newer biological agents that target interleukin-6 may be even more effective in treating this disease.

Therapy should be continued until laboratory parameters show no signs of inflammation and clinical examination indicates no active disease is present. Medication can then be tapered slowly with the hope of maintaining a remission on the lowest effective dose. Disease-modifying agents should be continued for a 1-year disease-free interval before being discontinued altogether.

The clinical course of AOSD is variable. One-third of patients remit after one extended symptomatic period that can last up to 1 year. One-third of patients with AOSD relapse with a polycyclic course. In these patients, remission can occur between flares. Another third of patients with AOSD will have a persistent active clinical course with chronic active arthritis the main ongoing symptom. Relapse in this disorder can occur years after the initial diagnostic episode.