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A 52-year-old previously healthy man was admitted to an inpatient internal medicine resident hospital service with a 2-week history of profound generalized fatigue, nocturnal fevers (temperature as high as 39.4°C [103°F]), cold sweats, anorexia, and bilateral hand swelling and numbness. The swelling progressed to symmetrically involve his elbows, shoulders, knees, and ankles. He also reported arthralgias and profound weakness that had caused him to be confined to a wheelchair. He experienced joint stiffness of less than 30 minutes' duration in the morning that improved with activity. He denied recent tick bites, exposures to sick contacts, or travel outside of Minnesota and reported no recent weight loss, sore throat, or infection. A full review of systems was otherwise unremarkable. Family history was remarkable for an aunt and cousin with lupus.
On physical examination, swelling and tenderness were observed at multiple sites, most prominently at the dorsum of hands, elbows, wrists, knees, and ankles, suggesting tenosynovitis. He also had significant effusions in his knees bilaterally and moderate nonpitting edema, particularly in his hands and feet. A macular, nontender, purple rash was noted on the dorsum of his left hand. No lymphadenopathy was present. Bibasilar crackles were heard in his lungs. Findings on neurologic examination, including strength testing, were normal. No hepatosplenomegaly was observed. The remainder of the examination was unremarkable.
Laboratory studies yielded the following results (reference ranges provided parenthetically): hemoglobin, 15.8 g/dL (13.5-17.5 g/dL); leukocyte count, 19.7 × 109/L (3.5-10.5 × 109/L), with a neutrophil count of 17.5 × 109/L (1.7-7.0 × 109/L); platelet count, 270 × 109/L (150-450 × 109/L); creatinine level, 0.8 mg/dL (0.8-1.2 mg/dL); blood urea nitrogen, 14 mg/dL (8-24 mg/dL); bicarbonate, 28 mEq/L (22-29 mEq/L); glucose, 129 mg/dL (70-100 mg/dL); alanine aminotransferase, 98 U/L (8-48 U/L), aspartate aminotransferase, 46 U/L (8-48 U/L); alkaline phosphatase, 173 U/L (45-115 U/L); total bilirubin, 0.8 mg/dL (0.1-1.0 mg/dL); albumin, 3.7 g/dL (3.5-5.0 g/dL); and international normalized ratio, 1.0. Urinalysis showed a predicted 24-hour protein of 1011 mg, with 4 to 10 red blood cells per high-power field, less than 25% of which were dysmorphic, and 1-3 white blood cells per high-power field. No casts were seen. Chest radiography revealed infiltrates or atelectasis in the right middle lobe and lingula.
Adult Still disease is an inflammatory disorder characterized by fever, arthritis, and evanescent rash. The etiology of ASD is not well understood, but various bacterial and viral pathogens have been suspected to play a role. It also has no clear association with human leukocyte antigen typing. The annual incidence is approximately 0.16 cases per 100,000 person-years and is slightly higher in women. The mean age of presentation is 38 years, but more than 67% of those who present with ASD are older than 35 years.4
Multiple diagnostic criteria have been proposed. The most commonly used and those with the highest sensitivity (94%) for the diagnosis of ASD are the Yamaguchi diagnostic criteria.5 A diagnosis of ASD requires the presence of 5 features, with at least 2 being major diagnostic criteria (Table).6
The fevers of ASD typically occur daily or twice daily and often in the evening hours, with wide fluctuations of body temperature in a short time period. In about 20% of cases, the fever may persist between spikes and does not completely resolve. The rash of ASD is typically a nonpruritic, evanescent, salmon-colored maculopapular rash that tends to occur with fever spikes.7 It predominantly involves the trunk and extremities and may be elicited by scratching or heat. If performed, skin biopsy usually demonstrates mild perivascular inflammation and dermal edema.
Arthralgias, arthritis, and myalgias are present in almost all patients with ASD. The most commonly involved joints, in descending order, are the knees, wrists, ankles, elbows, proximal interphalangeal joints, and shoulders. The synovial fluid is typically inflammatory, with a mean leukocyte count of 13.0 × 109/L. Myalgias may be profound and debilitating and may be accompanied by a mild increase in aldolase and creatine kinase levels. Findings on electromyography and muscle biopsy studies are typically normal.
Mild lymphadenopathy is seen in approximately 65% of patients. Splenomegaly may also be present. Lymph node biopsy typically shows paracortical proliferation, which may cause confusion with lymphoma. However, unlike lymphoma, immunohistochemistry reveals benign polyclonal B-cell hyperplasia. In 70% of patients, levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and alkaline phosphatase and other results on liver function tests are elevated at some point during the illness. Pleuritis, pericarditis, myocarditis, pleural effusions, and transient pulmonary infiltrates are common and may either be presenting symptoms or asymptomatic findings. Renal involvement may also be present.3 A sore throat may occur in up to a third of patients and is often the first symptom.4 Granulocytic leukocytosis is also seen and is thought to be secondary to bone marrow granulocyte hyperplasia. During periods of active disease, a precipitous drop in red blood cell count may occur. Levels of acutephase reactants, such as erythrocyte sedimentation rate, C-reactive protein, and ferritin, may be elevated. Elevated ferritin levels are associated with high fever spikes.4 The elevated ferritin level is unrelated to iron metabolism and may be a consequence of cytokine-induced synthesis by the reticuloendothelial system.
The clinical course for ASD can be divided into 3 main patterns, with most patients having a high functional status.7 A third of patients have a monophasic, self-limiting course with complete resolution within a year. Another third of patients have intermittent ASD with disease flares, with complete remission between episodes. The remaining patients have a persistently active disease with associated destructive arthritis. In some patients, disease may progress to the point that joint arthroplasty is required.
However, case reports of fatal outcomes, including disseminated intravascular coagulation, acute hepatic failure, acute renal failure, cardiac tamponade, and acute respiratory distress syndrome, have been reported.
Treatment options include nonsteroidal anti-inflammatory drugs and glucocorticoids. The usual dose of prednisone is 0.5 to 1 mg/kg per day. Pulse methylprednisolone may also be used in life-threatening cases. Methotrexate is frequently used in treatment of ASD, particularly when corticosteroids may be contraindicated. Other disease-modifying agents, such as cyclosporine, azathioprine, and cyclophosphamide, have been tried in severe cases with mixed results. Limited data are available for treatment of ASD with biological agents such as rituximab and tumor necrosis factor inhibitors.
Adult Still disease can masquerade as numerous diseases. Consequently, the initial differential diagnosis should include infectious arthritis, reactive arthritis, rheumatoid arthritis, diffuse connective tissue disorder, vasculitis, crystalline arthropathies, sarcoidosis, familial Mediterranean fever, and hematologic malignancies.
See end of article for correct answers to questions.
Correct answers: 1. e, 2. d, 3. b, 4. e, 5. b