Characteristic rash, intermittent fever and painful joints: possible coexistence of adult-onset Still disease and sarcoidosis

Adult-onset Still disease (AOSD), also known as systemic-onset juvenile idiopathic arthritis, is a rare systemic inflammatory disorder characterised by inflammatory polyarthritis, daily fever and a transient salmon-coloured maculopapular rash. Serum ferritin above 1,000 ng/mL is common.

Introduction
AOSD has no single specific diagnostic test. Its cause is unknown. One hypothesis is that it is a reactive syndrome in which infectious agents trigger disease in a genetically predisposed person. Proposed triggers include viruses, bacteria such as Yersinia enterocolitica and Mycoplasma pneumoniae, and other infections. The relevant factors may not be the same in every patient. A French study of 62 patients reported an association between AOSD and particular HLA antigen subtypes.

Epidemiology
Adult-onset Still disease is very rare, with an estimated annual incidence of 0.1–0.4 cases per 100,000 people in Europe. Women are affected slightly more often than men. The age distribution is bimodal, with peaks at 15–25 and 36–46 years. Around three quarters of patients report onset between 16 and 35 years of age.

Pathophysiology
Two types of immune dysregulation have been described. The first involves innate immunity, with activation of neutrophils and macrophages under the influence of the pro-inflammatory cytokine interleukin-18. Increased CD64 expression, a marker of neutrophil activation, has been reported in active disease. The second involves CD4-positive helper T cells, with a predominance of the Th1 subset over Th2. Studies have also suggested a role for the Th17 response; levels of cytokines associated with Th17 activity, including interleukins 1, 6, 17, 18, 21 and 23, may be elevated.

Diagnosis
Inflammatory markers, ESR and CRP are elevated in almost all patients. Blood findings may include leukocytosis, usually above 15,000 cells/microlitre with more than 80% neutrophils, normocytic normochromic anaemia and thrombocytosis. These abnormalities can sometimes resemble a primary haematological disease. Bone-marrow biopsy may show granulocytic precursor hyperplasia, hypercellularity and, in some cases, haemophagocytosis.

Liver transaminases are elevated in approximately 75% of patients, and aldolase may also rise because of liver inflammation. Ferritin is generally more than five times the upper limit of normal. Elevated ferritin suggests AOSD with reported sensitivity of about 80% and specificity of about 46%. When combined with a glycosylated-ferritin fraction below 20%, specificity may rise to approximately 93%.

Fewer than 10% of patients have antinuclear antibodies (ANA) or rheumatoid factor (RF), generally at low titres. Synovial fluid is usually inflammatory, with reported white-cell counts ranging from 100 to 48,000 cells/microlitre. Early radiographs may be normal or show mild joint-space narrowing or periarticular osteopenia. Narrowing of the carpometacarpal and intercarpal joint spaces of the wrist, potentially progressing to bony ankylosis, is a classic radiographic finding.

Treatment and management
Treatment aims to control symptoms, physical signs and laboratory markers of inflammation, prevent damage to vital organs and minimise long-term treatment effects. Evidence comes mainly from observational studies and clinical experience. Initial treatment is selected according to disease activity and adjusted according to the clinical response.

Mild disease may cause fever, rash, arthralgia or mild arthritis. Some patients respond to non-steroidal anti-inflammatory drugs, although many require at least a low dose of glucocorticoid.

Moderately severe disease may cause disabling joint symptoms, high fever or non-life-threatening organ involvement. Initial treatment may include prednisone at approximately 0.5–1 mg/kg/day, depending on severity. If steroids cannot be reduced successfully, biological or conventional disease-modifying antirheumatic drugs may be needed. Anakinra may be preferred when there are no erosive joint changes, while methotrexate may be preferred when joint disease predominates.

Severe disease involves life-threatening organ complications such as cardiac tamponade, disseminated intravascular coagulation or severe liver involvement. Such cases may require intravenous methylprednisolone pulses, sometimes 1,000 mg daily for three days, followed by specialist treatment. Early biological therapy may be recommended. Among biological medicines, the IL-1 inhibitor anakinra and IL-6 inhibitor tocilizumab have shown greater effectiveness in some studies than TNF inhibitors. Limited evidence suggests that canakinumab, rilonacept, rituximab and abatacept may help patients who are resistant to other treatments.

All doses and treatment decisions must be made by a specialist. This page does not establish that Still disease and sarcoidosis coexist in a particular patient; both diagnoses require appropriate clinical assessment and exclusion of other causes.

Source and further information:
https://www.ncbi.nlm.nih.gov/books/NBK538345/

This page is educational and does not replace examination or individual medical advice.