Still Disease

Etiology

The etiology of AOSD remains unknown. The prevailing hypothesis suggests that AOSD is a reactive syndrome wherein various infectious agents may act as triggers in individuals with a genetic predisposition. Both genetic factors and various infectious agents, including viruses and bacteria like Yersinia enterocolitica and Mycoplasma pneumoniae, have been proposed as significant contributors to the development of AOSD.[2][3] 

Uncertainty persists regarding the uniform presence of etiopathogenic factors among all AOSD patients. A French study involving 62 patients demonstrated an association between AOSD and specific human leukocyte antigen (HLA) subtypes (B17, B18, B35, and DR2).[4] Specific case reports have highlighted instances of the disease occurring in twins.[5]

Epidemiology

AOSD is a very uncommon condition, with an estimated annual incidence ranging from 0.1 to 0.4 cases per 100,000 people in Europe. There is a slight predilection for females over males. The age distribution follows a bimodal pattern, with the first peak occurring between 15 and 25 years and the second between 36 and 46. Notably, about three-quarters of patients experience the onset of the disease between 16 and 35. Although unusual, instances of onset beyond the age of 70 have also been documented.[6]

Pathophysiology

Two immune dysregulations play a crucial role in the pathogenesis of AOSD: innate and adaptive immunity.

Immunopathology in innate immunity:

• Activation of neutrophils and macrophages
  • Increased CXCL8 levels:
    • Not correlated with disease activity
    • Recruits neutrophils to the inflammation site
    • Associated with the persistence of chronic articular AOSD
  • Elevated macrophage activation markers:
    • Macrophage-colony stimulating factor (M-CSF)
    • Calprotectin
    • Intracellular adhesion molecule-1 (ICAM-1)
    • Migration inhibitory factor (MIF)
    • Interferon-gamma (INF-γ)
  • Elevated cytokines:
    • Interleukin 1β (IL-1β)
    • IL-6 in skin rash specimens and serum correlating with disease activity
    • IL-18 in serum, synovial fluid, liver, and lymph nodes
    • Tumor necrosis factor-α (TNF) in sera and tissues
  • Overexpression of toll-like receptor (TLR) 7-MyD88 pathway in dendritic cells:
    • Correlates with disease activity and treatment

Immunopathology in adaptive immunity:

• Increased Th1 cellular immune response
  • Predominance of T cells produced by  IL-4T over IFN-γ in serum, skin, and synovium compared to healthy controls [7]
  • Increased α-soluble receptor of IL-2 (CD25)

Furthermore, the role of Th-17 responses is emerging in the pathogenesis of AOSD. Elevated levels of Th-17-related cytokines, including IL-1,6,17,18,21, and 23, contribute to the complex immunopathology associated with the disease.

History and Physical

Three primary patterns characterize the clinical course of AOSD: monophasic, intermittent, and chronic.[4][8][9] Each category exhibits approximately equal distribution; however, some studies suggest a higher prevalence of the chronic articular pattern. Notably, it is common for the initial monophasic or intermittent patterns to evolve into a chronic articular manifestation.[10]

The key clinical features observed in AOSD include fever, rash, and arthritis or arthralgia, occurring in approximately 75% to 95% of patients.[11] Other common symptoms encompass myalgia, pharyngitis, lymphadenopathy, and splenomegaly. Less frequently observed symptoms comprise hepatomegaly, pleurisy, pericarditis, and abdominal pain.

Fever in AOSD usually follows a quotidian pattern (daily recurring fever with temperature returning to normal between fever spikes), often occurring late during the day and generally preceding other symptoms. The temperature can fluctuate by 4 °C within 4 hours.[12] In approximately 20% of cases, complete defervescence does not occur, fever persists between spikes, or an additional spike occurs in the morning, leading to a double quotidian fever. Sometimes, AOSD may present as a fever of unknown origin (FUO), and a temperature of more than 39.5 °C strongly suggests a monophasic pattern.

The rash in AOSD is classically characterized as evanescent, displaying a salmon-colored, macular, or maculopapular appearance. It is usually nonpruritic and tends to coincide with the onset of fever. While primarily observed on the trunk and extremities, the rash can manifest on the palms, soles, and face. The rash can sometimes be induced by heat (hot shower or towel) or skin friction, known as the Koebner phenomenon.

Arthritis in AOSD may initially present as mild, transient, and oligoarticular, potentially progressing into severe, destructive, and symmetric polyarticular forms.[1] Predominantly affected joints are the knees, wrists, and ankles, although elbows, proximal interphalangeal joints, shoulders, metacarpophalangeal, metatarsophalangeal, hips, distal interphalangeal, and temporomandibular joints can also be involved. Fusion of the wrist joint is characteristic of AOSD but is observed in only a few patients.

Myalgia tends to exacerbate during fever spikes and can occasionally be severe and debilitating. Muscle weakness is not a typical feature, although case reports have indicated a slight elevation of serum creatine kinase and aldolase levels. Electromyographic studies and muscle biopsies are typically either normal or may show nonspecific findings associated with inflammatory myopathy.

Patients with AOSD may present with a sore throat during the initial evaluation, which frequently recurs during disease flares. In such cases, examination typically reveals severe, nonsuppurative pharyngitis, and bacterial cultures are generally negative. A review of 341 cases of AOSD reported a sore throat in 69% of the patients.[13] 

Symmetrical slightly tender lymphadenopathy is reported in one-third to two-thirds of patients with AOSD, while splenomegaly is observed in one-third to one-half of patients. Liver abnormalities encompass hepatomegaly ranging from 12% to 45% and, more commonly, modest elevations of serum hepatic transaminases and alkaline phosphatase levels. About 30% to 40% of patients with AOSD may experience pericarditis, pleural effusions, and transient pulmonary infiltrates.[10][11][14] 

Macrophage activation syndrome (MAS) occurs in a small minority of patients with AOSD, potentially underdiagnosed, as indicated by retrospective studies reporting MAS occurred in 6 out of 50 patients and 21 out of 109 patients. Unlike AOSD, patients with MAS may exhibit markedly elevated levels of serum triglycerides, along with normal or low haptoglobin and fibrinogen, and may experience leukopenia and thrombocytopenia.[15][16] Abdominal pain is reported in 1% to 48% of the patients, and additional symptoms such as nausea, anorexia, lymphadenitis, aseptic or acute pancreatitis, and weight loss can also occur.

Evaluation

The lab findings discussed below are characteristic of AOSD but are not pathognomonic. Therefore, their presence, in conjunction with clinical manifestations, assists the clinician in establishing the diagnosis after ruling out alternate causes.

Ferritin levels typically exceed five times the upper limits of normal in patients with AOSD. An elevated ferritin level indicates the presence of the disease with an 80% sensitivity and 46% specificity. When coupled with a decrease in the proportion of glycosylated ferritin (<20%), the specificity increases to 93%. Ferritin levels are also monitored during treatment.[17]

In almost all patients, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated.[4] Hematological findings include leukocytosis, typically exceeding 15,000 cells per microliter with a predominant neutrophil count greater than 80%, normocytic normochromic anemia, and thrombocytosis. These hematological abnormalities can be severe enough to mimic primary hematologic disease, and in some instances, red cell aplasia has been observed.[18]

Bone marrow biopsy reports have indicated hyperplasia of granulocytic precursors, and hypercellularity and hemophagocytosis have been observed in some cases. Hepatic transaminases can be elevated in 75% of patients, and elevated aldolase levels can also occur, attributed to liver inflammation.

In less than 10% of patients, antinuclear antibodies (ANA) and rheumatoid factor (RF) are detected, typically in low titers. The scarcity of these autoantibodies underscores the importance of considering additional diagnostic factors and clinical manifestations for a thorough evaluation in establishing a comprehensive diagnosis of AOSD.

The synovial fluid typically exhibits signs of inflammation, with a mean leukocyte range of 100 to 48,000 cells per microliter.[4] Furthermore, inflammatory markers in the synovial fluid underscore the systemic nature of AOSD and guide clinicians in tailoring appropriate therapeutic interventions.

Radiographs in the early stages of the disease are typically either normal or may reveal slight joint space narrowing or periarticular osteopenia.[4] A classic radiographic finding of AOSD involves narrowing the wrist carpometacarpal and intercarpal joint spaces, which may progress to bone ankylosis.[19][20]

Computed tomography (CT) and F-fluorodeoxyglucose positron emission tomography (FDG-PET) can detect abnormalities, revealing lymph node enlargement, splenomegaly, pulmonary abnormalities, and hepatomegaly. These imaging modalities play a crucial role in assessing the extent of systemic involvement and contribute to a comprehensive diagnostic evaluation.

The following additional tests can also be conducted to establish the diagnosis:

• Complete blood count (CBC) with differential and platelet count
• ANA, RF, and anti-citrullinated peptide (anti-CCP) antibody testing
• Blood cultures
• Liver enzymes, including bilirubin, aminotransferase, alkaline phosphatase, and serum albumin
• Serologic testing for hepatitis B and C, Epstein Barr virus, and human parvovirus B19; and testing for HIV
• Plain radiographs of the chest
• Blood urea nitrogen (BUN), creatinine
• Urinalysis with microscopic examination and urine culture

Treatment / Management

The therapeutic objects include managing symptoms, physical signs, and laboratory markers of inflammation. Additionally, the goals involve preventing end-organ damage and minimizing the long-term effects of therapy.

The effectiveness of treatment interventions for AOSD is derived from observational studies and clinical experience.[8][10] Initial therapeutic decisions are guided by the degree of disease activity, with subsequent decisions informed by the clinical response.(B3)

Mild disease presentation in AOSD is characterized by symptoms such as fevers, rash, arthralgia, or mild arthritis. While some patients with mild disease may respond to nonsteroidal anti-inflammatory drugs (NSAIDs) alone, most benefit from at least a low dose of glucocorticoid for better control. Typical choices include:

• Naproxen 500 mg twice daily
• Indomethacin 25 to 50 mg 3 times daily
• Ibuprofen 800 mg 3 times daily

Moderate disease presentation in AOSD is marked by debilitating joint symptoms, high-grade fever, or internal organ involvement that is not life-threatening. In contrast, severe disease involves life-threatening organ complications like cardiac tamponade, disseminated intravascular involvement, or severe hepatic involvement. Patients with moderate to severe disease are managed as follows:

• Anakinra is favored as the initial agent in patients without joint erosions, while methotrexate is preferred in patients with prevalent joint disease. The initial dose is 100 mg administered subcutaneously daily, with the option to increase to 100 mg twice daily if a partial response is observed within 2 weeks.

• Glucocorticoids serve as the second-line treatment after anakinra, typically at a dose of prednisone 20 to 60 mg orally. In some instances, intraarticular steroids may be considered, and a pulse dose of methylprednisolone 100 mg daily for up to three days is used in patients with MAS or those with refractory systemic or arthritic disease.[21]
(B3)

• Limited evidence suggests that canakinumab, rilonacept, rituximab, and abatacept may effectively treat patients refractory to other therapies.

Patients should undergo regular monitoring, including periodic assessments of CBC, BUN, creatinine, electrolytes, ferritin, D-dimer, alanine transaminase (ALT), and aspartate aminotransferase (AST).

Most patients with AOSD eventually achieve the ability to discontinue therapy. Some may experience a monocyclic form of AOSD. There are no established protocols for tapering and discontinuing disease-modifying antirheumatic drugs.

For patients in complete remission for at least 3 months, the recommended approach is to taper medications to discontinue all drugs gradually. Regular monitoring during tapering contributes to individualized management for each patient with AOSD.

Differential Diagnosis

The accurate diagnosis of AOSD relies on a thorough evaluation of clinical, laboratory, and imaging findings to differentiate it from its diverse array of potential mimickers. The broad differential encompasses infections, malignancy, rheumatologic disorders, and adverse drug reactions.

Among infectious etiologies, several acute viral infections, including parvovirus B19, hepatitis, and others, can produce symptoms similar to AOSD. Bacteremia can also cause fever, elevated white blood cell (WBC) count, and acute phase reactants.

Among rheumatologic diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and reactive arthritis can also cause elevation of acute phase reactants. Vasculitic disorders, like polyarteritis nodosa (PAN), presenting with fever, arthralgia, skin lesions, and abdominal pain, may also mimic AOSD.

Malignancy, especially lymphomas, can mimic AOSD due to shared features of lymphadenopathy, fever, and leukocytosis.

Prognosis

The course of AOSD generally aligns with 1 of 3 patterns: self-limited illness, intermittent flares, or chronic Still disease. Predictors for chronicity and unfavorable outcomes include the presence of erosive polyarthritis at the time of presentation and involvement of shoulders or hips.[4][12][22] Additionally, the need for systemic glucocorticoids for more than 2 years before routine use of biologics is also considered a poor prognostic marker.

Complications

Complications of AOSD include MAS, amyloidosis, disseminated intravascular coagulopathy (DIC), pulmonary arterial hypertension (PAH), thrombotic thrombocytopenic purpura (TTP), and diffuse alveolar hemorrhage. Timely recognizing and managing these complications is crucial in optimizing patient outcomes and minimizing potential long-term sequelae.