Adult-onset Still’s disease (AOSD) is an uncommon systemic inflammatory condition distinguished by inflammatory polyarthritis, daily fever, and a fleeting salmon-pink maculopapular rash. A hallmark of this condition is a frequently elevated serum ferritin level, typically exceeding 1000 ng/ml. Effective management of AOSD hinges on a collaborative interprofessional healthcare team to ensure holistic patient care.
For clinicians engaged in continuing education on AOSD, this resource offers an in-depth exploration of the disease. It encompasses clinical presentation, diagnostic evaluations, and therapeutic strategies, emphasizing the crucial role of an interprofessional healthcare team in delivering comprehensive care for individuals affected by this rare systemic inflammatory disorder. Accurately reaching a still’s disease diagnosis is the first critical step in effective patient management.
Objectives
Upon completion of this educational activity, participants should be able to:
- Identify the core clinical indicators of adult-onset Still’s disease during patient assessments, which include inflammatory polyarthritis, daily fever, and a transient salmon-pink maculopapular rash, all crucial for still’s disease diagnosis.
- Select appropriate early therapeutic interventions, tailored to the specific needs and disease severity of each patient following a confirmed still’s disease diagnosis.
- Evaluate and monitor the effectiveness of chosen treatment approaches, adapting interventions based on patient response and the progression of Still’s disease.
- Coordinate patient care effectively within the healthcare team to improve patient outcomes, highlighting the significance of a multidisciplinary strategy in the treatment of AOSD after still’s disease diagnosis.
Introduction to Adult-Onset Still’s Disease and Diagnosis
Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder characterized by a triad of symptoms: daily fever, inflammatory polyarthritis, and a transient salmon-pink maculopapular rash. Initially described in children by George Still in 1896, “Still disease” originally referred to systemic juvenile idiopathic arthritis. AOSD, however, denotes the onset of this condition in individuals aged 16 and older.[1] A timely and accurate still’s disease diagnosis is essential for initiating appropriate treatment and managing the condition effectively.
Etiology of Still’s Disease
The precise cause of AOSD remains elusive. The prevailing theory suggests that AOSD is a reactive syndrome triggered by various infectious agents in genetically predisposed individuals. Genetic factors and infectious agents, including viruses and bacteria such as Yersinia enterocolitica and Mycoplasma pneumoniae, have been implicated as potential contributors to AOSD development.[2][3] Understanding potential etiologies can indirectly aid in the still’s disease diagnosis process by considering risk factors and differential diagnoses.
The consistent presence of a single etiopathogenic factor across all AOSD patients remains uncertain. A French study involving 62 patients revealed an association between AOSD and specific human leukocyte antigen (HLA) subtypes (B17, B18, B35, and DR2).[4] Isolated case reports have documented the occurrence of the disease in twins.[5] These genetic links highlight the complexity of still’s disease diagnosis and the need for multifactorial assessment.
Epidemiology of Adult-Onset Still’s Disease
AOSD is a notably rare condition, with an estimated annual incidence of 0.1 to 0.4 cases per 100,000 individuals in Europe. There is a slight female preponderance. The age distribution is bimodal, with peaks between 15 and 25 years and 36 and 46 years. Approximately three-quarters of patients experience disease onset between 16 and 35 years. Though uncommon, onset after age 70 has been reported.[6] Considering epidemiological data is important in the context of still’s disease diagnosis, particularly in ruling out more common conditions.
Pathophysiology of Still’s Disease
Two key aspects of immune dysregulation are central to AOSD pathogenesis: innate and adaptive immunity. Understanding these mechanisms is not directly involved in still’s disease diagnosis but provides context for disease manifestations and treatment strategies.
Immunopathology in Innate Immunity:
- Activation of neutrophils and macrophages:
- Increased CXCL8 levels:
- Not correlated with disease activity
- Recruits neutrophils to the inflammation site
- Linked to chronic articular AOSD persistence
- 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
- Increased CXCL8 levels:
Immunopathology in Adaptive Immunity:
The role of Th-17 responses is increasingly recognized in AOSD pathogenesis. Elevated levels of Th-17-related cytokines, including IL-1, 6, 17, 18, 21, and 23, contribute to the complex immunopathology of the disease.
History and Physical Examination for Still’s Disease Diagnosis
The clinical course of AOSD typically follows one of three patterns: monophasic, intermittent, and chronic.[4][8][[9]](#article-29502.r9] These patterns are roughly equally distributed, although some studies suggest a higher prevalence of the chronic articular pattern. Importantly, initial monophasic or intermittent patterns can evolve into chronic articular manifestations.[10] Recognizing these patterns is crucial for still’s disease diagnosis and prognosis.
Key clinical features of AOSD include fever, rash, and arthritis or arthralgia, present in approximately 75% to 95% of patients.[11] Other common symptoms are myalgia, pharyngitis, lymphadenopathy, and splenomegaly. Less frequent symptoms include hepatomegaly, pleurisy, pericarditis, and abdominal pain. A comprehensive history and physical examination are paramount in the process of still’s disease diagnosis.
Fever in AOSD often exhibits a quotidian pattern (daily recurring fever with temperature returning to normal between spikes), typically occurring in the late afternoon or evening and often preceding other symptoms. Temperature fluctuations can be significant, up to 4 °C within 4 hours.[12] In about 20% of cases, fever may not fully resolve between spikes, persist continuously, or present with a double quotidian pattern. AOSD can sometimes manifest as a fever of unknown origin (FUO), and temperatures exceeding 39.5 °C are suggestive of a monophasic pattern. Fever pattern analysis is a critical component of still’s disease diagnosis.
The characteristic rash of AOSD is evanescent, salmon-colored, macular or maculopapular. It is usually nonpruritic and often appears with fever onset. While primarily on the trunk and extremities, it can occur 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. Visual recognition of this rash is a valuable clue in still’s disease diagnosis.
Arthritis in AOSD can initially be mild, transient, and oligoarticular, potentially progressing to severe, destructive, symmetric polyarticular forms.[1] Commonly affected joints are knees, wrists, and ankles, but elbows, proximal interphalangeal joints, shoulders, metacarpophalangeal, metatarsophalangeal, hips, distal interphalangeal, and temporomandibular joints can also be involved. Wrist joint fusion is characteristic but infrequent. Joint assessment is essential for still’s disease diagnosis and monitoring disease progression.
Myalgia tends to worsen during fever spikes and can be severe. Muscle weakness is not typical, though case reports indicate mild elevations in serum creatine kinase and aldolase. Electromyographic studies and muscle biopsies are usually normal or show nonspecific inflammatory myopathy findings. These musculoskeletal symptoms contribute to the clinical picture of still’s disease diagnosis.
Sore throat is a common presenting symptom or recurs during flares. Examination typically reveals severe, nonsuppurative pharyngitis, with negative bacterial cultures. A review of 341 AOSD cases reported sore throat in 69% of patients.[13] Pharyngitis, while non-specific, is a frequent finding to consider during still’s disease diagnosis.
Symmetrical, slightly tender lymphadenopathy is reported in one-third to two-thirds of AOSD patients, and splenomegaly in one-third to one-half. Liver abnormalities include hepatomegaly (12% to 45%) and, more commonly, mild elevations in hepatic transaminases and alkaline phosphatase. Pericarditis, pleural effusions, and transient pulmonary infiltrates occur in about 30% to 40% of patients.[10][11][[14]](#article-29502.r14] Systemic involvement is a key feature that aids in still’s disease diagnosis and differentiation from other conditions.
Macrophage activation syndrome (MAS) occurs in a minority of AOSD patients but may be underdiagnosed. MAS is characterized by markedly elevated triglycerides, normal or low haptoglobin and fibrinogen, leukopenia, and thrombocytopenia.[15][[16]](#article-29502.r16] Abdominal pain is reported in 1% to 48% of patients, with other symptoms including nausea, anorexia, lymphadenitis, aseptic or acute pancreatitis, and weight loss. Recognizing potential complications like MAS is crucial after still’s disease diagnosis and during management.
Evaluation and Diagnostic Tests for Still’s Disease
Laboratory findings in AOSD are characteristic but not pathognomonic. They support the clinical diagnosis after excluding other conditions. The evaluation process is vital for accurate still’s disease diagnosis.
Ferritin levels are typically elevated, often exceeding five times the upper limit of normal. Elevated ferritin has 80% sensitivity and 46% specificity for AOSD. Combined with a decrease in glycosylated ferritin proportion (<20%), specificity increases to 90%.[17] Serum ferritin is a highly valuable marker in still’s disease diagnosis.
Inflammatory markers like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in almost all patients.[4] Hematological findings include leukocytosis (typically >15,000 cells/µL with >80% neutrophils), normocytic normochromic anemia, and thrombocytosis. These hematological abnormalities can mimic primary hematologic disease, and red cell aplasia has been reported.[18] These non-specific but supportive lab findings are part of the still’s disease diagnosis process.
Bone marrow biopsy may show hyperplasia of granulocytic precursors, hypercellularity, and hemophagocytosis in some cases. Hepatic transaminases are elevated in 75% of patients, and aldolase levels can also be elevated due to liver inflammation. While not routine, bone marrow findings can be considered in complex still’s disease diagnosis cases.
Antinuclear antibodies (ANA) and rheumatoid factor (RF) are detected in less than 10% of patients, typically at low titers. The absence of these autoantibodies is a characteristic feature distinguishing AOSD from other rheumatologic conditions and is important for still’s disease diagnosis.
Synovial fluid analysis typically shows inflammation, with leukocyte counts ranging from 100 to 48,000 cells/µL.[4] Inflammatory markers in synovial fluid further support the systemic inflammatory nature of AOSD. Synovial fluid analysis can be helpful in still’s disease diagnosis, especially in cases with prominent joint involvement.
Radiographs in early disease are usually normal or show slight joint space narrowing or periarticular osteopenia.[4] A classic radiographic finding in AOSD is narrowing of wrist carpometacarpal and intercarpal joint spaces, potentially progressing to bone ankylosis.[19][20] Radiographic findings are not typically early diagnostic features but can be supportive in later stages of still’s disease diagnosis.
Computed tomography (CT) and F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans can reveal lymph node enlargement, splenomegaly, pulmonary abnormalities, and hepatomegaly, aiding in assessing systemic involvement and contributing to a comprehensive still’s disease diagnosis.
Additional tests to consider for still’s disease diagnosis include:
- Complete blood count (CBC) with differential and platelet count
- ANA, RF, and anti-citrullinated peptide (anti-CCP) antibody testing
- Blood cultures
- Liver enzymes (bilirubin, aminotransferase, alkaline phosphatase, serum albumin)
- Serologic testing for hepatitis B and C, Epstein Barr virus, human parvovirus B19, and HIV
- Plain chest radiographs
- Blood urea nitrogen (BUN), creatinine
- Urinalysis with microscopic examination and urine culture
Treatment and Management after Still’s Disease Diagnosis
Therapeutic goals after still’s disease diagnosis include managing symptoms, physical signs, and inflammatory laboratory markers, preventing end-organ damage, and minimizing long-term therapy effects.
Treatment effectiveness is based on observational studies and clinical experience.[8][10] Initial treatment decisions are guided by disease activity, with subsequent adjustments based on clinical response.
Mild AOSD, characterized by fevers, rash, arthralgia, or mild arthritis, may respond to nonsteroidal anti-inflammatory drugs (NSAIDs) alone, but most patients benefit from low-dose glucocorticoids for better control. Typical NSAID choices include:
- Naproxen 500 mg twice daily
- Indomethacin 25 to 50 mg three times daily
- Ibuprofen 800 mg three times daily
Moderate AOSD involves debilitating joint symptoms, high-grade fever, or non-life-threatening internal organ involvement. Severe disease involves life-threatening organ complications. Management for moderate to severe disease includes:
- Anakinra is favored as the initial agent in patients without joint erosions, while methotrexate is preferred in patients with prevalent joint disease. The starting anakinra dose is 100 mg subcutaneous daily, potentially increased to 100 mg twice daily if partial response is seen within 2 weeks.
- Limited evidence suggests canakinumab, rilonacept, rituximab, and abatacept may be effective for patients refractory to other therapies.
Regular monitoring, including periodic assessments of CBC, BUN, creatinine, electrolytes, ferritin, D-dimer, ALT, and AST, is essential after still’s disease diagnosis and during treatment.
Most AOSD patients eventually discontinue therapy, particularly those with a monocyclic form. There are no established protocols for tapering disease-modifying antirheumatic drugs. For patients in complete remission for at least 3 months, gradual medication tapering to complete discontinuation is recommended, with regular monitoring to individualize management after still’s disease diagnosis.
Differential Diagnosis for Still’s Disease
Accurate still’s disease diagnosis relies on differentiating it from a wide range of conditions, including infections, malignancy, rheumatologic disorders, and adverse drug reactions.
Infectious etiologies include acute viral infections like parvovirus B19 and hepatitis, which can mimic AOSD. Bacteremia can also cause fever, elevated WBC count, and acute phase reactants. Excluding infections is a crucial step in still’s disease diagnosis.
Rheumatologic diseases in the differential diagnosis include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and reactive arthritis, all of which can elevate acute phase reactants. Vasculitic disorders like polyarteritis nodosa (PAN), presenting with fever, arthralgia, skin lesions, and abdominal pain, may also mimic AOSD. Careful consideration of other rheumatologic conditions is important in still’s disease diagnosis.
Malignancy, especially lymphomas, can mimic AOSD due to shared features of lymphadenopathy, fever, and leukocytosis. Ruling out malignancy is a critical component of still’s disease diagnosis, particularly in atypical presentations.
Prognosis of Adult-Onset Still’s Disease
AOSD course typically follows one of three patterns: self-limited illness, intermittent flares, or chronic Still disease. Predictors of chronicity and unfavorable outcomes include erosive polyarthritis at presentation and shoulder or hip involvement.[4][12][22] Need for systemic glucocorticoids for over 2 years before biologics is also a poor prognostic marker. Prognostic factors are considered after still’s disease diagnosis to guide long-term management.
Complications of Still’s Disease
Complications of AOSD include MAS, amyloidosis, disseminated intravascular coagulopathy (DIC), pulmonary arterial hypertension (PAH), thrombotic thrombocytopenic purpura (TTP), and diffuse alveolar hemorrhage. Prompt recognition and management of these complications are crucial for optimizing outcomes after still’s disease diagnosis.
Deterrence and Patient Education Following Still’s Disease Diagnosis
Effective AOSD management requires collaboration between healthcare professionals and patients. Early recognition is vital; patients should be educated about AOSD hallmark signs and symptoms, including persistent fevers, rash, and joint pain. Prompt medical attention should be encouraged for these symptoms. Regular monitoring, medication adherence, healthy lifestyle choices, and access to support networks are essential. Patient education is a cornerstone in managing AOSD effectively after still’s disease diagnosis.
Pearls and Key Considerations for Still’s Disease Diagnosis and Management
Key facts to remember about AOSD:
- AOSD has a variable course, from self-limiting episodes to chronic, debilitating conditions.
- Multiple systems can be involved, including joints, skin, and internal organs, complicating still’s disease diagnosis.
- Elevated ferritin levels, often exceeding five times normal, are a critical diagnostic and monitoring marker for still’s disease diagnosis.
- Treatment strategies involve NSAIDs, steroids, and biologics, tailored to disease severity after still’s disease diagnosis.
- AOSD can mimic various infectious, rheumatologic, and neoplastic conditions, necessitating careful differential still’s disease diagnosis.
- Vigilant monitoring for complications like MAS and cardiovascular involvement is essential for optimal patient care following still’s disease diagnosis.
Enhancing Healthcare Team Outcomes in Still’s Disease Management
AOSD is partly a diagnosis of exclusion and often presents diagnostic challenges. While rheumatologists typically lead care, collaboration with specialists like cardiologists, gastroenterologists, and oncologists is crucial for comprehensive management after still’s disease diagnosis. Nurses are vital in monitoring, medication administration, and reporting patient status changes. Physical and occupational therapy are essential for rehabilitation due to joint involvement. Detailed history and physical examination are imperative when AOSD is suspected, crucial for early detection, complication prevention, and improved prognosis.
Review Questions
(Note: Review questions are present in the original article but are not included here as per instructions to only rewrite the article content.)
References
(Note: References are present in the original article and are retained here for completeness.)
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Disclosure: Juhi Bhargava declares no relevant financial relationships with ineligible companies.
Disclosure: Sreelakshmi Panginikkod declares no relevant financial relationships with ineligible companies.
