Adult-Onset Still’s Disease: 7 Warning Symptoms & Powerful Treatments

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder characterised by inflammatory polyarthritis, daily fevers, and a transient salmon-pink maculopapular rash.

A hallmark of AOSD is a markedly elevated serum ferritin level, often exceeding 1000 ng/mL. Effective management of AOSD highlights the essential role of an interprofessional healthcare team in delivering comprehensive care to affected individuals.

Clinicians participating in an AOSD continuing education activity will gain a comprehensive understanding of the disease, including its clinical presentation, diagnostic findings, and treatment options. This activity emphasises both the management of AOSD and the vital role of an interprofessional healthcare team in providing holistic care for individuals affected by this rare systemic inflammatory disorder.

Objectives:

Identify the key clinical features of adult-onset Still disease during patient assessments, including inflammatory polyarthritis, daily fever, and transient salmon-pink maculopapular rash.
Select early appropriate therapeutic approaches, considering each patient’s individualised needs and severity of AOSD.
Assess and monitor the efficacy of selected treatment modalities, adapting interventions based on patient response and disease progression.
Coordinate care seamlessly within the healthcare team to optimise patient outcomes, emphasizing the importance of a multidisciplinary approach in treating AOSD.

Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder characterised by daily fever, inflammatory polyarthritis, and a transient salmon-pink maculopapular rash. First described in children by George Still in 1896, the term “Still disease” refers to systemic juvenile idiopathic arthritis, whereas AOSD designates the condition that manifests after age 16.

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.

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). Specific case reports have highlighted instances of the disease occurring in twins.

AOSD is a rare condition, with an estimated annual incidence of 0.1 to 0.4 cases per 100,000 people in Europe. There is a slight female predominance. The age distribution is bimodal, with the first peak between ages 15 and 25 and the second between 36 and 46. Approximately three-quarters of patients develop the disease between 16 and 35 years of age. Although rare, onset beyond the age of 70 has been reported.

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 correlates with disease activity
IL-18 in serum, synovial fluid, liver, and lymph nodes
Tumour 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
Increased α-soluble receptor of IL-2 (CD25)
Additionally, Th-17 responses are increasingly recognised as important in the pathogenesis of AOSD. Elevated levels of Th-17-related cytokines—including IL-1, IL-6, IL-17, IL-18, IL-21, and IL-23—contribute to the complex immunopathology of the disease.

Three primary patterns characterise the clinical course of AOSD: monophasic, intermittent, and chronic. 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.

The principal clinical features of AOSD are fever, rash, and arthritis or arthralgia, present in approximately 75% to 95% of patients. Other common manifestations include myalgia, pharyngitis, lymphadenopathy, and splenomegaly. Less frequent symptoms are 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 in the day and generally preceding other symptoms. The temperature can fluctuate by 4 °C within 4 hours. 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 above 39.5 °C strongly suggests a monophasic pattern.

The rash in AOSD is classically evanescent, appearing salmon-colored, macular, or maculopapular. 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 (a hot shower or a hot towel) or by 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. 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.

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.

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.

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 serum triglycerides, along with normal or low haptoglobin and fibrinogen levels, and may experience leukopenia and thrombocytopenia. Abdominal pain is reported in 1% to 48% of patients, and additional symptoms such as nausea, anorexia, lymphadenitis, aseptic or acute pancreatitis, and weight loss can also occur.

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

Ferritin levels are typically 5 times the upper limit 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.

In almost all patients, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated. 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.

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 to establish 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. Furthermore, inflammatory markers in synovial fluid underscore the systemic nature of AOSD and help clinicians tailor appropriate therapeutic interventions.

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

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

The therapeutic objectives are to control symptoms, physical signs, and laboratory markers of inflammation. Additional goals include preventing end-organ damage and minimising the long-term effects of therapy.

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

Mild disease presentation in AOSD is characterised 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 coagulation , or severe hepatic involvement. Patients with moderate to severe disease are managed as follows:

Anakinra is favoured 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, intra-articular
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.
Limited evidence suggests that canakinumab, rilonacept, rituximab, and abatacept may be effective in 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 individualised management for each patient with AOSD.

The accurate diagnosis of AOSD relies on a thorough evaluation of clinical, laboratory, and imaging findings to differentiate it from its diverse mimics. 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 mimic AOSD. Bacteremia can also cause fever, an 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 lymphoma, can mimic AOSD because of shared features such as lymphadenopathy, fever, and leukocytosis.

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

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

In managing AOSD, healthcare professionals must foster a collaborative relationship with patients to optimise prevention and care. Early recognition is pivotal; thus, Patients should be educated about the hallmark signs and symptoms of AOSD, such as persistent fevers, rash, and joint pain, so that they can recognise the disease early. Encourage patients to seek prompt medical attention if they experience such manifestations. Regular monitoring through scheduled check-ups and appropriate diagnostic tests is imperative to track disease progression and adjust treatment plans accordingly. Medication adherence, stressing the significance of following prescribed regimens meticulously, should be emphasised.

Adopting lifestyle choices that promote overall well-being, such as maintaining a healthy diet and engaging in regular exercise, is essential. Patient education is fundamental, empowering individuals with knowledge about AOSD, treatment options, and potential complications. Facilitating access to support networks and connecting patients with relevant organizations and groups is important. Emphasising emotional well-being and encouraging patients to prioritise mental health and seek appropriate support is crucial. Ultimately, collaboration between healthcare professionals and patients is key to effectively navigating the complexities of AOSD management.

Key facts to keep in mind about AOSD are as follows:

AOSD exhibits a variable course, ranging from self-limiting episodes to chronic and debilitating conditions.
Multiple systems can be involved, including joints, skin, and internal organs.
Elevated ferritin levels, often exceeding the upper limit of normal by 5-fold or more, serve as a critical marker for diagnosing and monitoring AOSD.
Treatment strategies may involve NSAIDs, steroids, and biologics tailored to disease severity.
AOSD can mimic various infectious, rheumatologic, and neoplastic conditions, necessitating careful consideration of differential diagnoses.
Vigilant monitoring for complications such as MAS and cardiovascular involvement is essential for optimal patient care.

AOSD is, in part, a diagnosis of exclusion and frequently presents a diagnostic challenge. While a rheumatologist typically leads the care team, collaboration with specialists such as cardiologists, gastroenterologists, and oncologists is crucial for comprehensive management. The disease can affect multiple organ systems, necessitating a multidisciplinary approach. As integral members of the healthcare team, nurses play a vital role in monitoring vital signs, administering medications, and alerting clinicians to changes in patient status or lack of progress, contributing significantly to the overall patient care strategy.

Due to the severe joint involvement in AOSD, physical and occupational therapy are essential components of the patient’s rehabilitation regimen. Given the potential for life-threatening complications, a detailed history and physical examination are imperative when AOSD is suspected. This approach is crucial for early detection, preventing complications, and improving the overall prognosis.

Source:
Wenker KJ, Quint JM. Ankylosing Spondylitis.
StatPearls Publishing; 2023.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK538345/

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