The Great Still-Usion: Unmasking Adult-Onset Still’s Disease Masquerading As Upper Respiratory Tract Infection

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology that presents with high-grade fever, arthritis, evanescent rash, and multiorgan involvement. It is a rare disorder and is a diagnosis of exclusion. AOSD is often misdiagnosed initially as viral exanthems or upper respiratory tract infections leading to a delay in diagnosis. Management includes non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and conventional or biologic disease-modifying antirheumatic drugs (DMARDs). We report a case of a 53-year-old female with prolonged fever, sore throat, arthralgia, and rash. She was initially presumed to have infectious pharyngitis but did not respond to antimicrobial therapy. After extensive evaluation that excluded infectious, malignant, and other rheumatological etiologies, she was noted to satisfy multiple Yamaguchi criteria and was subsequently diagnosed with AOSD. Glucocorticoids and biologic DMARDs were initiated, leading to improved clinical manifestations and a decline in inflammatory markers.


Introduction
Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder that occurs with an incidence of 0.16-0.4 per 100,000 adults. It has a bimodal age distribution that peaks between the ages of 15-25 years and 36-45 years and is proposed to occur due to immune dysfunction [1,2]. This condition most commonly presents with fever, rash, arthralgia, sore throat, lymphadenopathy, and hepatosplenomegaly. Due to overlapping clinical manifestations and lack of a specific diagnostic test, AOSD is commonly mistaken initially for acute viral syndromes, malignancy, or other autoimmune disorders leading to inappropriate therapy. This case highlights the importance of considering AOSD as a differential diagnosis of fever of unknown origin once other etiologies have been excluded, especially in the presence of serum hyperferritinemia.

Case Presentation
A 53-year-old female with a history of depression and hyperlipidemia presented with a two-week history of high-grade fever ranging from 38.3 to 39.4 C, chills, fatigue, sore throat, myalgia, and polyarthralgia involving both wrists, elbows, and ankle joints. This was accompanied by unintentional weight loss of 6 lb over two weeks and a non-pruritic rash occurring with fever spikes. She denied a recent history of sick contacts, recent travel, tick bites, or a family history of autoimmune conditions. On admission, vitals signs were temperature 38.3 C, heart rate 73 beats/minute, blood pressure 102/55 mm Hg, respiratory rate 15/minute, and oxygen saturation of 98% on room air. The examination was notable for a coalescent erythematous macular circular rash over the thighs and forearms, left axillary lymphadenopathy, and mild swelling and tenderness of bilateral wrist and ankle joints. The head and neck exam was unremarkable, with no evidence of pharyngeal exudates or follicles. Otherwise, the systemic exam was unrevealing. She was initially evaluated at urgent care, where tests for rapid streptococcal antigen and COVID-19 were negative. She was treated with oral amoxicillin for a week. Due to persistent symptoms and lack of response to antimicrobials, she was admitted for evaluation of a fever of unknown origin.
Investigations were notable for neutrophilic leukocytosis (WBC count 18,600/microliter, neutrophils 91%), normocytic anemia (hemoglobin 10.6 gram/deciliter), elevated inflammatory markers (erythrocyte sedimentation rate [ESR] 60 millimeter/hour, C-reactive protein 21.3 milligram/deciliter), marked hyperferritinemia (serum ferritin 5140 nanogram/milliliter), and transaminitis (aspartate transaminase 52 unit/liter) ( Tables 1-3). Initial infectious workup for other bacterial (tuberculosis, brucellosis, Q fever) and viral etiologies (COVID-19, respiratory 22 plex, HIV, Ebstein-Barr virus [EBV], parvovirus) was negative ( Table 4). In view of persistently negative blood cultures, lack of cardiac murmur, embolic phenomenon, or vegetations on transthoracic echo, infective endocarditis was ruled out. Next, the possibility of malignancy was considered. CT of the chest, abdomen, and pelvis was negative for malignancy, incidentally showing mild splenomegaly, trace pericardial effusion, and bilateral pulmonary atelectasis. Age-appropriate cancer screening was up to date. Her most recent pap smear was normal. A colonoscopy done two years prior revealed benign tubular adenomas that had been resected. Her most recent mammogram showed breast tissue with scattered areas of fibro glandular density (category B) and left supraclavicular lymphadenopathy. Subsequent excisional biopsy of the left supraclavicular lymph node did not reveal any evidence of malignancy or lymphoma. Apart from the positive anti-nuclear antibody (ANA) (1:160), the workup for rheumatoid arthritis, systemic lupus erythematosus (SLE), and other systemic autoinflammatory disorders was negative ( Table 5). No articular destruction was noted on wrist or hand X-rays. During admission, the patient endorsed a new-onset headache and jaw claudication. In view of these symptoms and elevated ESR, bilateral temporal artery biopsies were conducted that were negative for temporal arteritis.

Hematology
Lab      After extensive negative workup for malignancy and infectious diseases, the patient's clinical presentation was noted to satisfy multiple Yamaguchi criteria, and she was diagnosed with AOSD. A tapered regimen of oral prednisone starting from 20 mg was initiated, which led to clinical improvement and a decline in inflammatory markers. She followed an intermittent course and had a systemic flare of symptoms (fever, sore throat, rash) five weeks after initiation of prednisone. She was eventually transitioned to injectable canakinumab (anti-interleukin-1 [IL-1]) every 4-8 weeks, which led to improvement (Figure 1).
The leading clinical manifestations include fever (95%), arthralgia or arthritis (95%), and rash (77%). Fever classically follows a quotidian (daily recurrent fever) or double quotidian pattern (two spikes per day) with or without defervescence between spikes. However, our patient did not demonstrate a clear quotidian or double quotidian pattern. As seen in our patient, joint involvement may occur in the form of mild transient oligoarthritis involving the knees, wrists, ankles, elbows, interphalangeal joints, and shoulders. This can evolve into severe destructive polyarthritis over time. The typical rash of AOSD is a salmon-colored evanescent maculopapular eruption that occurs with fever spikes and disappears with defervescence, most commonly involving the trunk and extremities but can also affect the palms, soles, and face. However, atypical rashes have also been described [6]. Severe myalgia may occur during fever spikes with mild to no elevation of creatine kinase and aldolase. Non-suppurative pharyngitis due to cricothyroid perichondritis or aseptic pharyngitis occurs in 53% of cases. Other findings include pleuritis, pericarditis, weight loss, mild, tender symmetrical lymphadenopathy, and mild splenomegaly. Abdominal pain can occur due to lymphadenitis, acute pancreatitis, and aseptic peritonitis. Elevated acute phase reactants, leukocytosis, normocytic anemia, and transaminitis may be seen. Rheumatoid factor (RF) and ANA are negative in most cases. However, 7% of patients may be positive for ANA which does not exclude the diagnosis [7,8]. Serum ferritin levels are significantly higher in AOSD than other rheumatic conditions and correlate with disease activity. Marked hyperferritinemia >1000 nanogram/milliliter (ng/mL) (more than five times the upper limit of normal) is more suggestive of AOSD. Low glycosylated ferritin (<20%) is a more specific diagnostic test. However, its utility is limited due to the lack of widespread availability. Nonerosive narrowing of the carpometacarpal and intercarpal joint spaces of the wrist with ankylosis is a characteristic radiologic finding in AOSD.
AOSD is a diagnosis of exclusion based on clinical and laboratory features in the absence of other mimicking conditions. Several diagnostic criteria have been proposed for AOSD. The Yamaguchi criteria have high discriminative power with a sensitivity and specificity of 96% and 98%, respectively, and are often used to establish the diagnosis ( Table 6) [9,10]. The diagnosis of AOSD requires the presence of five Yamaguchi criteria, with at least two being major diagnostic criteria. Our patient appropriately underwent a comprehensive evaluation that ruled out infectious causes, including acute viral syndromes, infective endocarditis, systemic autoimmune conditions, and malignancy. Thereafter, she was found to satisfy three major and four minor criteria that led to the final diagnosis of AOSD. AOSD can follow a monocyclic course with a single systemic episode, intermittent/polycyclic, or chronic disease patterns. Systemic signs and symptoms predominate in monocyclic and polycyclic courses, while articular involvement is more common in chronic disease.  , cardiac tamponade, and hepatic involvement). Biologic DMARDs are indicated in severe or refractory disease resistant to glucocorticoids and second-line conventional DMARDs. These biologic agents target the blockade of pro-inflammatory cytokines such as IL-1 (anakinra-IL-1R antagonist), (canakinumab, rilonacept-anti-IL-1β monoclonal antibody), IL-6 (tocilizumab) and TNF (etanercept, infliximab).

Conclusions
Due to its rarity, overlapping clinical manifestations, and lack of specific serological markers, diagnosing AOSD is often challenging. This case emphasizes the importance of considering AOSD in the differential diagnosis of fever of unknown origin and persistent pharyngitis. In such cases, the presence of markedly elevated serum ferritin and the exclusion of other autoimmune, infectious, and malignant etiologies should prompt physicians to consider this diagnosis.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other