Diagnosis Of Adult-onset Still's Disease Research Articles

Persistent Pruritic Linear Streaks of Adult-Onset Still's Disease: Reconsidering the Yamaguchi Criteria.

Objective Adult-onset Still's disease (AOSD) is a rare orphan disease, the diagnosis of which remains challenging. This study aimed to identify additional clues for establishing early diagnosis beyond the existing criteria. Methods A retrospective longitudinal cohort study was conducted at two community hospitals in Japan between March 2012 and December 2022. The clinical characteristics and medical histories of patients with AOSD were extracted from the clinical records. The primary outcome was to identify the key manifestations of AOSD for an early diagnosis beyond the existing criteria. Results Twenty-one patients (mean age, 58 years) were included in the study. Fever was the first symptom in 13 out of 21 patients (62%). Six out of 21 patients (29%) presented with a pruritic rash only, while two out of 21 (10%) initially presented with a sore throat. All patients visited more than one medical institution. The median time to reach a correct diagnosis was 41 days (IQR 19-138). Nineteen out of 20 patients (95%) exhibited a pruritic rash, identified as persistent pruritic linear streaks, with a median duration of 21 days (IQR 12-64) before the diagnosis of AOSD as a cutaneous manifestation. Conclusions Persistent pruritic linear streaks were a key feature in the context of an early diagnosis of AOSD, offering an option for reconsidering and revising the existing classification criteria.

Renal manifestations in adult-onset Still's disease: a systematic review.

We aimed to review the literature on the clinical presentation, renal pathology, treatment, and outcome of renal manifestations in adult-onset Still's disease (AOSD). We used PRISMA guidelines for our systematic review and included all English-language original articles from inception till September 15, 2023, on AOSD and kidney involvement in any form. Data on patient demographics, diagnostic criteria, clinical presentation, renal pathology, treatment employed including dialysis, outcome, cause of death were collected and analyzed. The median age at the diagnosis of renal issues was 37, with a higher prevalence among females (58.1%). Among the cases, 28 experienced renal problems after being diagnosed with AOSD, 12 had simultaneous diagnoses of renal issues and AOSD, and in 4 cases, renal problems appeared before AOSD diagnosis. Out of the 44 cases, 36 underwent renal biopsy, revealing various pathology findings including AA amyloidosis (25%), collapsing glomerulopathy (11.4%), thrombotic microangiopathy (TMA) (11.4%), IgA nephropathy (9.1%), minimal change disease (6.8%), and others. Some cases were clinically diagnosed with TMA, proximal tubular dysfunction, or macrophage activation syndrome-related acute kidney injury. Treatment approaches varied, but glucocorticoids were commonly used. Renal involvement was associated with increased mortality and morbidity, with 6 out of 44 patients passing away, 4 progressing to end-stage renal disease (ESRD), and data on 2 cases' outcomes not available. Renal manifestations in AOSD are diverse but rarely studied owing to the rarity of the disease. Studies with larger data would be essential to study further on the pathogenesis and implications.

Analysis of clinical manifestations and spectrum of pharmacotherapy in Moscow and St. Petersburg cohorts of patients with adult-onset Still's disease

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease of unknown etiology characterized by clinical manifestations such as fever, non-stable maculopapular rash, arthritis and/or arthralgias and leukocytosis with neutrophilia.Objective: to analyze the spectrum of clinical manifestations of AOSD and pharmacotherapy in real clinical practice.Material and methods. A cross-sectional study included 111 patients with a confirmed diagnosis of AOSD according to the Yamaguchi criteria, who were treated in two large Russian centers from 2019 to 2022: V.A. Nasonova Research Institute of Rheumatology (Moscow) and Almazov National Medical Research Centre (Saint Petersburg).Results and discussion. We analyzed the spectrum of clinical manifestations throughout the course of the disease. The spectrum of clinical manifestations of AOSD in our study was shown to be similar to the results of other studies. It was found that the frequency of the different clinical manifestations did not differ significantly.The majority of patients (74%) in our cohort received glucocorticosteroids (GC) in combination with disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs (bDMARDs). Monotherapy with GC was used in only 9% of patients. Up to 80% of patients received methotrexate (MTX) at various stages of the disease. For the treatment of patients refractory to GC and MTX therapy, bDMARDs were prescribed (44% of cases), most frequently interleukin-6 inhibitors (34%). In the St. Petersburg cohort, 13 (31.7%) of 41 patients were taking colchicine, which enabled control of disease manifestations and a reduction in the need for GC in 9 of them.Conclusion. Thus, we can draw a preliminary conclusion about the presence of steroid dependence in patients with AOSD. Up to 79.3% of AOSD patients are forced to take GC for a long period of time, which is associated with the risk of complications. Further studies on the optimal profile of bDMARDs are needed, as well as the role of colchicine as a potential therapeutic option for certain clinical and immunological subtypes of AOSD.

Adult-Onset Still's Disease: A Rare Cause of Pyrexia Of Unknown Origin (Case Report with Literature Review)

Adult-onset Still's disease (AOSD) is a remarkably rare illness. One well-known pathogenic process that results in systemic manifestations is auto-inflammatory disease. We report on a young man who complained of joint pain, sore throat, and a high spiking fever. After a thorough assessment using the Yamaguchi criteria, the patient's clinical examination, elevated serum ferritin and C-reactive protein (CRP), absence of serologic markers (RA factor, Antinuclear antibody levels), and lymphadenopathy all contributed to the diagnosis of AOSD. He was treated with analgesics, steroids, and disease-modifying anti-rheumatic drugs (DMARDs). Three weeks later, at the follow-up, his symptoms and lab parameters had improved.

Increased human neutrophil lipocalin and its clinical relevance in adult-onset Still's disease.

Human neutrophil lipocalin (HNL) has been used extensively to differentiate acute bacterial infection from febrile diseases as a biomarker to reflect the activation of the neutrophil. The serum HNL levels in the adult-onset Still's disease (AOSD) patients with and without infection, as well as the healthy controls (HCs), were analyzed statistically in this study to evaluate the value of HNL for the diagnosis of AOSD. A total of 129 AOSD patients were enrolled, from whom blood samples were drawn and the AOSD diagnosis was confirmed through the review of the medical records, where the systemic score, demographic characteristics, clinical manifestations, and laboratory parameters were also collected for the patients; in addition, a total of 40 HCs were recruited among the blood donors from the healthcare center with the relevant information collected. The HNL test was done for the blood samples with the enzyme-linked immunosorbent assay and the analyses were done for the correlations of HNL with clinical manifestations and diagnostic effectiveness. The serum HNL increased significantly in the patients with only AOSD as compared with that in the HCs (139.76 ± 8.99 ng/mL vs . 55.92 ± 6.12 ng/mL; P < 0.001). The serum HNL level was correlated with the white blood cell (WBC) count ( r = 0.335, P < 0.001), neutrophil count ( r = 0.334, P < 0.001), erythrocyte sedimentation rate ( r = 0.241, P = 0.022), C-reactive protein ( r = 0.442, P < 0.0001), and systemic score ( r = 0.343, P < 0.0001) in the AOSD patients significantly. Patients with fever, leukocytosis ≥15,000/mm 3 , and myalgia in the HNL-positive group were observed relatively more than those in the HNL-negative group ( P = 0.009, P = 0.023, and P = 0.007, respectively). HNL was a more sensitive indicator than ferritin and C-reactive protein (CRP) to differentiate the AOSD patients with bacterial infection from AOSD-only patients, and the Youden index was 0.6 for HNL and 0.29 for CRP. Serum HNL can be used as a biomarker for the diagnosis of the AOSD, and HNL is also observed to be associated with the disease activity.

Interleukin-18 and Soluble Interleukin-2 Receptor Are Useful Markers for Enhanced Diagnosis of Intravascular Lymphoma

Intravascular lymphoma (IVL) is an extremely rare and aggressive form of non-Hodgkin's lymphoma characterized by lymphoma cells localized within blood vessels. Due to its rapid progression and life-threatening nature, prompt diagnosis and swift treatment are essential. However, IVL often presents with nonspecific systemic symptoms such as fever, fatigue, weight loss, skin rash, and neurological impairment without noticeable lymph node enlargement. As a result, diagnosing IVL is highly challenging, and it is frequently misdiagnosed as other conditions. A definitive diagnosis of IVL requires tissue biopsy, like a random skin biopsy, although this may not always lead to the identification of IVL from the biopsy site. Consequently, when IVL is suspected, repeated random skin biopsies may be necessary, but the optimal number of biopsies remains unknown. To avoid repetitive invasive procedures, clinical indicators that raise suspicion of IVL more aggressively in patients with nonspecific symptoms are needed. IVL often presents with clinical features that resemble adult-onset Still disease (AOSD), particularly with systemic symptoms such as fever and hemophagocytic lymphohistiocytosis (HLH). Distinguishing between IVL and AOSD is crucial, but the lack of disease-specific markers for each condition makes differentiation challenging. While recent studies suggest the utility of genetic mutation analysis using cell-free DNA for diagnosing IVL, cost and technical limitations call for the development of simpler diagnostic adjunct markers. Therefore, our study aimed to explore potential useful indicators for differentiating IVL by comparing clinical parameters used for AOSD diagnosis in both IVL and AOSD patients. We conducted a comparative analysis using clinical data and initial samples from seven patients diagnosed histologically with IVL and five AOSD patients who were confirmed negative for IVL through long-term follow-up. Additionally, samples from six healthy donors were included for comparison. The median age of IVL patients was 64 years, while AOSD patients were 47 years old, with no significant difference between the groups (p=0.668). White blood cell count, hemoglobin concentration, platelet count,lactate dehydrogenase (LDH), triglycerides, fibrinogen, and C-reactive protein showed no significant differences between IVL and AOSD patients. On the other hand, ferritin levels were significantly lower in IVL patients compared to AOSD patients (539-9164 vs. 4690-91917 ng/mL, p=0.018), and soluble interleukin-2 receptor (sIL-2R) levels were significantly higher in IVL patients (4714-37572 vs. 935-4441 U/mL, p=0.003). Furthermore, the inflammatory cytokines IL-1β, IL-6, and IL-18 were measured, and while IL-1β and IL-6 showed no significant differences between IVL and AOSD patients, IL-18 was significantly higher in AOSD (0.77x10 3-8.04x10 3 vs. 1.07x10 5-2.05x10 5 pg/mL, p=0.003) (Figure). The presence of HLH did not impact ferritin, sIL-2R, or IL-18 levels in IVL patients. Additionally, the presence of bone marrow infiltration by IVL cells did not influence the clinical parameters, including ferritin, sIL-2R, and IL-18. Furthermore, ROC analysis was performed to assess the usefulness of ferritin, sIL-2R, and IL-18 in differentiating IVL and AOSD, revealing that less than 10000 pg/mL for IL-18 and above 5000 U/mL for sIL-2R ensured a reliable differentiation between IVL and AOSD. In conclusion, IL-18 and sIL-2R showed significant differences between IVL and AOSD, suggesting their potential as useful indicators for distinguishing the two conditions. Furthermore, when investigating cases of fever of unknown origin, it is crucial to diligently perform procedures such as random skin biopsies in patients strongly suspected of having IVL based on the values of IL-18 and sIL-2R.

Establishment of a differential diagnosis method and an online prediction platform for AOSD and sepsis based on gradient boosting decision trees algorithm

ObjectiveThe differential diagnosis between adult-onset Still’s disease (AOSD) and sepsis has always been a challenge. In this study, a machine learning model for differential diagnosis of AOSD and sepsis was developed and an online platform was developed to facilitate the clinical application of the model.MethodsAll data were collected from 42 AOSD patients and 50 sepsis patients admitted to Affiliated Hospital of Xuzhou Medical University from December 2018 to December 2021. In addition, 5 AOSD patients and 10 sepsis patients diagnosed in our hospital after March 2022 were collected for external validation. All models were built using the scikit-learn library (version 1.0.2) in Python (version 3.9.7), and feature selection was performed using the SHAP (Shapley Additive exPlanation) package developed in Python.ResultsThe results showed that the gradient boosting decision tree(GBDT) optimization model based on arthralgia, ferritin × lymphocyte count, white blood cell count, ferritin × platelet count, and α1-acid glycoprotein/creatine kinase could well identify AOSD and sepsis. The training set interaction test (AUC: 0.9916, ACC: 0.9457, Sens: 0.9556, Spec: 0.9578) and the external validation also achieved satisfactory results (AUC: 0.9800, ACC: 0.9333, Sens: 0.8000, Spec: 1.000). We named this discrimination method AIADSS (AI-assisted discrimination of Still’s disease and Sepsis) and created an online service platform for practical operation, the website is http://cppdd.cn/STILL1/.ConclusionWe created a method for the identification of AOSD and sepsis based on machine learning. This method can provide a reference for clinicians to formulate the next diagnosis and treatment plan.

Successful complementary therapy with traditional Chinese medicine in a patient with Qi and Jin deficiency symptoms from adult-onset Still's disease: A case report

BackgroundAdult-onset Still's disease (AOSD) is a rare yet well-documented polygenic and systemic autoinflammatory disease characterized by recurrent spiking fever, transient skin rash, arthralgia, and sore throat. Traditional Chinese medicine (TCM) holds a significant role in complementary and alternative medicine. This study presents a unique case of a female AOSD patient with concurrent Qi and fluid deficiency syndrome who received combined treatment with formulated Zhu Ye Shi Gao Decoction (ZYSGD). Case presentationIn this case, a 28-year-old female patient presented with a 15-day history of fever and skin rash accompanied by sore throat, fatigue, myalgia, and arthralgia. Additionally, leucocytosis, aminotransferase abnormalities, and elevated inflammatory factor levels were observed. Infectious diseases, solid tumors, and hematological disorders were all ruled out. Anti-infective treatments proved ineffective, leading to the final diagnosis of AOSD. Glucocorticoid therapy provided only partial relief. Consequently, formulated ZYSGD and hepatoprotective drugs were added to the glucocorticoid treatment. Subsequently, the patient's symptoms and inflammatory biomarkers showed improvement. After discharge, the patient's condition remained stable while continuing the formulated ZYSGD in combination with 4 mg of Medrolol (qd) during a 10-month follow-up period. ConclusionThis case report suggests that formulated ZYSGD could be a viable option for complementary and alternative therapy for late-stage AOSD, especially in cases involving both Qi and body fluid imbalances.

Acute Severe Myocarditis as the Presenting Complaint of Adult-Onset Still's Disease: A Case Report

Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory condition characterised by a classical triad of symptoms: prolonged fever, polyarthritis, and a characteristic salmon-pink skin rash. It can affect a variety of organ systems, resulting in many different clinical presentations. Myocarditis complicated by cardiogenic shock is a rare and life-threatening manifestation of AOSD, typically affecting younger patients. There is limited experience and evidence in how to best manage this challenging patient cohort. Case: A previously fit and healthy 22-year-old male presented with fever, arthralgia, and general malaise. On clinical examination he was pyrexial and hypotensive, requiring vasopressor support for presumed septic shock. Subsequent transthoracic echocardiography and cardiac magnetic resonance imaging findings were in keeping with fulminant myocarditis. Further septic and autoimmune screens were negative, although he responded well to high-dose intravenous corticosteroids. Attempts to wean immunosuppression were unsuccessful. His ferritin was markedly elevated (20,233 ug/L), prompting haematological and rheumatological opinions. A diagnosis of AOSD was suspected using Yamaguchi criteria. The successful addition of tocilizumab (an interleukin-6 receptor antagonist) therapy enabled gradual de-escalation of steroid therapy with ongoing disease remission at 6 months. This case highlights the importance of considering AOSD as a rare cause of myocarditis, especially when fever is present or disease is severe. Failure to improve with first-line therapy involving high-dose corticosteroids, or inability to wean that therapy, should prompt consideration for escalation of therapy, with tocilizumab seemingly being an effective treatment option.

Adult-onset Still’s disease with secondary macrophage activation syndrome: a case report

We describe a case of adult-onset Still’s disease (AOSD) with secondary macrophage activation syndrome. AOSD is a rare disease with unknown origin. Rarely it’s complicated by secondary macrophage activation syndrome, which is a life-threatening disorder. Because the diagnosis of AOSD is essential for exclusion and complications are life-threatening, it is mandatory for a prompt and extensive diagnostic workup and treatment.

Development and validation of the AF score for diagnosis of adult-onset Still's disease in fever of unknown origin

ObjectiveTo develop and validate a diagnostic score to identify adult-onset Still's disease (AOSD) in fever of unknown origin (FUO). MethodsA single center, retrospective case-control study of inpatients with FUO from January 2018 to December 2021. Using clinical and laboratory data from 178 cases with AOSD and 486 cases with FUO, we developed an AOSD/FUO (AF) score with a Bayesian Model Averaging approach. AF score and Yamaguchi's criteria were evaluated by sensitivity, specificity, accuracy, and positive/negative predictive value for diagnosis of AOSD in developmental and validation samples. ResultsPersistent pruritic eruptions (PPEs) in patients with rashes was higher in AOSD group than FUO group (52.3% vs 7.4%; P < 0.01). PPEs yielded a specificity of 97.5% and a sensitivity of 44.9%. AF score = PPEs × 3.795+Evanescent rash × 2.774+Serum ferritin × 1.678+Myalgia × 0.958+Neutrophil count × 0.185+Platelet count × 0.004. A cut-off value ≥ 5.245 revealed the maximizing sensitivity of 88.7% and specificity of 95.8% in discriminating AOSD from FUO in the validation group. And AF score improved the accuracy from 82.6% to 93.3% compared with Yamaguchi's criteria. ConclusionsWe developed and validated a new score which can identify AOSD in FUO with higher classification accuracy than Yamaguchi's criteria. Future multi-centric prospective studies need to be designed to confirm the diagnosis value of AF score.

A Streamlined Diagnostic Process Improved the Outcomes of Patients with Adult-Onset Still's Disease: A Single-Center Retrospective Observational Study.

The diagnosis of adult-onset Still's disease (AOSD) is often delayed due to its clinical heterogeneity and lack of pathognomic features. Hence, there is an unmet need for an efficient diagnostic process. The major aim of this study was to compare the differences in disease outcomes between two groups of AOSD patients with and without implementation of the streamlined diagnostic process (SDP). Of 172 febrile patients with skin rash and/or arthralgia, 112 individuals had AOSD. The tentative diagnosis of AOSD or non-AOSD was made with or without the SDP implementation. The selection criteria for AOSD outcomes analysis were as follows: (1) age at study entry older than 20years, (2) fulfillment of the Yamaguchi criteria for AOSD diagnosis, and (3) a follow-up period longer than 6months after initiation of therapy. Three outcome parameters were evaluated, including diagnosis lag period, the proportion of "early diagnosis," and the proportion of achieving disease remission after a 6-month therapy. The SDP was implemented for expediting AOSD diagnosis in 41 (36%) enrolled patients (SDP-implemented group). The diagnosis lag period was significantly shorter in the SDP-implemented group (median 2.0 weeks, interquartile range [IQR] 1.0-2.5weeks) than in the non-SDP-implemented group (4.0 weeks, IQR 2.0-6.0 weeks, p < 0.001). A significantly higher proportion of "early diagnosis" was also found in the SDP-implemented group (75.6%) compared with the non-SDP-implemented group (33.8%, p < 0.001). We revealed a significantly higher proportion of achieving remission in the SDP-implemented group (85.4%) compared with the non-SDP-implemented group (67.6%, p < 0.05). Logistic regression analysis revealed SDP implementation as a potential predictor of achieving disease remission. Implementing an SDP for expediting diagnosis could improve outcomes for AOSD patients. This diagnostic process increased the early diagnosis rate and led to a higher disease remission rate. However, the beneficial effects of SDP implementation need further external validation.

Macrophage Activation Syndrome in Adult Onset Still’s Disease: A Life Threatening Complication

Adult onset Still’s disease (AOSD), a multi-systemic inflammatory disorder, is a rare disorder but an important differential to be considered in patients of Pyrexia of Unknown Origin, especially if patient presents with polyarthritis. Macrophage activation syndrome (MAS), a subset of Secondary Hemophagocytic Lymphohistiocytosis (HLH), considered as the most life threatening complication of AOSD, mostly develops around the onset of disease. Hence, in a previously undiagnosed case of AOSD, recognizing MAS as a presenting feature complicating underlying AOSD is essential for increased patient survival, as in our case.&#x0D; &#x0D; &#x0D; A 39 year old diabetic female presented with high grade fever with chills and multiple joint pains symmetrically involving proximal shoulder, knees and distal joints (involving MCP, PIP and DIP joints of hand) associated with swelling and early morning stiffness, relieved on activity, since past 6 months. No history of oral ulcers, rash, jaundice, weight loss, loss of appetite, foreign travel or close animal contact.&#x0D; &#x0D; On examination, Pallor was present, Blood Pressure was 120/70 mm Hg, pulse rate was 102/min and temperature was 100 F. On per abdomen, mild hepatomegaly was present and other system examination was unremarkable.&#x0D; &#x0D; Routine laboratory findings on day of presentation have been summarised (Table 1.1). Ultrasound Abdomen revealed hepatomegaly and Chest X-ray showed signs of old infective foci. Peripheral smear for Malarial parasite, Ns1Ag and dengue serology, Widal test and Montoux test were negative. Blood cultures and urine cultures were sterile. X-Ray of joints were normal. USG of B/L Knee joints showed mild joint effusion bilaterally with no internal echoes (non tappable). Trans-thoracic echo and Trans-esophageal echo were normal. CT chest, neck and abdomen showed old tubercular changes in lung. Tests for atypical bacterial infections which was normal (RK 39, Chickungunya, Brucella, Leptospirosis and Scrub typhus). Fever did not respond to Broad Spectrum Antibiotics, Antimalarials or Antitubercular therapy and patient continued to have persistent fever spikes.&#x0D; &#x0D; Autoimmune profile showed ANA and RA Factor negative but markers of inflammation were raised: CRP- 521, ESR -148, IL-6 – 84.0, Procalcitonin-6.9 and S.Ferritin &gt;2000. During the work up for Anemia, Microcytic hypochromic anemia was found with Elevated NAP SCORE-165. Incidentally, her triglycerides were found to be elevated (356) and a reduced fibrinogen. With these results, we planned for a bone marrow aspirate and biopsy which showed increased myeloid preponderance (32:1), increased histiocytes and evidence of hemophagocytosis.&#x0D; &#x0D; The 2004 diagnostic criteria of HLH was fulfilled. After ruling out almost all infectious and malignant causes of secondary HLH, we searched for a rheumatologic cause. Thus diagnosis of AOSD (after fulfilling Yamaguchi’s criteria) with MAS (a subset of 2’ HLH) was made. Patient had dramatic improvement after receiving steroids with her fever episodes and joint pains settling completely thereafter.&#x0D; &#x0D; &#x0D; Prompt recognition of life threatening complications like MAS which pose diagnostic difficulty due to overlapping features in a patient of AOSD, should be done at the earliest to improve patient prognosis and survival. Serum Ferritin levels can be considered a useful marker to assess the disease activity and to predict MAS occurrence in such patients.

The Spectrum of Still's Disease: A Comparative Analysis of Phenotypic Forms in a Cohort of 238 Patients.

Still's disease (SD) is a heterogeneous autoinflammatory disorder for which several phenotypes have been described. We conducted a retrospective study to re-evaluate the dichotomous view of the disease, to compare the juvenile and adult forms, and to look for prognostic factors. We collected data from ten French centers, seeking patients with a diagnosis of adult-onset SD (AOSD) or systemic juvenile idiopathic arthritis (sJIA). We identified 238 patients, 152 (64%) of whom had AOSD while 86 (36%) had sJIA. The median age at SD onset was 26.6 years. In patients with identifiable patterns, the course of SD was systemic in 159 patients (74%), chronic in 55 (26%). Sore throat and myalgia were more frequent in patients with AOSD. Abnormal liver tests, serum ferritin and C-reactive protein levels were higher in AOSD group. Fever and skin rash were predictive of complete remission or recovery and high lactate dehydrogenase level was a poor prognosis factor. Symptoms such as splenomegaly, skin rash, high polymorphonuclear neutrophils count and macrophage activation syndrome were predictive of a systemic phenotype. Overall, there were no major differences between sJIA and AOSD. Our results are consistent with the "biphasic" model of an autoinflammatory disease that can progress to chronic arthritis if not treated early.

Adult-onset Still's disease and fever of unknown origin in India.

Despite an essential differential diagnosis for fever of unknown origin (FUO) in young adults, adult-onset Still’s disease (AOSD) is infrequently considered and remained underdiagnosed in low-middle-income countries. The present study analyzed the clinical, serological, radiological, and pathological characteristics of AOSD presented as FUO in India. A hospital-based retrospective study of patients aged > 13 years admitted with FUO and later diagnosed with AOSD in Postgraduate Institute of Medical Education and Research, Chandigarh (India), was conducted between January 2014 and December 2020. Petersdorf and Beeson’s criteria were used to define FUO. The diagnosis of AOSD was made based on Yamaguchi’s criteria. Twenty-seven patients (median age 26 years, 14 females) were enrolled. All presented with intermittent fever with a median duration of 10 weeks. The typical features of AOSD at admission were arthralgia (n = 24), hepatosplenomegaly (n = 21), spiking fever ≥ 39 °C (n = 19), lymphadenopathy (n = 18), typical rash (n = 17), and sore throat (n = 11). Leukocytosis (n = 25) and neutrophilia (n = 19) were frequent. Hyperferritinemia was universal (range, 700–145,003 ng/ml; ≥ 2000, n = 23). At admission, AOSD was suspected in only nine FUO cases, while tuberculosis (n = 16), undifferentiated connective tissue disorder (n = 14), and lymphoproliferative disorder (n = 11) were common diagnostic possibilities. Crispin et al. clinical scale detected AOSD in only 15 (55.5%) FUO patients. Whole-body imaging (n = 27), including fluorodeoxyglucose positron emission tomography (n = 12), demonstrated reticuloendothelial organ-system involvement and serositis. Seventeen (63%) patients had macrophage activation syndrome at the time of AOSD diagnosis. AOSD FUO presents with typical but nonspecific features; thus, early differentiation from common causes (e.g., tuberculosis, lymphoma) is difficult. Macrophage activation syndrome is common in AOSD with FUO presentation.

P19 A case of pyrexia of unknown origin - wrong way round!

P19 A case of pyrexia of unknown origin - wrong way round!

Diagnostic utility of clinical characteristics, laboratory tests, and serum ferritin in diagnosis of adult-onset Still disease.

The diagnosis of adult-onset Still disease (AOSD) is challenging with ambiguous clinical presentation and no specific serological markers. We aim to evaluate the diagnostic utility of clinical, laboratory and serum ferritin features in established AOSD patients. We included all patients >18 years who were admitted to 2 tertiary medical centers (2003–2019) with serum ferritin above 1000 ng/mL. AOSD patients and non-AOSD controls were matched in 1:4 ratio for age and sex. The primary outcomes were sensitivity, specificity, positive/negative likelihood ratio and area under the curve (AUC) using clinical and laboratory characteristics based on the Yamaguchi classification criteria, in addition to serum ferritin. We identified 2658 patients with serum ferritin above 1000 ng/m, of whom 36 diagnosed with AOSD and 144 non-AOSD matched controls. Presence of arthralgia/arthritis showed the highest sensitivity (0.74), specificity (0.93), positive likelihood ratio (10.69), negative likelihood ratio (0.27) and AUC (0.83, 95% confidence interval 0.74–0.92) to the diagnosis of AOSD. On the other hand, serum ferritin showed variation and poorer results, depends on the chosen ferritin cutoff. Joint involvement showed the best diagnostic utility to establish the diagnosis of AOSD. Although clinicians use often elevated ferritin levels as an anchor to AOSD, the final diagnosis should be based on thorough clinical evaluation.

Evaluation of Glycosylated Ferritin in Adult-Onset Still's Disease and Differential Diagnoses.

Glycosylated ferritin (GF) has been reported as a good diagnostic biomarker for adult-onset Still’s disease (AOSD), but only a few studies have validated its performance. We performed a retrospective study of all adult patients with at least one GF measurement over a 2-year period in one hospital laboratory. The diagnosis of AOSD was based on the expert opinion of the treating physician and validated by two independent investigators. Patients’ characteristics, disease activity, and outcome were recorded and compared. Twenty-eight AOSD and 203 controls were identified. Compared to controls, the mean GF was significantly lower (22.3% vs. 39.3, p < 0.001) in AOSD patients. GF had a high diagnostic accuracy for AOSD, independent of disease activity or total serum ferritin (AUC: 0.674 to 0.915). The GF optimal cut-off value for AOSD diagnosis was 16%, yielding a specificity of 89% and a sensitivity of 63%. We propose a modified diagnostic score for AOSD, based on Fautrel’s criteria but with a GF threshold of 16% that provides greater specificity and increases the positive predictive value by nearly 5 points. GF is useful for ruling out differential diagnoses and as an appropriate classification criterion for use in AOSD clinical trials.

Adult-onset Still's disease: A disease at the crossroad of innate immunity and autoimmunity.

Adult-onset Still’s disease (AOSD) is a rare disease affecting multiple systems and organs with unknown etiology, and the clinical symptoms are usually described as spiking fever, arthritis, evanescent salmon-pink eruptions, lymphadenopathy, splenomegaly, and other manifestations. The laboratory indicators are not specific, often presenting as increased leukocyte counts and neutrophil percentage, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), hyperferritinemia, and increased inflammatory factors. ANA, ENA, and RF are negative. According to those unspecific clinical presentations and laboratory findings, infection, tumor, connective tissue disease, and other diseases must be ruled out before diagnosis. The diagnosis of AOSD is a great challenge for clinicians. The mechanism of AOSD pathogenesis is complicated and still being studied. There is a new opinion that atypical persistent skin eruptions (APSEs) with specific histological manifestations are unique for AOSD, and APSEs might be on a spectrum with classical evanescent eruptions. Studies on APSEs showed that IL-1β and IFN-γ are strongly correlated with the pathogenesis of necrosis keratinocytes in APSEs. IL-1β is strongly involved in inflammatory disease when it is abnormal, and plays an important role in the pathogenesis of neutrophil dermatosis. In the early stage of AOSD, skin lesions appear to be evanescent urticaria-like eruptions accompanied by fever, and only neutrophils infiltrate around the blood vessels in the dermis pathologically. As the course of the disease progresses, IL-1β is gradually released. Through the stimulation of other inflammatory factors and the influence of unknown factors, IL-1β gradually infiltrates into the stratum corneum and finally accumulates around the necrotic keratinocytes of the stratum corneum. However, the detailed mechanism is still unknown. IFN-γ could play a pro-inflammatory or regulatory role in some disorders. IL-1β can enhance the expression of IFN-γ, and IFN-γ can cause keratinocyte apoptosis by activating the autocrine of caspase. Also, several pieces of evidence indicate that adaptive immunity is also involved in the pathogenesis of AOSD. Increased α-soluble receptors of IL-2 may suggest T-cell activation and proliferation in AOSD patients. Increased IL-4- and IFN-γ-producing T cells were found in active AOSD and related to disease severity. Frequencies of Treg cells in AOSD were significantly lower and were inversely correlated with disease severity. According to these, more and more researchers have reached a consensus that AOSD is a disease at the crossroads of innate immunity and autoimmunity. In this review, we will provide a comprehensive insight into AOSD, describing research progress and the immunological mechanism contribution to the disease. In the meantime, different treatment options and the efficacy and safety of various biologic agents are also discussed. A further understanding of AOSD requires closer cooperation among doctors from different departments, and this review will provide a new idea for diagnosis and therapeutic options.

Recommendations of diagnosis and treatment of adult-onset Still's disease in China

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder. In China, standardized diagnosis and treatment for AOSD is insufficient. Based on the evidence from China and other countries, Chinese Rheumatology Association developed standardization of diagnosis and treatment of AOSD in China. The purpose is to standardize the methods for diagnosis of AOSD, treatment strategies, and reduce misdiagnosis, missed diagnosis and irreversible damage.