Neutrophilic urticarial dermatosis preceding adult-onset Still's disease.

Neutrophilic urticarial dermatosis is a distinct entity strongly associated with underlying autoinflammatory disease. The pathogenesis of this condition has been considered to center around interleukin-1. We report a young woman with neutrophilic urticarial dermatosis who presented with a recurrent urticarial rash for two years prior to the onset of other systemic features including persistent fevers, sore throat, leukocytosis, elevated ferritin, and splenomegaly. She was ultimately diagnosed with adult-onset Still disease and responded well to treatment with systemic corticosteroids. Although neutrophilic urticarial dermatosis is known to occur in the setting of systemic symptoms and disease, its occurrence preceding the onset of systemic inflammation is less well-described in current literature.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1ß (IL-1ß) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1ß and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Still disease with persistent atypical dermatomyositis-like skin eruption: two cases associated with macrophage activation syndrome.

The typical rash of Still disease is an asymptomatic, salmon-coloured, macular, or maculopapular eruption that appears along with the fever spikes and fades when the body temperature drops. Although not included in the diagnostic criteria, there are other frequent, persistent, pruritic and polymorphic skin manifestations of Still disease that have distinctive clinical features and specific histological findings. Among these atypical persistent pruritic eruptions (PPEs), periorbital erythema and linear flagellate papules and plaques can resemble the cutaneous manifestations of dermatomyositis (DM). The presence of these lesions in adult-onset Still disease has been associated with worse prognosis and higher mortality rates, perhaps due to the development of a secondary macrophage activation syndrome (MAS). We report two cases of Still disease with persistent atypical DM-like eruption, one in a paediatric patient (a very underreported finding) and the other in an adult. Both cases developed a secondary MAS.

Persistent papules and plaques in systemic juvenile idiopathic arthritis.

A 6-year-old girl presented with nightly fever, persistent joint pain of the knees, ankles, lower back, and hip. Her skin lesions were evanescent salmon-colored patches along with persistent pruritic light to dark pink papules and plaques on her face, post-auricular scalp, trunk, thigh, and bilateral upper extremities. Skin biopsy supported the diagnosis of fixed papules and plaques of systemic juvenile idiopathic arthritis (sJIA). We report this case to highlight diagnostic features of this exceedingly rare cutaneous presentation of sJIA presenting with typical cutaneous salmon-colored evanescent eruptions.

Fever and flagellate dermatosis in an otherwise healthy woman.

We report a rare presentation of adult-onset Still disease (AoSD) with flagellate dermatosis and unknown trigger. Atypical skin findings have been increasingly reported for AoSD and may be associated with worse prognosis and systemic complications. Increased awareness of nonclassic skin findings in AoSD may lead to earlier diagnosis and treatment.

An Update on the Pathogenic Role of Neutrophils in Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease.

Neutrophils are innate immune phagocytes that play a key role in immune defense against invading pathogens. The main offensive mechanisms of neutrophils are the phagocytosis of pathogens, release of granules, and production of cytokines. The formation of neutrophil extracellular traps (NETs) has been described as a novel defense mechanism in the literature. NETs are a network of fibers assembled from chromatin deoxyribonucleic acid, histones, and neutrophil granule proteins that have the ability to kill pathogens, while they can also cause toxic effects in hosts. Activated neutrophils with NET formation stimulate autoimmune responses related to a wide range of inflammatory autoimmune diseases by exposing autoantigens in susceptible individuals. The association between increased NET formation and autoimmunity was first reported in antineutrophil cytoplasmic antibody-related vasculitis, and the role of NETs in various diseases, including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, has since been elucidated in research. Herein, we discuss the mechanistic role of neutrophils, including NETs, in the pathogenesis of systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still's disease (AOSD), and provide their clinical values as biomarkers for monitoring and prognosis.

Adult-Onset Still's Disease: Novel Biomarkers of Specific Subsets, Disease Activity, and Relapsing Forms.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17-32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.

Adult-onset Still's disease with multiple lymphadenopathy: a case report and literature review.

BACKGROUND: Adult-onset Still's disease (AOSD) often presents with systemic multiple lymphadenopathy. In addition to the common paracortical and mixed patterns in AOSD lymph node histopathological features, other morphological patterns include diffuse, necrotic, and follicular patterns. However, to date, there have been few reports on the histopathological description of AOSD lymph nodes. CASE PRESENTATION: An 18-year-old woman presented 2 months earlier with pain in her large joints with painless rash formation; bilateral posterior cervical lymph node, left supraclavicular lymph node, and left posterior axillary lymph node enlargement, and no tenderness. Left cervical lymph node resection was performed for pathological examination. The lymph node structure was basically preserved, and subcapsular and medullary sinus structures were observed. Many histiocytes in the sinus were observed, the cortical area was reduced, a few lymphoid follicles of different sizes were observed, and some atrophy and hyperplasia were noted. The lymphoid tissue in the paracortical region of the lymph node was diffusely proliferative and enlarged, mainly comprising histiocytes with abundant cytoplasm, immunoblasts and numerous lymphocytes with slightly irregular, small- to medium-sized nuclei. Nuclear karyorrhexis was easily observed, showing a few nuclear debris and the "starry sky" phenomenon, accompanied by abundantly branching high endothelial small vessels with few scattered plasma cells and eosinophil infiltration. Lymphoid follicle immunophenotype with reactive proliferative changes was observed. Approximately 40% of the cells in the paracortical region were positive for Ki-67, and the histiocytes expressed CD68, CD163, and some expressed S-100, with the absence of myeloperoxidase. The immunoblasts expressed CD30 and CD20, not ALK or CD15. Background small- to medium-sized T cells expressed CD2, CD3, CD5, CD7, CD4, and CD8; the number of CD8-positive T cells was slightly predominant, and a small number of T cells expressed granzyme B and T-cell intracellular antigen 1. The patient received a comprehensive medical treatment after the operation, and her condition was stable without progression at the 11-month follow-up evaluation. CONCLUSIONS: The pathological features of AOSD lymphadenopathy raises the awareness of AOSD among pathologists and clinicians and aids in the diagnosis and differential diagnosis of AOSD lymphadenopathy from other reactive lymphadenopathies (lupus lymphadenitis, etc.) and lymphomas.

Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still's disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in AOSD. METHODS: Serum samples were obtained from 44 patients with active AOSD or 50 patients with rheumatoid arthritis (RA), 20 patients with systemic lupus erythematosus (SLE), and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay. Results were compared among AOSD patients, RA patients, SLE patients and HCs. Results were also analyzed according to the clinical features of AOSD. RESULTS: Serum CIRP levels were significantly higher in AOSD patients compared with RA patients (median: 9.6 ng/mL, IQR [5.7-14.4] versus 3.2 ng/mL, IQR [1.9-3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4-4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and AOSD disease activity score (Pouchot's score r = 0.45, p = 0.003) as well as between AOSD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among AOSD patients with three different disease phenotypes. CONCLUSIONS: These results suggest that CIRP may play a significant role in the pathophysiology of AOSD and could be a potential biomarker for monitoring the disease activity of AOSD.

The Association of ATG16L1 Variations with Clinical Phenotypes of Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease, which has elevated autophagosome levels regulated by autophagy-related gene (ATG) expression. We investigated the associations of ATG polymorphisms with AOSD susceptibility, clinical manifestations, and disease course. The six-candidate single-nucleotide polymorphisms (SNPs) involved in autophagy were genotyped using direct sequencing on samples from 129 AOSD patients and 129 healthy participants. The differentially expressed gene products were quantified using PCR and ELISA. Significant linkage disequilibrium was noted in three SNPs of autophagy-related 16-like 1 (ATG16L1) gene (rs10210302, rs2241880, and rs1045100). Although the AA/CC/TT haplotype of ATG16L1 was not associated with the susceptibility of our AOSD patients compared with other haplotypes, those carrying this haplotype had lower mRNA expression levels of LC3-II, reflecting by autophagosome formation (p = 0.026). Patients carrying AA/CC/TT haplotype also have a significantly higher proportion of skin rash and a lower proportion of arthritis compared with other haplotypes. The AA/CC/TT haplotype was significantly associated with systemic pattern (odds ratio, 3.25; 95% confidence interval, 1.15-9.14; p = 0.026). In summary, the AA/CC/TT haplotype encoded lower levels of autophagosome formation and was associated with a higher proportion of skin rash and systemic pattern of AOSD compared with other haplotypes.

The joint involvement in adult onset Still's disease is characterised by a peculiar magnetic resonance imaging and a specific transcriptomic profile.

Adult onset Still's disease (AOSD) is a rare systemic autoinflammatory disease, characterised by fever, arthritis, and skin rash, and joint involvement is one of its clinical manifestations. The aims of this work were to assess joint involvement, to describe main patterns of involvement, and associated clinical characteristics. In this work, we aimed at assessing the joint involvement in AOSD by using MRI, to describe main patterns and associated clinical characteristics. In addition, we aimed at assessing the global transcriptomic profile of synovial tissues in AOSD to elucidate possible pathogenic pathways involved. We also evaluated the global transcriptomic profile of synovial tissues to elucidate possible pathogenic pathways involved in the disease. Thus, AOSD patients, who underwent to MRI exam on joints, were assessed to describe patterns of joint involvement and associated clinical characteristics. Some synovial tissues were collected for RNA-sequencing purposes. The most common MRI finding was the presence of synovitis on 60.5%, mainly in peripheral affected joints, with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. Bone oedema and MRI-bone erosions were reported on 34.9% and 25.6% MRI exams, respectively. Patients with MRI-bone erosions showed a higher prevalence of splenomegaly, a more frequent chronic disease course, lower levels of erythrocyte sedimentation rate, and ferritin. In AOSD synovial tissues, a hyper-expression of interleukin (IL)-1, IL-6, and TNF pathways was shown together with ferritin genes. In conclusion, in AOSD patients, the most common MRI-finding was the presence of synovitis, characterised by intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. MRI-bone erosions and bone oedema were also observed. In AOSD synovial tissues, IL-1, IL-6, and TNF pathways together with ferritin genes resulted to be hyper-expressed.

An Unusual Presentation of Adult-Onset Still's Disease in a Patient with Recurrent Pleural and Pericardial Effusions.

Adult-Onset Still's Disease (AOSD) usually presents with a salmon-colored skin rash and arthralgias. However, it can also be present with pleural and pericardial effusions. These effusions are often misdiagnosed as having an infectious etiology because AOSD usually present with fever, leukocytosis, elevated inflammatory markers, procalcitonin and CRP. There is usually a delay in giving steroids until the exclusion of all infectious etiologies, including extensive workups. Herein, we present a case report of AOSD in a patient with recurrent pleural and pericardial effusions, with no skin rashes or joint pain. Patient initially presented with fever, pleural and pericardial effusions, which was then treated as pneumonia with parapneumonic effusions. Patient returned for the second time with shortness of breath, productive cough, and fever, with no resolutions of pleural and pericardial effusions. Patient was found to have an extremely high ferritin levels, whereby a diagnosis of AOSD was made after excluding infection, malignancy and other rheumatological disorders based on the Yamaguchi criteria. AOSD is a rare disease with unusual presentation and diagnosis is often delayed. This case aimed to raise awareness among physicians of the multifaceted presentation of AOSD.

Characteristics and risk factors of relapses in patients with adult-onset Still's disease: a long-term cohort study.

OBJECTIVES: To describe the detailed characteristics and explore the potential risk factors of relapses in patients with adult-onset Still's disease (AOSD). METHODS: We enrolled patients with AOSD admitted to the Department of Rheumatology and Immunology, Ruijin Hospital from August 2016 to September 2019. Kaplan-Meier curves and the log rank test were used to estimate the cumulative relapse probability and persistent remission rate before the first occurrence of relapse. The multivariate Cox proportional hazard method was utilized to identify risk factors associated with relapses of AOSD. RESULTS: A total of 122 patients with AOSD were enrolled with a median follow-up of 12.6 months. Among them, 26 (21.3%) patients had at least one relapse. The cumulative relapse rates of AOSD patients were 14.42%, 21.79%, 24.81% and 28.57% at 6, 12, 18 and 36 months, respectively. According to the multivariate analysis, intensive treatment (odds ratio: 6.848; 95% CI: 2.441, 19.211) and macrophage activation syndrome (odds ratio: 4.020, 95% CI: 1.564, 10.322) were associated with increased risk of relapse. CONCLUSION: Our study indicated that relapses occurred in at least one-fifth of patients with AOSD, and patients with high disease severity at initial attack may have an increased risk of relapse, which needs more intensive therapy and close follow-up.

Dissecting the clinical heterogeneity of adult-onset Still's disease: results from a multi-dimensional characterization and stratification.

OBJECTIVES: To stratify adult-onset Still's disease (AOSD) patients in distinct clinical subsets to be differently managed, by using a multi-dimensional characterization. METHODS: AOSD patients were evaluated by using a hierarchical unsupervised cluster analysis comprising age, laboratory markers systemic score and outcomes. The squared Euclidean distances between each pair of patients were calculated and put into a distance matrix, which served as the input clustering algorithm. Derived clusters were descriptively analysed for any possible difference. RESULTS: Four AOSD patients clusters were identified. Disease onset in cluster 1 was characterized by fever (100%), skin rash (92%) and arthritis (83%), with the highest ferritin levels [mean (S.D.) 14 724 (6837) ng/ml]. In cluster 2, the onset was characterized by fever (100%), arthritis (100%) and liver involvement (90%), together with the highest CRP levels [288.10 (46.01) mg/l]. The patients in cluster 3 presented with fever (100%), myalgia (96%) and sore throat (92%). The highest systemic score values [8.88 (1.70)] and the highest mortality rate (54.2%) defined cluster 3. Fever (100%) and arthritis (90%) were the symptoms at the onset in cluster 4, which was characterized by the lowest ferritin and CRP levels [1457 (1298) ng/ml and 54.98 (48.67) mg/l, respectively]. CONCLUSION: Four distinct phenotypic subgroups in AOSD could be suggested, possibly associated with different genetic background and pathogenic mechanisms. Our results could provide the basis for a precision medicine approach in AOSD in an attempt to find a clinical and laboratory multidimensional stratification and characterization, which would drive a tailored therapeutic approach in these patients.

Clinical features of elderly-onset Adult-onset Still's disease.

OBJECTIVES: To clarify the characteristics of patients with elderly-onset Adult-onset Still's disease (AOSD). METHODS: Patients were classified into elderly-onset (>60 years: 47 patients) and younger-onset (≤60 years: 95 patients) groups according to their age at diagnosis of AOSD. Clinical features, treatments, and prognosis were compared between the elderly-onset and younger-onset groups. RESULTS: In the elderly-onset group, compared with the younger-onset group, typical skin rashes were less frequent (21.3% vs 58.9%, respectively; p < .0001), whereas pleuritis (27.7% vs 7.4%, respectively; p = .0011) and disseminated intravascular coagulation (19.1% vs 2.1%, respectively; p = .0004) were more frequent, and serum ferritin levels were higher (median 12,700 ng/ml vs 2526 ng/ml, respectively; p < .0001). Overall survival and AOSD-related survival were reduced (p = .0006 and p = .0023, respectively) and drug-free remission was less frequent (p = .0035) in the elderly-onset group compared with the younger-onset group. CONCLUSIONS: Our results demonstrated that elderly-onset AOSD patients had several characteristics that differed from younger-onset AOSD patients, including less typical skin lesions, more AOSD-related complications, higher ferritin levels, and poorer prognoses.

Neutrophil-derived lipocalin-2 in adult-onset Still's disease: a novel biomarker of disease activity and liver damage.

OBJECTIVE: Liver damage is a common manifestation and can be life-threatening in adult-onset Still's disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD. METHODS: Transcriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed. RESULTS: LCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694. CONCLUSION: Our results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.

The Role of RIPK1/3 in Adult Onset Still's Disease Patients With Liver Damage: A Preliminary Study.

Objective: This study aimed to investigate the distributions of lymphocytes in adult onset Still's disease (AOSD) with liver dysfunction, and further prospectively explore whether receptor interacting serine/threonine kinases (RIPKs) in lymphocytes play a role in the pathogenesis of AOSD especially liver involvement. Methods: Seventy-two AOSD patients and 19 cases of healthy controls (HCs) were retrospectively reviewed, the AOSD group was then divided into liver damage (LD) group and non-liver damage (NLD) group, and the distributions of lymphocytes in peripheral blood were analyzed. Another independent 24 AOSD patients and 20 HCs were recruited for prospective study of RIPKs; the RIPKs in peripheral blood lymphocytes were detected by flow cytometry. Liver biopsy specimens were obtained from two AOSD patients and underwent immunochemistry analysis with RIPK1 and RIPK3 antibody. Results: In the retrospective study, AOSD showed significantly abnormal lymphocytes distributions, and disease activity was positively correlated with percentage of CD3+ T cells. LD patients were younger in age and showed higher disease activity score than NLD patients; they had higher frequencies of CD3+ T cells, especially higher CD8+ T cells (all p<0.05). In the prospective study, RIPKs in lymphocytes were significantly higher in AOSD patients than that of HCs, and LD patients also showed higher RIPKs expression than NLD patients. In addition, RIPKs were positively correlated with erythrocyte sedimentation rate (ESR) and disease activity in AOSD patients and LD and NLD subgroups (all p<0.05). Further, RIPKs expression was confirmed in two AOSD patients' liver. ROC curve analysis indicated that RIPKs in lymphocytes (%) could be potential biomarkers in the diagnosis of AOSD and liver damage. Conclusions: Abnormal lymphocytes distributions and RIPKs expression were detected in AOSD. Aberrant expression of RIPKs in lymphocytes might be involved in the pathogenesis of AOSD. RIPKs could be candidate markers for AOSD and liver damage.

Case Report: Adult Still's Disease in an Alemtuzumab-Treated Multiple Sclerosis Patient.

Background: Autoimmune adverse events are the most relevant risks of alemtuzumab therapy. We present a patient with relapsing-remitting multiple sclerosis, who developed adult-onset Still's disease (AOSD) following alemtuzumab treatment. Case Presentation: The patient suffered from sore throat, swallowing difficulties, high spiking quotidian fever, generalized skin rash, arthritis, and myalgia 2 months after the second course of alemtuzumab. Laboratory tests revealed elevated acute-phase reactants, anemia, neutrophilic leukocytosis, and thrombocytosis. Serum calprotectin, interleukin-2, and interleukin-6 levels were strongly increased. Autoimmune, rheumatic, neoplastic, infectious, and granulomatous disorders were excluded. The NLRP1 and NLRP3 gene test, which was performed under the presumption of a cryopyrin-associated autoinflammatory syndrome, was negative. Based on the Yamaguchi and Fautrel criteria, and supported by the histological findings from a skin biopsy of the rash, the diagnosis of AOSD was established. Therapy with the anti-IL-1 agent (anakinra) led to a significant improvement of symptoms and blood parameters. However, anakinra had to be converted to rituximab due to generalized drug eruption. Following therapy with rituximab, the patient has fully recovered. Conclusion: The current case highlights AOSD as another rare and potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment.

[Adult onset Still's disease and lymphoma: a rare association]. / Maladie de Still de l'adulte et lymphome: une association rare.

Adult onset Still's disease (AOSD) and lymphomas are diseases characterized by very similar clinical and histopathological manifestations. The association between these diseases has rarely been reported in the literature. We here report the case of a 26-year old patient diagnosed with adult onset Still's disease. She had been previously treated for large B-cell Non-Hodgkin lymphoma (LBCNHL) with chemotherapy and haemopoietic stem-cell autograft with complete remission. The association between AOSD and lymphoma is rare and in all cases AOSD has been diagnosed before lymphoma. The peculiarity of this study lies in the succession LBCNHL- AOSD and raises several hypotheses on the association between these two diseases. The association between non-autoimmune diseases and lymphoid hemopathies have been widely demonstrated, whether it is the progression of autoimmune diseases vs lymphoma or non-autoimmune disease manifestations occurring in patients with this disease. This study highlights the difficult distinction between these diseases.