Tocilizumab for treating mevalonate kinase deficiency and TNF receptor-associated periodic syndrome: a case series and literature review.

BACKGROUND: Mevalonate kinase deficiency (MKD) and TNF receptor-associated periodic syndrome (TRAPS) are categorized as systemic autoinflammatory diseases (SAIDs), which are rare diseases characterized by early onset, severe conditions, and challenging diagnosis and treatment. Although different SAIDs have varying standard treatments, some SAIDs are poorly controlled after routine treatment, seriously affecting the growth and development of children and their quality of life. This study aims to provide more treatment strategies for SAIDs. CASE PRESENTATION: We present two Chinese patients with MKD and TRAPS who were resistant to TNF- (tumor necrosis factor-) α blockade. After using etanercept, baricitinib, and glucocorticoid, patients with MKD and TRAPS still had periodic fever and rash. Due to the unavailability of IL-1 antagonists in the Chinese Mainland, we started administering intravenous tocilizumab (TCZ) at a dosage of 240 mg every three weeks. They had not experienced fever or rash after receiving one or two doses of TCZ. Before treatment with TCZ in the MKD patient, white blood cell (WBC) count, and TNF-α level were normal, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) increased significantly, and IL-6 increased slightly. After treatment with TCZ, ESR and CRP levels returned to normal; however, IL-6 increased occasionally. In the TRAPS patient, ESR, CRP, WBC, IL-6, and TNF-α levels were increased significantly. After TCZ treatment, ESR, CRP, WBC, IL-6, and TNF-α levels returned to normal. The two patients were treated with TCZ for more than six months and achieved clinical and serological remission. Furthermore, they had no adverse reactions after injection of TCZ. CONCLUSION: In the absence of IL-1 antagonists in mainland China, tocilizumab emerges as an alternative drug in SAIDs that are resistant to TNF-α blockade.

Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death.

Infections like COVID-19 are the primary cause of death around the world because they can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis. Inflammatory cells serve as crucial protective barriers in these diseases. However, excessive accumulation of inflammatory cells is also one of the major causes of organ damage. The non-muscular myosin light chain kinase (nmMLCK) plays crucial of cytoskeletal components involved in endothelial cell-matrix and cell-cell adhesion, integrity, and permeability. Our previous investigations found that ML-7, a specific inhibitor of MLCK, promoted neutrophil apoptosis through various signaling pathways. In this study, we found that knockout of MLCK significantly promote apoptosis of neutrophils and macrophages in the BALF of the LPS-induced ALI, meanwhile it had no effect on the apoptosis of neutrophils in the circulatory system. RNA-sequencing revealed that the effect of MLCK knockout in inducing apoptosis of inflammatory cells was mediated through lysosomes. Administering ML-7 into the lungs significantly promoted neutrophil apoptosis, accelerating their clearance. In the LPS- or CLP-induced sepsis models, ML-7 administration significantly improves the apoptosis of inflammatory cells, especially neutrophils, at the infection site but had no impact on neutrophils in the circulatory system. ML-7 also significantly improved the survival rate of mice with LPS- or CLP-induced sepsis. Taken together, we found that MLCK plays a crucial role in the survival of inflammatory cells at the infection site. Inhibiting MLCK significantly induces apoptosis of inflammatory cells at the infection site, promoting inflammation resolution, with no impact of the circulatory system.

Expression, purification, and activity of novel allergen Tyr p 31 from Tyrophagus putrescentiae.

Allergen component products, such as recombinant proteins and epitope peptides of allergic components, are used as an adjunct to allergen-specific immunotherapy. We characterized a novel allergen, Tyr p 31, from Tyrophagus putrescentiae, a common allergenic mite. T. putrescentiae total RNA was amplified to Tyr p 31-encoding cDNA, which was inserted into pET28a(+). pET28a(+)-Tyr p 31 was then transformed into Rosetta 2 (DE3) pLysS cells and expressed under isopropyl ß-D-thiogalactoside induction. Next, we visualized Tyr p 31 through sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting based on its theoretical molecular weight. Recombinant Tyr p 31 (rTyr p 31) was purified, and its secondary structure was noted to comprise α-helices, antiparallel coils, ß-turns, parallel coils, and random coils. Our enzyme-linked immunosorbent assay and Western blotting results for T. putrescentiae-positive sera from children with allergic disorders demonstrated rTyr p 31-specific IgE-positivity rates of 72.41 % and 85.7 %, respectively. In BEAS-2B cells, rTyr p 31 increased IL-6 and IL-8 expression; furthermore, BEAS-2B cells treated with 30 µg/mL rTyr p 31 demonstrated 100 upregulated and 12 downregulated genes. In summary, we identified Tyr p 31, a novel T. putrescentiae allergen component, and noted rTyr p 31 to have a high IgE-binding rate and strong immunogenicity.

IL-10 and IFN-γ as markers for early recognition of pediatric systemic lupus erythematosus complicated with macrophage activation syndrome.

OBJECTIVES: To compare the clinical and laboratory characteristics of pediatric-onset systemic lupus erythematosus (pSLE), pSLE with macrophage activation syndrome (MAS), and pSLE with recurrent MAS, and to find biomarkers for the differential diagnosis of these diseases. METHODS: Demographic, clinical, laboratory and radiological data were analyzed for three groups of patients: 18 cases of pSLE with MAS, 48 age- and sex-matched cases of active pSLE without MAS and 40 age- and sex-matched cases of pSLE with inactive disease. One case of a 9-year-old girl with recurrent MAS as the primary manifestation of SLE also was recorded. RESULTS: IL-10 and IFN-γ levels were significantly higher in pSLE patients with MAS than in pSLE patients without MAS, and were significantly correlated with SLE and MAS laboratory features. Levels of IL-10 > 7.25 pg/ml had a high sensitivity and levels of IFN-γ > 6.7 pg/ml had a high specificity for predicting MAS in pSLE. Constitutional symptoms were evident in the case of recurrent MAS in pSLE, and traditional immunosuppressive therapies were unable to prevent the next MAS episode. CONCLUSION: Compared with pSLE and pSLE-MAS with a single episode, pSLE with recurrent MAS has different clinical manifestations and responses to treatment, requiring intensive studies to elucidate the underlying pathogenic mechanisms. Elevated serum levels of IL-10 and IFN-γ may be correlated with pSLE with MAS, and can serve as serum biomarkers for pSLE with MAS.

Clinical nomogram assisting in discrimination of juvenile dermatomyositis-associated interstitial lung disease.

OBJECTIVE: To establish a prediction model using non-invasive clinical features for early discrimination of DM-ILD in clinical practice. METHOD: Clinical data of pediatric patients with JDM were retrospectively analyzed using machine learning techniques. The early discrimination model for JDM-ILD was established within a patient cohort diagnosed with JDM at a children's hospital between June 2015 and October 2022. RESULTS: A total of 93 children were included in the study, with the cohort divided into a discovery cohort (n = 58) and a validation cohort (n = 35). Univariate and multivariate analyses identified factors associated with JDM-ILD, including higher ESR (OR, 3.58; 95% CI 1.21-11.19, P = 0.023), higher IL-10 levels (OR, 1.19; 95% CI, 1.02-1.41, P = 0.038), positivity for MDA-5 antibodies (OR, 5.47; 95% CI, 1.11-33.43, P = 0.045). A nomogram was developed for risk prediction, demonstrating favorable discrimination in both the discovery cohort (AUC, 0.736; 95% CI, 0.582-0.868) and the validation cohort (AUC, 0.792; 95% CI, 0.585-0.930). Higher nomogram scores were significantly associated with an elevated risk of disease progression in both the discovery cohort (P = 0.045) and the validation cohort (P = 0.017). CONCLUSION: The nomogram based on the ESIM predictive model provides valuable guidance for the clinical evaluation and long-term prognosis prediction of JDM-ILD.

Kaposiform hemangioendothelioma presented with raynaud phenomenon: a case report.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm affecting infants or young children. KHE includes a spectrum of lesions, ranging from small and superficial tumors to large and invasive lesions with Kasabach-Merritt phenomenon (KMP). Currently, no published studies have reported a KHE presenting as thrombocytopenia and Raynaud phenomenon. CASE PRESENTATION: A 2-year-old boy with right hand swelling and thrombocytopenia was admitted to our hospital. His right hand turned swelling and red, even occasionally cyanotic. This condition became worse in response to cool environments and improved with warming, and platelet counts were between 50 ~ 80 × 10^9/L. Physical examination on admission revealed the swelling and frostbite-like rash of the right-hand fingers, and the skin temperature of the right hand was lower than the left. On day 3 of admission, chest CT results showed an irregular mass on the right side of the spine. The puncture biopsy demonstrated positive CD31, D2-40, and FLI1 immunohistochemical staining, but negative GLUT1 staining, confirming the diagnosis of KHE. Furthermore, endothelin-1 (ET1) expression levels significantly increased, and eNOS and A20 expression levels significantly decreased comparing with control patients. The patient received methylprednisolone and sirolimus treatments, and his condition gradually improved during the follow-up. CONCLUSIONS: We reported the first case of KHE presenting with thrombocytopenia and Raynaud phenomenon. The development of Raynaud phenomenon could be associated with increased ET-1 and reduced eNOS and A20 expressions. Careful differential diagnosis of hidden KHE should be considered in children with thrombocytopenia and Raynaud phenomenon.

Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy.

BACKGROUND: Gain-of-function mutations in STING1 (also known as TMEM173) which result in constitutive activation of STING, have been reported to cause STING-associated vasculopathy with onset in infancy (SAVI). Although a wider spectrum of associated manifestations and perturbations in disease onset have been observed since its description, the genotype-phenotype correlations are not definite, and there is no established treatment protocol for SAVI. CASE PRESENTATION: Herein, we report a kindred, heterozygous STING mutation (p.V155M) in which the 2-year-old proband suffered from severe interstitial lung disease (ILD) while her father was initially misdiagnosed with connective tissue disease associated with ILD at an adult age. Baricitinib was initiated after the diagnosis of SAVI in the proband combined with steroids, and during the 14-month follow-up, the respiratory symptoms were improved. However, as the improvement of laboratory indicators was limited, especially in autoimmune indices, and the lung CT images remained unaltered, it seems that JAK1/2 inhibition was unsatisfactory in completely controlling the inflammation of the disease in our study. CONCLUSIONS: Baricitinib was shown to elicit some effect on the ILD but failed to control the inflammation of the disease completely. Further exploration of JAK inhibitors or other therapeutic strategies are needed to more optimally treat this inflammatory disease.

Janus kinase inhibitor, tofacitinib, in refractory juvenile dermatomyositis: a retrospective multi-central study in China.

OBJECTIVES: Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients. METHODS: A total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann-Whitney U test, and chi-square test. RESULTS: Compared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis. CONCLUSION: In this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Performance of interferon-gamma levels may lead to earlier diagnosing macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of rheumatic diseases, predominantly in systemic juvenile idiopathic arthritis (SJIA), and is considered as an autoinflammatory disease. Specific cytokine profiles could play a pivotal role in this inflammatory response. Gram-negative bacteremia, bacterial pneumonia, Kawasaki disease, and active SJIA exhibited similar cytokine profiles with elevated interleukin-6 (IL-6) and/or IL-10, further suggesting a correlation between them. Only when JIA is complicated by MAS can increased interferon-γ (IFN-γ) levels be observed. Therefore, increased serum IFN-γ levels could contribute to early diagnosing MAS in patients with SJIA in combination with other variables such as serum ferritin. A prospective multi-center study will be performed to further confirm the role of IFN-γ in the early recognition of MAS in SJIA.

Combination of omalizumab with allergen immunotherapy versus immunotherapy alone for allergic diseases: A meta-analysis of randomized controlled trials.

BACKGROUND: Allergen immunotherapy (AIT)-associated adverse events (AEs) limit its usage in the management of allergic diseases. The monoclonal anti-IgE antibody (omalizumab) and AIT have complementary actions. However, no consensus has been reached on whether their combination could exert superior efficacy and safety. OBJECTIVE: To evaluate whether the combination of AIT with omalizumab is superior to AIT alone in treating allergic diseases. METHODS: The MEDLINE/PubMed, Embase, Scopus and Cochrane Library databases were searched to identify randomized control trials (RCTs) reporting the outcomes of omalizumab combined with AIT (omalizumab + AIT) versus AIT alone. A random-effect model was established to estimate outcomes with a 95% confidence interval (CI). RESULTS: A total of 11 eligible RCTs (involving 901 patients) were screened out for the meta-analysis. According to a pooled analysis, omalizumab + AIT significantly increased the number of patients achieving the target maintenance dose (TMD) and sustained unresponsiveness (SU) to allergens (odds ratio [OR] = 2.43; 95% CI: 1.33-4.44; p = 0.004; I2  = 35%, and OR = 6.77; 95% CI: 2.10-21.80; p = 0.001; I2  = 36%, respectively). Similarly, individuals receiving the combination therapy reported significantly fewer episodes of severe systemic AEs than AIT alone (OR = 0.32; 95% CI: 0.18-0.59; p = 0.0003; I2  = 0%). Meanwhile, the improvements in symptom severity score (mean difference [MD] = -0.26), rescue medication daily means score (MD = -0.14), and number of patients consuming epinephrine in AIT (OR = 0.20) were all more evident than those in AIT alone. CONCLUSION: Omalizumab + AIT can significantly enhance the efficacy and safety of AIT by increasing TMD and SU to allergens, while decreasing severe systemic AEs.

Type I interferon signature and cycling lymphocytes in macrophage activation syndrome.

BACKGROUNDMacrophage activation syndrome (MAS) is a life-threatening complication of Still's disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS.METHODWe profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies.RESULTSBulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell, and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 - both elevated in MAS patients - synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response.CONCLUSIONMAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.

Evaluation of genetic variants in ferroptosis-related genes and house dust mite-induced allergic rhinitis risk.

BACKGROUND: Ferroptosis-related genes disrupt iron homeostasis and enhance lipid peroxidation to initiate respiratory system diseases. However, the association between genetic variants in the ferroptosis-related genes with house dust mite (HDM)-induced allergic rhinitis (AR) susceptibility remains unclear. METHODS: A case-control study, involving 222 cases and 237 healthy controls from a Chinese population, was conducted to evaluate the relationship between single nucleotide polymorphisms (SNPs) in ferroptosis-related genes and HDM-induced AR risk. A gene-based analysis was performed by multi-marker analysis of genomic annotation (MAGMA) to identify candidate associated ferroptosis-related genes. A logistic regression model and joint analysis were used to assess the effect of SNPs on HDM-induced AR susceptibility. RESULTS: Two independent SNPs (rs2305128 in ENPP2 and rs1868088 in EPAS1) were significantly associated with HDM-induced AR risk (OR = 1.82, 95% CI = 1.19-2.79, P = 5.98 × 10-3, PFDR = 4.88 × 10-2; OR = 2.14, 95% CI = 1.23-3.72, P = 6.95 × 10-3, PFDR = 4.87 × 10-2, respectively). Moreover, combined analysis of these two SNPs revealed that an increased risk of HDM-induced AR was positively associated with an increasing number of risk genotypes (Ptrend = 8.48 × 10-5). The stratification analysis showed that the cumulative effect of two SNPs on HDM-induced AR risk was more pronounced among patients presenting more serious symptoms and harboring one or two risk genotypes. CONCLUSIONS: These findings suggest that the genetic variants in ferroptosis-related genes ENPP2 and EPAS1 may increase HDM-induced AR risk and serve as potential predictors of HDM-induced AR susceptibility.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

OBJECTIVE: The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE). METHODS: This multicentre, one arm pre-post intervention study was conducted at 15 centers in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6, and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage. RESULT: 193 (92.2% female) with active cSLE from 15 centers were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6, and 12 months. At baseline, all patients received steroids at a mean (SD) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved. CONCLUSION: This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

SUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways.

Allergic asthma is characterized by goblet cell metaplasia and subsequent mucus hypersecretion that contribute to the morbidity and mortality of this disease. Here, we explore the potential role and underlying mechanism of protein SUMOylation-mediated goblet cell metaplasia. The components of SUMOylaion machinery are specifically expressed in healthy human bronchial epithelia and robustly upregulated in bronchial epithelia of patients or mouse models with allergic asthma. Intratracheal suppression of SUMOylation by 2-D08 robustly attenuates not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Phosphoproteomics and biochemical analyses reveal SUMOylation on K1007 activates ROCK2, a master regulator of goblet cell metaplasia, by facilitating its binding to and activation by RhoA, and an E3 ligase PIAS1 is responsible for SUMOylation on K1007. As a result, knockdown of PIAS1 in bronchial epithelia inactivates ROCK2 to attenuate IL-13-induced goblet cell metaplasia, and bronchial epithelial knock-in of ROCK2(K1007R) consistently inactivates ROCK2 to alleviate not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Together, SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signaling in regulating the pathological conditions of asthma and thus SUMOylation is an additional target for the therapeutic intervention of this disease.

[Research progress and clinical application of allergen nasal provocation test].

The allergen nasal provocation testing（NPT）, in which allergens are applied directly to the nasal mucosa under standard and controlled conditions to provoke the main symptoms of allergic rhinitis（AR）, reproduces the response of the upper respiratory tract to natural exposure to allergens under controlled conditions and is the only test currently available to confirm nasal reactivity to allergens. It is invaluable in studying the mechanisms of AR and in assessing the response to novel anti-allergic treatments. The test may play an increasingly important role in clinical practice, especially in the identification of local AR, the diagnosis of occupational AR, the clarification of the composition of allergens, the assessment of the efficacy of AR treatment and the selection of candidates undergoing allergen immunotherapy. This article reviewed the application of NPT in the diagnosis of allergic and non-allergic rhinitis, and also introduces the indications, contraindications, advantages and limitations of NPT in evaluating nasal response.

Case report: Aggressive progression of acute heart failure due to juvenile tuberculosis-associated Takayasu arteritis with aortic stenosis and thrombosis.

Background: Takayasu arteritis (TA) is a chronic granulomatous vasculitis with unknown pathophysiology. TA with severe aortic obstruction has a poor prognosis. However, the efficacy of biologics and appropriate timing of surgical intervention remain controversial. We report a case of tuberculosis (TB)-associated TA with aggressive acute heart failure (AHF), pulmonary hypertension (PH), thrombosis, and seizure, who failed to survive after surgery. Case presentation: A 10-year-old boy who developed a cough with chest tightness, shortness of breath, hemoptysis with reduced left ventricular ejection fraction, PH, and increased C-reactive protein and erythrocyte sedimentation rate was hospitalized at the pediatric intensive care unit of our hospital. He had strongly positive purified protein derivative skin test and interferon-gamma release assay result. Computed tomography angiography (CTA) showed occlusion of proximal left subclavian artery and stenosis of descending aorta and upper abdominal aorta. His condition did not improve after administration of milrinone, diuretics, antihypertensive agents, and intravenous methylprednisolone pulse followed by oral prednisone. Intravenous tocilizumab was administered for five doses, followed by two doses of infliximab, but his HF worsened, and CTA on day 77 showed complete occlusion of the descending aorta with large thrombus. He had a seizure on day 99 with deterioration of renal function. Balloon angioplasty and catheter-directed thrombolysis were performed on day 127. Unfortunately, the child's heart function continued to deteriorate and died on day 133. Conclusion: TB infection may be related to juvenile TA. The biologics, thrombolysis, and surgical intervention failed to achieve the anticipated effect in our case with aggressive AHF due to severe aortic stenosis and thrombosis. More studies are needed to determine the role of biologics and surgery in such dire cases.

Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Texture analysis of diffusion kurtosis imaging for differentiating malignant from benign sinonasal lesions: added value to conventional imaging features.

OBJECTIVES: To evaluate the performance of texture analysis (TA) of diffusion kurtosis imaging (DKI) in differentiating malignant from benign sinonasal lesions, and its added value to the conventional imaging features. METHODS: Fifty-eight patients with malignant and 40 patients with benign sinonasal lesions were retrospectively enrolled. Conventional CT and MRI features were reviewed. Texture parameters were obtained and compared between two groups. Multivariate logistic regression analysis was used to identify the most valuable variables. Receiver operating characteristic curves were performed to assess the differentiating performance of independent variables and their combination. RESULTS: There were significant differences in tumor necrosis, bone erosion and soft tissue invasion between the two groups (all p < 0.05). There were significant differences in the 10th and entropy of Apparent diffusion coefficient map, the mean, 10th and entropy of D map, the mean and 90th of K map between the two groups (all p < 0.002). The bone erosion, entropy of D, and mean of K were independent variables associated with malignant tumors. Receiver operating characteristic analyses indicated that the combination of three features possessed better differentiating performance than bone erosion alone (p = 0.003). CONCLUSION: TA of DKI could supply incremental value to conventional imaging features for pre-operative differential diagnosis between benign and malignant sinonasal lesions. ADVANCES IN KNOWLEDGE: The present study is the first to combine conventional imaging features and the TA of DKI in the differential diagnosis between benign and malignant sinonasal lesions. Our findings suggest that TA of DKI could supply incremental value to conventional imaging features.