1.Trends in mortality rate and years of life lost due to premature deaths from colorectal cancer in Danyang City, Jiangsu Province, 2013‒2023
Jiahui HU ; Jiaye WANG ; Lili CHEN ; Tao JIANG
Shanghai Journal of Preventive Medicine 2025;37(5):416-420
ObjectivesTo analyze the trends in mortality and disease burden of colorectal cancer (CRC) among the registered residents in Danyang City, Jiangsu Province, from 2013 to 2023, and to provide a scientific basis for developing CRC prevention and control strategies. MethodsMortality surveillance data on CRC among the registered residents in Danyang City from 2013 to 2023 were collected and analyzed. Crude mortality rate (CMR), age-standardized mortality rate (ASMR), years of life lost (YLL) due to premature death, and YLL rate were calculated. The annual percentage change (APC) and average annual percent change (AAPC) of CMR, ASMR and YLL rate were calculated with Joinpoint Regression Program 4.9.0.1. ResultsA total of 1 920 deaths from colorectal cancer were recorded in Danyang City during 2013‒2023, with an average annual CMR of 21.75/100 000, which showed an upward trend (APC=6.47%, 95%CI: 4.21%‒8.79%, P<0.001), with higher CMR observed in males than that in females. The overall ASMR by Chinese standard population was 12.10/100 000, with no obvious temporal trends (APC=1.37%, P=0.364). ASMR increased with age, particularly after 45 years. The total YLL due to CRC was 34 711 person-years, with an average YLL rate of 3.93‰. The YLL rate showed a significant upward trend from 2013 to 2023 (APC=4.96%, 95%CI: 4.08%‒18.16%, P<0.001) in Danyang City. ConclusionThe mortality rate of colorectal cancer in Danyang City is relatively high and has shown a rising trend, resulting in an increasing disease burden on the residents year by year. Continued efforts to strengthen CRC prevention and control are needed, particularly targeting males and the elderly population.
2.Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report.
Yun GAO ; Fengjiao LI ; Rong LUO ; Guohui CHEN ; Danyang LI ; Dayong WANG ; Qiuju WANG
Journal of Clinical Otorhinolaryngology Head and Neck Surgery 2024;38(1):73-76
CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A(Glu818Lys) heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.
Humans
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Child
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Female
;
Cerebellar Ataxia/diagnosis*
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Talipes Cavus
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Hearing Loss, Sensorineural/diagnosis*
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Optic Atrophy/diagnosis*
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Mutation
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Phenotype
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Sodium-Potassium-Exchanging ATPase/genetics*
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Foot Deformities, Congenital
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Reflex, Abnormal
3.Herbal Textual Research on Olibanum in Famous Classical Formulas
Haiyan ZHOU ; Qingqing WANG ; Qi ZHANG ; Suping XIAO ; Meng CHEN ; Jianxin ZHOU ; Yeda ZHANG ; Danyang JIA ; Zhilai ZHAN
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(4):55-66
By consulting the ancient and moderm literature, this paper makes a textual research on the name, origin, quality evaluation, harvesting and processing of Olibanum, so as to provide a basis for the development of the famous classical formulas containing this medicinal material. According to the herbal textual research, the results showed that Olibanum was first described as a medicinal material by the name of Xunluxiang in Mingyi Bielu(《名医别录》), until Ruxiang had been used as the correct name since Bencao Shiyi(《本草拾遗》) in Tang dynasty. The main origin was Boswellia carterii from Burseraceae family. The mainly producing areas in ancient description were ancient India and Arabia, while the modern producing areas are Somalia, Ethiopia and the southern Arabian Peninsula. The medicinal part of Olibanum in ancient and modern times is the resin exuded from the bark, which has been mainly harvested in spring and summer. It is concluded that the better Olibanum has light yellow, granular, translucent, no impurities such as sand and bark, sticky powder and aromatic smell. There were many processing methods in ancient times, including cleansing(water flying, removing impurities), grinding(wine grinding, rush grinding), frying(stir-frying, rush frying, wine frying), degreasing, vinegar processing, decoction. In modern times, the main processing methods are simplified to cleansing, stir-frying and vinegar processing. Nowadays, the commonly used specifications include raw, fried and vinegar-processed products. Among the three specifications, raw products is the Olibanum after cleansing, fried products is a kind of Olibanum processed by frying method, vinegar-processed products is the processed products of pure frankincense mixed with vinegar. Based on the research results, it is recommended to select the resin exuded from the bark of B. carterii for the famous classical formulas such as Juanbitang containing Olibanum, processing method should be carried out in accordance with the processing requirements of the formulas, otherwise used the raw products if the formulas without clear processing requirements.
4.Therapeutic effect of transplantation of bone marrow mesenchymal stem cells co-cultured with bone marrow M2 macrophages on a rat model of liver cirrhosis
Xinrui ZHENG ; Yannan XU ; Danyang WANG ; Feifei XING ; Mengyao ZONG ; Shihao ZHANG ; Junyi ZHAN ; Wei LIU ; Gaofeng CHEN ; Jiamei CHEN ; Ping LIU ; Yongping MU
Journal of Clinical Hepatology 2024;40(1):96-103
ObjectiveTo investigate the effect of transplantation of bone marrow mesenchymal stem cells (BMSCs) co-cultured with bone marrow-derived M2 macrophages (M2-BMDMs), named as BMSCM2, on a rat model of liver cirrhosis induced by carbon tetrachloride (CCl4)/2-acetaminofluorene (2-AAF). MethodsRat BMDMs were isolated and polarized into M2 phenotype, and rat BMSCs were isolated and co-cultured with M2-BMDMs at the third generation to obtain BMSCM2. The rats were given subcutaneous injection of CCl4 for 6 weeks to establish a model of liver cirrhosis, and then they were randomly divided into model group (M group), BMSC group, and BMSCM2 group, with 6 rats in each group. A normal group (N group) with 6 rats was also established. Since week 7, the model rats were given 2-AAF by gavage in addition to the subcutaneous injection of CCl4. Samples were collected at the end of week 10 to observe liver function, liver histopathology, and hydroxyproline (Hyp) content in liver tissue, as well as changes in the markers for hepatic stellate cells, hepatic progenitor cells, cholangiocytes, and hepatocytes. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the N group, the M group had significant increases in the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P<0.01); compared with the M group, the BMSC and BMSCM2 groups had significant reductions in ALT and AST (P<0.01), and the BMSCM2 group had significantly better activities than the BMSC group (P<0.05). Compared with the N group, the M group had significant increases in Hyp content and the mRNA and protein expression levels of alpha-smooth muscle actin (α-SMA) in the liver (P<0.01); compared with the M group, the BMSC and BMSCM2 groups had significant reductions in Hyp content and the expression of α-SMA (P<0.05), and the BMSCM2 group had a significantly lower level of α-SMA than the BMSC group (P<0.01). Compared with the N group, the M group had significant increases in the mRNA expression levels of the hepatic progenitor cell markers EpCam and Sox9 and the cholangiocyte markers CK7 and CK19 (P<0.01) and significant reductions in the expression levels of the hepatocyte markers HNF-4α and Alb (P<0.01); compared with the M group, the BMSC and BMSCM2 groups had significant reductions in the mRNA expression levels of EpCam, Sox9, CK7, and CK19 (P<0.05) and significant increases in the mRNA expression levels of HNF-4α and Alb (P<0.05), and compared with the BMSC group, the BMSCM2 group had significant reductions in the mRNA expression levels of EpCam and CK19 (P<0.05) and significant increase in the expression level of HNF-4α (P<0.05). ConclusionM2-BMDMs can enhance the therapeutic effect of BMSCs on CCl4/2-AAF-induced liver cirrhosis in rats, which provides new ideas for further improving the therapeutic effect of BMSCs on liver cirrhosis.
5.Epidemiological characteristics of Chlamydia trachomatis infection in Hubei Province in 2008 - 2022
Danyang LI ; Huadao XIONG ; Xiong ZHOU ; Huizhen SUN ; Xue YANG ; Hui CHEN
Journal of Public Health and Preventive Medicine 2024;35(6):63-67
Objective To understand the epidemiological characteristics of Chlamydia trachomatis infection in Hubei province, and to provide scientific basis for prevention and control. Methods The data of Chlamydia trachomatis infection cases reported through the China Information System for Disease Control and Prevention from 2008 to 2022 were collected for epidemiological statistical analysis. Results The incidence of Chlamydia trachomatis infection in Hubei Province showed an increasing trend from 2008 to 2022, with an average annual reported incidence of 2.26/100 000. The top three reported incidence areas were Shiyan (6.04/100 000), Yichang (5.62/100 000) and Shennongjia (3.47/ 100 000). The reported incidence in southeast area was significantly higher than that in other areas (χ2=2869.603 , P < 0.001). The high incidence age group was 20-39 years old, accounting for more than 70%. The reported incidence in females was higher than that in males (χ2=1429.27 , P < 0.001). Housework and unemployment were the most common professions (43.54%). The case reporting institutions were mainly comprehensive hospitals (87.29%). Conclusion To effectively control the infection and transmission of Chlamydia trachomatis, it is necessary to strengthen the health popularization of STD knowledge, intervention and early active screening of high-risk groups.
6.Effect of Yiguan Decoction on the efficacy of M1 bone marrow-derived macrophages in treatment of liver cirrhosis rats and its mechanism
Mengyao ZONG ; Xun JIAN ; Danyang WANG ; Yannan XU ; Xinrui ZHENG ; Feifei XING ; Gaofeng CHEN ; Jiamei CHEN ; Ping LIU ; Yongping MU
Journal of Clinical Hepatology 2024;40(8):1612-1619
Objective To investigate the effect and mechanism of Yiguan Decoction(YGJD)on the efficacy of M1 bone marrow-derived macrophages(M1-BMDMs)in the treatment of rats with liver cirrhosis induced by 2-AAF/CCl4.Methods BMDMs were isolated and induced into M1-BMDMs by lipopolysaccharide.A total of 50 male Wistar rats were randomly divided into normal group with 5 rats and model group with 45 rats.The rats for modeling were given subcutaneous injection of 50%CCl4 twice a week.Since week 7,the rats for modeling were randomly divided into model group(M group),YGJD group,M1-BMDM group,M1-BMDM+YGJD group,and sorafenib(SORA)group,and they were given subcutaneous injection of 30%CCl4 to maintain the progression of liver cirrhosis and intragastric administration of 2-AAF.CCR2 inhibitors were added to the drinking water,and each group was given the corresponding intervention.Related samples were collected at week 9.The rats were observed in terms of serum liver function parameters,liver pathology,hydroxyproline(Hyp)content in liver tissue,hepatic stellate cell activation,hepatic fibrosis and inflammation factors,and the expression levels of molecules associated with the Wnt signaling pathway.A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups.Results Compared with the M group,the M1-BMDM+YGJD group had significant reductions in the serum levels of alanine aminotransferase,aspartate aminotransferase,and total bilirubin(TBil)(all P<0.05)and a significant increase in the content of albumin(Alb)(P<0.05),and compared with the M1-BMDM group,the M1-BMDM+YGJD group had a significant reduction in the serum level of TBil(P<0.05)and a significant increase in the serum level of Alb(P<0.05).Compared with the M1-BMDM group,the M1-BMDM+YGJD group had significant reductions in the expression levels of CD68 and TNF-α(P<0.05).Compared with the M1-BMDM group,the M1-BMDM+YGJD group had significant reductions in Hyp content and Sirius red positive area(P<0.05).As for the non-canonical Wnt signaling pathway molecules,compared with the M1-BMDM group,the M1-BMDM+YGJD group had significantly lower mRNA and protein expression levels of Wnt5a(P<0.05)and mRNA expression level of Fzd2(P<0.05),as well as significant reductions in the mRNA expression levels of Wnt4,Wnt5b,and Fzd3(P<0.05),while there were no significant changes in the mRNA expression levels of the canonical Wnt signaling pathway molecules β-catenin,LRP5,LRP6,Fzd5,and TCF.Conclusion YGJD can enhance the therapeutic effect of M1-BMDMs on rats with liver cirrhosis induced by 2-AAF/CCl4,possibly by inhibiting the non-canonical Wnt5a/Fzd2 signaling pathway,which provides new ideas for the synergistic effect of traditional Chinese medicine on M1-BMDMs in the treatment of liver cirrhosis.
7.Research on the variation in distortion product otoacoustic emissions in patients with auditory neuropathy during the natural course of the disease
Ziyi CHEN ; Hongyang WANG ; Lan LAN ; Linyi XIE ; Jin LI ; Danyang LI ; Kaili WU ; Tao SHI ; Qiuju WANG
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2024;59(5):423-431
Objective:The purpose of this study was to investigate the characteristics of distortion product otoacoustic emissions (DPOAE) in patients with auditory neuropathy (AN). The factors affecting DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate of first and last diagnosis in the natural course were analyzed.Methods:The sample was obtained from the Multicenter Study on Clinical Diagnosis and Intervention of AN (registration number: ChiCTR2100050125), and the diagnostic criteria for AN were based on the Chinese Clinical Practice Guidelines of Auditory Neuropathy (version 2022). Patients with bilateral AN who underwent 2 or more DPOAE tests were screened and divided into infant groups (≤3 years old) and non-infant groups (>3 years old) according to the age of detection, and the trend of DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate in the natural course of disease were analyzed, in order to explore the relevant influencing factors.Results:A total of 165 patients (330 ears) with AN were included in the study. The overall DPOAE elicitation rate per ear was 77.0%±29.4% at the initial diagnosis and 65.1%±35.2% at the final diagnosis, with a reduction observed in the elicitation rate of 171 ears (51.82%). In the infant group, there were 49 cases (98 ears), including 28 males and 21 females, whose found age ranged from 0 to 3 years old, with a median age of 0.7 years. DPOAE elicitation rate per ear was 57.9%±35.5% in the initial diagnosis, and 32.4%±32.1% in the final diagnosis, with a reduction observed in the elicitation rate of 69 ears (70.41%). In the non-infant group, there were 116 cases (232 ears), including 59 males and 57 females, ranging in found age from 3.9 to 40 years old, with a median age of 14 years old. DPOAE elicitation rate per ear was 84.6%±23.4% in the initial diagnosis, and 78.3%±27.1% in the final diagnosis, with a reduction observed in the elicitation rate of 102 ears (43.97%). Age was found to be correlated with DPOAE changes by multicategorical unordered logistic regression analysis ( B=-0.224, OR=0.799, P<0.001). Conclusions:The elicitation rate of DPOAE in AN patients decreases or even disappears with increasing disease duration; The rate of DPOAE extraction is found to be lower in infant patients with auditory neuropathy (AN) compared to non-infant AN patients. Additionally, it is observed that the decrease in DPOAE extraction rate is more pronounced in infant AN patients as the disease progressed, as compared to non-infant AN patients. DPOAE and cochlear microphonic potentials should be fully combined for accurate diagnosis, and regular follow-up should be conducted to understand the natural course of the disease and give personalized guidance and assistance.
8.Guidance on traditional Chinese medicine intervention for symptoms related to palliative care
Jingshu CHANG ; Yang CHEN ; Qian SONG ; Lei LIN ; Danyang HAN ; Yuning LIU ; Ye LI
Chinese Journal of Geriatrics 2024;43(7):785-796
Palliative care not only embodies modern life perspectives, but also encompasses significant traditional Chinese cultural elements.The primary objective of palliative care is to alleviate patient suffering, preserve their dignity, and facilitate a peaceful passing.Traditional Chinese medicine, known for its simplicity, accessibility, affordability, and efficacy in disease prevention and treatment, adopts a holistic approach to address systemic pain through personalized treatment based on symptom differentiation.This approach aims to enhance the quality of life for terminally ill patients.To equip palliative care providers with essential clinical skills in traditional Chinese medicine, the National Center of Gerontology and Beijing Palliative Care Guidance Center collaborated with experts and scholars to develop guidelines focusing on common end-of-life symptoms.Through extensive deliberation, expert evaluation, and revisions, this guidance document was crafted as a valuable resource for palliative care practitioners, traditional Chinese medicine clinicians, and researchers in the field.
9.Dupilumab combined with minocycline or with minocycline and systemic glucocorticoids for the treatment of bullous pemphigoid: a cohort study
Junyu HU ; Danyang CHEN ; Xixue CHEN ; Mingyue WANG
Chinese Journal of Dermatology 2024;57(10):917-924
Objective:To compare the efficacy, dosage, and safety of dupilumab combined with minocycline or with minocycline and systemic glucocorticoids (sGC) versus minocycline alone or in combination with sGC in patients with bullous pemphigoid (BP) .Methods:A retrospective cohort study was conducted on BP patients who visited the Department of Dermatology, Peking University First Hospital from March 2021 to June 2022 and were treated with one of the following two therapeutic regimens: minocycline alone or in combination with sGC (M-MG group), and dupilumab combined with minocycline or with minocycline and sGC (MD-MGD group). Disease control rates, time to disease control, complete remission rates, time to complete remission, BP disease area index (BPDAI) scores, drug usage, time to pruritus relief, relapse rates, and occurrence rates of adverse reactions were compared between the two groups. Survival analysis was performed using Kaplan-Meier (KM) curves and Log-rank test. Confounders were controlled by 1∶1 matching on the propensity score in the two groups.Results:A total of 164 patients were collected, including 110 in the M-MG group (62 males and 48 females, aged 74.6 ± 12.8 years) and 54 in the MD-MGD group (33 males and 21 females, aged 74.6 ± 13.3 years). After two-week follow-up, there was no significant difference in the disease control rate between the two groups ( P = 0.341); however, the minocycline dose, proportion of patients using sGC, sGC dose, and cumulative sGC dose were all significantly higher in the M-MG group than in the MD-MGD group (all P < 0.05). A total of 152 patients (92.7%) achieved disease control in the two groups during the follow-up, while the disease control rate and time to disease control did not differ between the two groups (both P > 0.05); 52 patients (31.7%) achieved complete remission, there was no significant difference in the complete remission rate between the MD-MGD group (16/54, 29.6%) and M-MG group (36/110, 32.7%; χ2 = 0.16, P = 0.689), but the time to complete remission ( M[ Q1, Q3]) was significantly shorter in the MD-MGD group (98.5[78.0, 185.2] days) than in the M-MG group (223.5 [175.2, 277.0] days, P = 0.001). KM survival curve analysis showed that the cumulative complete remission rate was significantly higher in the MD-MGD group than in the M-MG group ( P = 0.024). A total of 73 patients (44.5%) recorded the time to pruritus relief during the follow-up, and the MD-MGD group showed significantly shorter time to pruritus relief (54 patients, 14.0 [3.0, 14.0] days) compared with the M-MG group (19 patients, 14.0 [7.0, 19.0] days; P = 0.015). After propensity score matching, each group included 42 patients; during the follow-up, there was no significant difference in the complete remission rate between the M-MG group and MD-MGD group ( P > 0.05), but the time to complete remission was significantly longer in the M-MG group than in the MD-MGD group ( P = 0.019); KM survival curve analysis showed that the cumulative complete remission rate was significantly higher in the MD-MGD group than in the M-MG group ( P = 0.041). Among the 164 patients, adverse reactions occurred in 58 (35.4%), grade 3 or more severe adverse reactions occurred in 11 (6.70%), but no dupilumab-related adverse reactions were reported. Conclusions:Compared with minocycline alone or in combination with sGC in the treatment of BP, the dupilumab combination therapy could relieve pruritus and result in complete remission in a shorter time. Additionally, dupilumab could help to accelerate the reduction in dosages of sGC and minocycline, with few adverse reactions and favorable safety.
10.Application of dupilumab in the treatment of 104 patients with bullous pemphigoid and analysis of factors influencing the efficacy
Yan CHEN ; Danyang CHEN ; Xixue CHEN ; Panpan SHANG ; Mingyue WANG
Chinese Journal of Dermatology 2024;57(10):925-930
Objective:To analyze the short- and medium-term efficacy, factors influencing the efficacy, and safety of dupilumab alone or in combination for the treatment of bullous pemphigoid (BP) .Methods:A single-center retrospective cohort study was conducted. Clinical data were collected from adult BP patients, who were regularly followed up and treated with dupilumab at the Department of Dermatology, Peking University First Hospital between March 2021 and June 2022. Dupilumab was administered subcutaneously every 2 weeks at a dose of 300 mg (except for the initial dose being 600 mg). Previous medications included glucocorticoids, minocycline, immunosuppressants, etc., and their dose remained unchanged or decreased according to patient condition. The short- and medium-term response rates were evaluated at weeks 2 and 16 after the first injection of dupilumab, respectively. Multivariate logistic regression analysis was conducted to identify factors influencing the disease control rate at week 2, and odds ratios ( ORs) were calculated; a multivariate Cox regression model was employed to analyze factors influencing the disease control rate within 16 weeks of follow-up, and hazard ratios ( HRs) were calculated; multiple linear regression analysis was performed to determine factors associated with the time to pruritus relief. Results:A total of 104 BP patients were eligible, including 60 males and 44 females; they were aged 75.6 ± 12.8 years, and the disease duration ( M [ Q1, Q3]) was 4.0 (2.0, 17.0) months. According to the percentage of the lesion area to the total body surface area, the disease severity was graded, and there were 17 mild cases, 30 moderate cases, 31 severe cases, and 26 extremely severe cases; 56 patients (53.9%) were treated with dupilumab combined with oral glucocorticoids at doses of 20.0 (15.0, 30.0) mg/d. At week 2 after the start of treatment, 63 patients (60.6%) achieved disease control, and 37 (35.6%) achieved marked disease control, resulting in a short-term response rate of 96.2%. Fifty-five patients were followed up for 16 weeks, 54 (98.2%) achieved improvement, and the systemic glucocorticoid dose was reduced to 10.0 (10.0, 17.5) mg/d. Disease control was achieved in 92 of 104 patients (88.5%) within 16 weeks, with the time to disease control being 14.0 (13.0, 26.0) days and the time to pruritus relief being 12.0 (3.0, 14.0) days. Multivariate logistic regression analysis showed that the higher the baseline disease severity, the lower the disease control rate at week 2 (compared with extremely severe cases, mild cases: OR = 37.655, 95% CI: 3.664, 386.981; moderate cases: OR = 12.143, 95% CI: 2.609, 56.528; severe cases: OR = 4.014, 95% CI: 1.121, 14.369, all P < 0.05). Multivariate Cox regression analysis showed that compared with severe BP patients, mild ( HR = 2.478, 95% CI: 1.200, 5.114, P = 0.014) and moderate BP patients ( HR = 2.076, 95% CI: 1.067, 4.038, P = 0.031) were more likely to achieve disease control during the 16-week treatment and follow-up. Multiple linear regression analysis revealed that the disease duration significantly influenced the time to pruritus relief ( P = 0.006), and the longer the disease duration, the longer the time to pruritus relief. During the follow-up, 13 adverse events occurred in 11 patients (10.6%), including 6 with pulmonary infections, 2 with heart failures, 1 with scabies, 1 with viral conjunctivitis, 1 with pericardial effusion (with a high likelihood of idiopathic pericarditis), 1 with organ failure, and 1 with intracerebral hemorrhage, but none of them were clearly related to dupilumab and most of them did not affect the treatment continuation; 3 deaths were reported, including 2 due to organ failures and 1 due to lung infection, which were all unrelated to dupilumab as determined by specialists. Conclusion:Dupilumab combination therapy for BP could result in rapid disease control, relieve pruritus, and reduce systemic glucocorticoid dosage, with a good safety profile.


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