The anti-inflammatory effects of exercise on autoimmune diseases:A 20-year systematic review

Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease.Methods:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,2023.All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included.The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool.Results:A total of 14,565 records were identified.After screening the titles,abstracts,and full texts,87 were eligible for the systematic review.These studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise interventions.Regular exercise interventions combined with multiple exercise modes were associated with greater benefits.Conclusion:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence.This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease.Most patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at best.Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.

Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases

Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.

Autoimmune hepatitis-primary biliary cholangitis overlap syndrome complicated by various autoimmune diseases:A case report

BACKGROUND Autoimmune hepatitis(AIH)and primary biliary cholangitis(PBC)are two common clinical autoimmune liver diseases,and some patients have both diseases;this feature is called AIH-PBC overlap syndrome.Autoimmune thyroid disease(AITD)is the most frequently overlapping extrahepatic autoimmune disease.Immunoglobulin(IgG)4-related disease is an autoimmune disease recognized in recent years,characterized by elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in tissues.CASE SUMMARY A 68-year-old female patient was admitted with a history of right upper quadrant pain,anorexia,and jaundice on physical examination.Laboratory examination revealed elevated liver enzymes,multiple positive autoantibodies associated with liver and thyroid disease,and imaging and biopsy suggestive of pancreatitis,hepatitis,and PBC.A diagnosis was made of a rare and complex overlap syndrome of AIH,PBC,AITD,and IgG4-related disease.Laboratory features improved on treatment with ursodeoxycholic acid,methylprednisolone,and azathioprine.CONCLUSION This case highlights the importance of screening patients with autoimmune diseases for related conditions.

The Value of Traditional Medicine Should not be Underestimated-Traditional Chinese Medicine in Treatment of Autoimmune Diseases

Autoimmune diseases of the nervous system(ADNS)are characterized by the formation of a pronounced neurologic deficit and often lead to disability.The attention of doctors and researchers is increasingly attracted by complementary medicine as adjuvant or preventive therapy for various diseases,including autoimmune diseases.Traditional Chinese medicine(TCM)is a combination of treatment methods that include acupuncture,herbal medicine,dietetics,physical exercises,and other methods that are often used in conjunction with recognized approaches of official medical science.The article describes the application of TCM techniques in autoimmune diseases of the nervous system,and demonstrates clinical experience in the use of acupuncture,herbal medicine,diets and physical exercises.Traditional and complementary medicine is an important and often underestimated healthcare resource,especially in the prevention and treatment of autoimmune diseases of the nervous system.

Association of autoimmune thyroid disease with type 1 diabetes mellitus and its ultrasonic diagnosis and management

As a common hyperglycemic disease,type 1 diabetes mellitus(T1DM)is a complicated disorder that requires a lifelong insulin supply due to the immunemediated destruction of pancreaticβcells.Although it is an organ-specific autoimmune disorder,T1DM is often associated with multiple other autoimmune disorders.The most prevalent concomitant autoimmune disorder occurring in T1DM is autoimmune thyroid disease(AITD),which mainly exhibits two extremes of phenotypes:hyperthyroidism[Graves'disease(GD)]and hypothyroidism[Hashimoto's thyroiditis,(HT)].However,the presence of comorbid AITD may negatively affect metabolic management in T1DM patients and thereby may increase the risk for potential diabetes-related complications.Thus,routine screening of thyroid function has been recommended when T1DM is diagnosed.Here,first,we summarize current knowledge regarding the etiology and pathogenesis mechanisms of both diseases.Subsequently,an updated review of the association between T1DM and AITD is offered.Finally,we provide a relatively detailed review focusing on the application of thyroid ultrasonography in diagnosing and managing HT and GD,suggesting its critical role in the timely and accurate diagnosis of AITD in T1DM.

Trends of autoimmune liver disease inpatient hospitalization and mortality from 2011 to 2017:A United States nationwide analysis

BACKGROUND Autoimmune liver diseases(AiLD)encompass a variety of disorders that target either the liver cells(autoimmune hepatitis,AIH)or the bile ducts[primary biliary cholangitis(PBC),and primary sclerosing cholangitis(PSC)].These conditions can progress to chronic liver disease(CLD),which is characterized by fibrosis,cirrhosis,and hepatocellular carcinoma.Recent studies have indicated a rise in hospitalizations and associated costs for CLD in the US,but information regarding inpatient admissions specifically for AiLD remains limited.AIM To examine the trends and mortality of inpatient hospitalization of AiLD from 2011 to 2017.METHODS This study is a retrospective analysis utilizing the National Inpatient Sample(NIS)databases.All subjects admitted between 2011 and 2017 with a diagnosis of AiLD(AIH,PBC,PSC)were identified using the International Classification of Diseases(ICD-9)and ICD-10 codes.primary AiLD admission was defined if the first admission code was one of the AiLD codes.secondary AiLD admission was defined as having the AiLD diagnosis anywhere in the admission diagnosis(25 diagnoses).Subjects aged 21 years and older were included.The national estimates of hospitalization were derived using sample weights provided by NIS.χ^(2)tests for categorical data were used.The primary trend characteristics were in-hospital mortality,hospital charges,and length of stay.RESULTS From 2011 to 2017,hospitalization rates witnessed a significant decline,dropping from 83263 admissions to 74850 admissions(P<0.05).The patients hospitalized were predominantly elderly(median 53%for age>65),mostly female(median 59%)(P<0.05),and primarily Caucasians(median 68%)(P<0.05).Medicare was the major insurance(median 56%),followed by private payer(median 27%)(P<0.05).The South was the top geographical distribution for these admissions(median 33%)(P<0.05),with most admissions taking place in big teaching institutions(median 63%)(P<0.05).Total charges for admissions rose from 66031 in 2011 to 78987 in 2017(P<0.05),while the inpatient mortality rate had a median of 4.9%(P<0.05),rising from 4.67%in 2011 to 5.43%in 2017.The median length of stay remained relatively stable,changing from 6.94 days(SD=0.07)in 2011 to 6.51 days(SD=0.06)in 2017(P<0.05).Acute renal failure emerged as the most common risk factor associated with an increased death rate,affecting nearly 68%of patients(P<0.05).CONCLUSION AiLD-inpatient hospitalization showed a decrease in overall trends over the studied years,however there is a significant increase in financial burden on healthcare with increasing in-hospital costs along with increase in mortality of hospitalized patient with AiLD.

Predictors of survival in autoimmune liver disease overlap syndromes

BACKGROUND Survival in patients with autoimmune liver disease overlap syndromes(AILDOS)compared to those with single autoimmune liver disease is unclear.AIM To investigate the survival of patients with AILDOS and assess the accuracy of non-invasive serum models for predicting liver-related death.METHODS Patients with AILDOS were defined as either autoimmune hepatitis and primary biliary cholangitis overlap(AIH-PBC)or autoimmune hepatitis and primary sclerosing cholangitis overlap(AIH-PSC)and were identified from three tertiary centres for this cohort study.Liver-related death or transplantation(liver-related mortality)was determined using a population-based data linkage system.Prognostic scores for liver-related death were compared for accuracy[including liver outcome score(LOS),Hepascore,Mayo Score,model for end-stage liver disease(MELD)score and MELD incorporated with serum sodium(MELD-Na)score].RESULTS Twenty-two AILDOS patients were followed for a median of 3.1 years(range,0.35-7.7).Fourteen were female,the median age was 46.7 years(range,17.8 to 82.1)and median Hepascore was 1(range,0.07-1).At five years post enrolment,57%of patients remained free from liver-related mortality(74%AIH-PBC,27%AIH-PSC).There was no significant difference in survival between AIH-PBC and AIH-PSC.LOS was a significant predictor of liver-related mortality(P<0.05)in patients with AIH-PBC(n=14)but not AIH-PSC(n=8).A LOS cut-point of 6 discriminated liver-related mortality in AIH-PBC patients(P=0.012,log-rank test,100%sensitivity,77.8%specificity)(Harrell's C-statistic 0.867).The MELD score,MELD-Na score and Mayo Score were not predictive of liver-related mortality in any group.CONCLUSION Survival in the rare,AILDOS is unclear.The current study supports the LOS as a predictor of liver-related mortality in AIH-PBC patients.Further trials investigating predictors of survival in AILDOS are required.

Enzyme-linked immunosorbent assay of 3 Screen Islet Cell Autoantibody in patients with autoimmune thyroid disease

BACKGROUND In recent years,the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes(T1D).While it has been established that 20%-30%of T1D patients suffer from autoimmune thyroid disease(AITD),there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients.Among commercially available anti-islet autoantibodies,glutamic acid decarboxylase 65 autoantibodies(GADAs)are often the first marker measured in general clinical practice.AIM To investigate the frequency of anti-islet autoantibodies in AITD patients.METHODS Our study involved four hundred ninety-five AITD patients,categorized into three distinct groups:AITD with T1D(n=18),AITD with phenotypic type 2 diabetes(T2D)(n=81),and AITD without diabetes(n=396),and the enzyme-linked immunosorbent assay(ELISA)was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody(3 Screen ICA),GADA,insulinoma-associated antigen-2 autoantibodies(IA-2As),and zinc transporter 8 autoantibodies(ZnT8As)within these groups.RESULTS The frequency of 3 Screen ICA in AITD patients with T1D,T2D,and those without diabetes were 88.9%,6.2%,and 5.1%,respectively,with no significant difference seen between the latter two groups.Notably,the frequency of 3 Screen ICA was 11.1%higher in AITD patients with T1D,1.3%higher in AITD patients with T2D,and 1.1%higher in AITD patients without diabetes compared to GADA,respectively.Furthermore,12.5%,20.0%,and 20.0%of the 3 Screen ICA-positive patients were negative for GADA.Additionally,1.3%of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies.Among the 3 Screen ICA-positive patients,there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes(37.5%vs 5.0%,P<0.05).However,this proportion was similar to that in AITD patients with T2D(20.0%).Nevertheless,there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes(436.8±66.4 vs 308.1±66.4 index).Additionally,no significant difference in 3 Screen ICA titers was observed between Graves’disease and Hashimoto’s thyroiditis in any of the groups.CONCLUSION Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D.Thus,3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.

Respiratory Mechanics, Respiratory Muscle Strength, Control of Ventilation and Gas Exchange in Patients with Autoimmune Liver Disease

Objectives: To assess respiratory elastance and resistive properties in patients with autoimmune liver disorders using the passive relaxation expiration technique and compare findings to a group of patients with non-autoimmune liver disease and control subjects. These findings were then related to control of ventilation and gas exchange. A secondary objective was to assess respiratory muscle strength and gas exchange and their relation to respiratory mechanics. Methods: Measurements included respiratory elastance and resistance using the passive relaxation method. Pulmonary function, gas exchange and control of ventilation were assessed using standard methods. Results: a) Compared to control subjects, Ers in patients with liver disease was on average 50% greater than in controls;b) mean respiratory resistance, expressed as the respiratory constants, K1 and K2 in the Rohrer relationship, Pao/V’ = K1 + K2V’, was not different from control resistance;c) mean maximal inspiratory and maximal expiratory pressures averaged 36% and 55% of their respective control values;d) inspiratory occlusion pressure in 0.1 sec (P0.1) was increased and negatively associated with FVC;and e) increases in P0.1, mean inspiratory flow (Vt/Ti) and presence of respiratory alkalosis confirmed the increase in ventilatory drive. Despite inspiratory muscle weakness in patients, P0.1/Pimax averaged 5-fold higher than in control subjects. Conclusions: Despite inspiratory muscle weakness and a V’E similar to that in normal subjects, central drive is increased in patients with chronic liver disease. The increase in ventilatory drive is related to smaller lung volumes and weakly associated with increase in respiratory elastance. Findings confirm that P0.1 is a reliable measure of central drive and is an approach that can be used in the evaluation of control of ventilation in patients with chronic liver disease.

Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

AIM To investigate whether immune mediated diseases(IMD) are more frequent in patients with inflammatory bowel disease(IBD).METHODS In this population based registry study,a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16,2013. Controls were randomly selected from the Danish Civil Registration System(CRS) and matched for sex,age,and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis(UC),Crohn's disease(CD) and Both the latter referring to those registered with both diagnoses. Subsequently,odds-ratios(OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher's exact test.RESULTS There were significantly more women than men in the registry,and a greater percentage of comorbidity in the IBD groups(P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased(P < 0.00125) for primary sclerosing cholangitis(PSC),celiac disease,type 1 diabetes(T1D),sarcoidosis,asthma,iridocyclitis,psoriasis,pyoderma gangrenosum,rheumatoid arthritis,and ankylosing spondylitis. Restricted to UC(P < 0.00125) were autoimmune hepatitis,primary biliary cholangitis,Grave's disease,polymyalgia rheumatica,temporal arteritis,and atrophic gastritis. Restricted to CD(P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC(P < 0.00125) were atrophic gastritis,rheumatoid arthritis,temporal arteritis,and polymyalgia rheumatica. Restricted to women with CD were episcleritis,rheumatoid arthritis,and psoriatic arthritis. The only disease restricted to men(P < 0.00125) was sarcoidosis. CONCLUSION Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways.

Radiation-induced inflammation and autoimmune diseases

Currently,ionizing radiation(IR)plays a key role in the agricultural and medical industry,while accidental exposure resulting from leakage of radioactive sources or radiological terrorism is a serious concern.Exposure to IR has various detrimental effects on normal tissues.Although an increased risk of carcinogenesis is the best-known long-term consequence of IR,evidence has shown that other diseases,particularly diseases related to inflammation,are common disorders among irradiated people.Autoimmune disorders are among the various types of immune diseases that have been investigated among exposed people.Thyroid diseases and diabetes are two autoimmune diseases potentially induced by IR.However,the precise mechanisms of IR-induced thyroid diseases and diabetes remain to be elucidated,and several studies have shown that chronic increased levels of inflammatory cytokines after exposure play a pivotal role.Thus,cytokines,including interleukin-1(IL-1),tumor necrosis factor(TNF-α)and interferon gamma(IFN-α),play a key role in chronic oxidative damage following exposure to IR.Additionally,these cytokines change the secretion of insulin and thyroid-stimulating hormone(TSH).It is likely that the management of inflammation and oxidative damage is one of the best strategies for the amelioration of these diseases after a radiological or nuclear disaster.In the present study,we reviewed the evidence of radiation-induced diabetes and thyroid diseases,as well as the potential roles of inflammatory responses.In addition,we proposed that the mitigation of inflammatory and oxidative damage markers after exposure to IR may reduce the incidence of these diseases among individuals exposed to radiation.

Non-invasive assessment of liver fibrosis using twodimensional shear wave elastography in patients with autoimmune liver diseases

AIM To determine the diagnostic accuracy of two-dimensional shear wave elastography(2D-SWE) for the noninvasive assessment of liver fibrosis in patients with autoimmune liver diseases(AILD) using liver biopsy as the reference standard.METHODS Patients with AILD who underwent liver biopsy and 2D-SWE were consecutively enrolled. Receiver operating characteristic(ROC) curves were constructed to assess the overall accuracy and to identify optimal cut-off values.RESULTS The characteristics of the diagnostic performance were determined for 114 patients with AILD. The areas under the ROC curves for significant fibrosis, severe fibrosis, and cirrhosis were 0.85, 0.85, and 0.86, respectively, and the optimal cut-off values associated with significant fibrosis(≥ F2), severe fibrosis(≥ F3), and cirrhosis(F4) were 9.7 k Pa, 13.2 k Pa and 16.3 k Pa, respectively. 2D-SWE showed sensitivity values of 81.7% for significant fibrosis, 83.0% for severe fibrosis,and 87.0% for cirrhosis, and the respective specificity values were 81.3%, 74.6%, and 80.2%. The overall concordance rate of the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages was 53.5%.CONCLUSION2D-SWE showed promising diagnostic performance for assessing liver fibrosis stages and exhibited high cut-off values in patients with AILD. Low overall concordance rate was observed in the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages.

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.

Measurement of Serum IgG4 Levels by an Established ELISA System and Its Clinical Applications in Autoimmune Diseases

Summary： IgG4-related disease （IgG4-RD） is a novel and rare autoimmune disease entity. Elevated serum IgG4 level is strongly suggestive of IgG4-RD. But it is still unknown whether serum IgG4 eleva tion commonly occurs in other autoimmune diseases. In this study, the serum IgG4 levels were detected by an established enzyme-linked immunosorbent assay （ELISA） in a variety of autoimmune diseases including systemic lupus erythematosus （SLE）, Sjogren＇s syndrome （SS）, polymyositis or dermatomy- ositis （PM/DM） and IgG4-RD. To evaluate the reliability of this ELISA system, some of our samples were sent to a lab in Kanazawa Medical University, Japan, and detected by using the nephelometric as-say. The results showed that our findings were consistent with theirs. Moreover, it was found that the serum IgG4 levels were 0.23±0.16 g/L in 53 healthy controls, 0.16±0.15 g/L in 103 SLE patients, 0.22±0.18 g/L in 41 SS patients and 0.40±0.32 g/L in 21 PM/DM patients. No significant difference in the serum IgG4 level was observed among these groups （P〉0.05）. The serum IgG4 levels of two cases of IgG4-RD were 1.63 and 4.65 g/L respectively, and both decreased markedly after treatment with glucocorticoids. These data indicated that this established ELISA system can be used for detecting serum IgG4 levels. Elevated serum IgG4 levels help diagnose IgG4-RD and evaluate the curative effect of this condition rather than other autoimmune diseases.

Autoimmune thyroid diseases and Helicobacter pylori: The correlation is present only in Graves's disease

AIM: To investigate the correlation between autoimmune thyroid diseases (ATDs) and the prevalence of Cag-A positive strains of Helicobacter pylori (H. pylori) in stool samples. METHODS: We investigated 112 consecutive Caucasian patients (48 females and 4 males with Graves' disease and 54 females and 6 males with Hashimoto' s thyroiditis HT), at their first diagnosis of ATDs. We tested for H. pylori in stool samples using an amplified enzyme immunoassay and Cag-A in serum samples using an enzyme-linked immunoassay method (ELISA). The results were analyzed using the two-sided Fisher' s exact test and the respective odds ratio (OR) was calculated. RESULTS: A marked correlation was found between the presence of H. pylori (P ≤ 0.0001, OR 6.3) and, in particular, Cag-A positive strains (P ≤ 0.005, OR 5.3)in Graves' disease, but not in Hashimoto's thyroiditis, where we found only a correlation with Cag-A strains (P ≤ 0.005, OR 8.73) but not when H. pylori was present. CONCLUSION: The marked correlation between H. pylori and Cag-A, found in ATDs, could be dependent on the different expression of adhesion molecules in the gastric mucosa.

Autoimmune liver diseases in systemic rheumatic diseases

Systemic rheumatic diseases(SRDs)are chronic,inflammatory,autoimmune disorders with the presence of autoantibodies that may affect any organ or system.Liver dysfunction in SRDs can be associated with prescribed drugs,viral hepatitis,alternative hepatic comorbidities and coexisting autoimmune liver diseases(AILDs),requiring an exclusion of secondary conditions before considering liver involvement.The patterns of overlap diseases depend predominantly on genetic determinants with common susceptible loci widely distributing in both disorders.In AILDs,it is important to identify the overlapping SRDs at an early stage since such a coexistence may influence the disease course and prognosis.Commonly co-occurring SRDs in AILDs are Sjögren syndrome(SS),rheumatoid arthritis(RA)or systemic lupus erythematosus(SLE)in autoimmune hepatitis(AIH),and SS,RA or systemic sclerosis in primary biliary cholangitis.Owing to different disease complications and therapies,it is imperative to differentiate between SLE liver involvement and SLE-AIH overlap disease.Therapeutic options can be personalized to control coexisting conditions of liver autoimmunity and rheumatic manifestations in AILD-SRD overlap diseases.The collaboration between hepatologists and rheumatologists can lead to significant advances in managing such a complex scenario.In this review,we provide a comprehensive overview on coexisting AILDs in different SRDs and the therapeutic approach in managing these overlap diseases.

Smoking under hypoxic conditions: a potent environmental risk factor for inflammatory and autoimmune diseases

Autoimmune disease management presents a significant challenge to medical science. Environmental factors potentially increase the risk of developing inflammatory and autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and lupus. Among various environmental stresses, cigarette smoke and hypoxia have both been reported to lead to an enhanced risk of inflammatory and autoimmune diseases. In this review, we shed light on all reported mechanisms whereby cigarette smoke and a hypoxic environment can induce inflammatory and autoimmune diseases and discuss how hypoxic conditions influence the cigarette smoke-induced threat of inflammatory and autoimmune disease development. Cigarette smoke and hypoxia both lead to increased oxidative stress and production of reactive oxygen species and other free radicals, which have various effects including the generation of autoreactive pro-inflammatory T cells and autoantibodies, reductions in T regulatory(Treg) cell activity, and enhanced expression of pro-inflammatory mediators [e.g., interleukin-6(IL-6), interleukin-4(IL-4) and interleukin-8(IL-8)]. Accordingly, smoking and hypoxic environments may synergistically act as potent environmental risk factors for inflammatory and autoimmune diseases. To our knowledge, no studies have reported the direct association of cigarette smoke and hypoxic environments with the risk of developing inflammatory and autoimmune diseases. Future studies exploring the risk of autoimmune disease development in smokers at high altitudes, particularly military personnel and mountaineers who are not acclimatized to high-altitude regions, are required to obtain a better understanding of disease risk as well as its management.

Iguratimod: a valuable remedy from the Asia Pacific region for ameliorating autoimmune diseases and protecting bone physiology

Autoimmune diseases are affected by complex pathophysiology involving several cell types,cytokines,antibodies,and mimicking factors.Different drugs are used to ameliorate these autoimmune reactions,including nonsteroidal anti-inflammatory drugs(NSAIDs),corticosteroids,antiantibodies,and small molecular drugs(DMARDs),and they are clinically in vogue for diseases such as rheumatoid arthritis(RA).Nevertheless,low cost-effectiveness,reduced efficacy,adverse effects,and patient nonresponse are unappealing factors driving the development of new drugs such as iguratimod.Iguratimod is primarily used to ameliorate RA in Japanese and Chinese clinics.However,its efficacy against other autoimmune ailments is also under intense investigation,and the number of investigations is becoming increasingly larger with each passing day.The articular structure comprises synovium,ligaments,and bone.The latter is more complex than the others since it regulates blood cells and autoimmunity in addition to providing skeletal support to the body.Therefore,its protection is also of prime importance in RA and other autoimmune diseases.Herein,we have highlighted the role of iguratimod in autoimmune diseases and bone protection.We suggest that iguratimod’s unique mode of action compared with that of other DMARDs and its good patient response makes it a suitable antirheumatic and bone-protecting drug.

Hepatocellular carcinoma in viral and autoimmune liver diseases:Role of CD4+CD25+Foxp3+regulatory T cells in the immune microenvironment

More than 90%of cases of hepatocellular carcinoma(HCC)occurs in patients with cirrhosis,of which hepatitis B virus and hepatitis C virus are the leading causes,while the tumor less frequently arises in autoimmune liver diseases.Advances in understanding tumor immunity have led to a major shift in the treatment of HCC,with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells.Regulatory T cells(Tregs)are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression,invasiveness,as well as metastasis.Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function.Notably,Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor(ICI)immunotherapy.Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity,it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events(irAEs).Since the use of ICI becomes common in oncology,with an increasing number of new ICI currently under clinical trials for cancer treatment,the occurrence of irAEs is expected to dramatically rise.Herein,we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease,and we discuss their involvement in irAEs due to the new immunotherapies.

Risk of hepatitis B virus reactivation in patients with autoimmune diseases undergoing non-tumor necrosis factor-targeted biologics

Hepatitis B virus reactivation(HBVr)can occur in patients treated with immunosuppressive medications.Risk stratification for HBVr based on hepatitis B virus(HBV)serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use.Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies.Tumor necrosis factor(TNF)-αinhibitors have been widely used for patients with inflammatory bowel disease,psoriasis,and rheumatic diseases.Further,the clinical benefits of interleukin(IL)-12/23,IL-17,or Janus kinases inhibitors have been demonstrated in these patients.It is well known that TNF-αinhibitor use can lead to HBVr,however,the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood.In this review,we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics,and immunological mechanisms of these medications causing HBVr.