Pembrolizumab-induced psoriatic arthritis treated with disease-modifying anti-rheumatic drugs in a patient with gastric cancer:A case report

BACKGROUND Immune checkpoint inhibitor(ICI)-induced rheumatic immune-related adverse events(ir AEs)have been infrequently reported,and the treatment of severe or refractory arthritis as ir AEs has not been established yet.CASE SUMMARY The patient was a 67-year-old man with a history of well-controlled foot psoriasis who presented with polyarthralgia.He had received pembrolizumab for metastatic gastric adenocarcinoma 2 mo previously.Physical examination revealed erythematous swelling in the distal interphalangeal joints,left shoulder,and both knees.He had plaque psoriasis with psoriatic nail dystrophy and dactylitis in the distal joints of the fingers and toes.Inflammatory markers including C-reactive protein and erythrocyte sedimentation rate were elevated but rheumatoid factor and anticyclic citrullinated peptide antibody were negative.The patient was diagnosed with psoriatic arthritis(PsA)and started on methylprednisolone 1 mg/kg/day after pembrolizumab discontinuation.However,despite 1 wk of methylprednisolone treatment,PsA worsened;hence,leflunomide and methotrexate were started.After 4 wk of steroid treatment,PsA worsened and improved repeatedly with steroid tapering.Therefore,the therapy was intensified to include etanercept,a tumor necrosis factor inhibitor,which ultimately resulted in adequate PsA control.CONCLUSION This is the first report of ICI-induced PsA in a gastric cancer patient.Some rheumatic ir AEs with refractory severe arthritis may require disease-modifying anti-rheumatic drugs and long-term management.

Compensated liver cirrhosis:Natural course and disease-modifying strategies

Compensated liver cirrhosis(CLC)is defined as cirrhosis with one or more decompensating events,such as ascites,variceal haemorrhage,or hepatic encephalopathy.Patients with CLC are largely asymptomatic with preserved hepatic function.The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors.The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis,as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years.Furthermore,early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition.With the advent of effective non-invasive tools for detecting hepatic fibrosis,more and more patients with CLC are currently being recognised.This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or,at the very least,prevent its progression.There are numerous emerging approaches for preventing or delaying decompensation in CLC patients.A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression,and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension.Additionally,address-ing various cofactors(such as obesity,diabetes,dyslipidaemia,and alcoholism)and precipitating factors(such as infection,viral hepatitis,and hepatotoxic drugs)that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC.However,high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these diseasemodifying techniques for CLC patients.This article discussed the natural history of CLC,risk factors for its progression,and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis： perspectives and approaches

Multiple sclerosis（MS） is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies（DMTs） for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

State-of-the-Art management of knee osteoarthritis

Osteoarthritis(OA) is the most common type of arthritis found in the United States' population and is also the most common disease of joints in adults throughout the world with the knee being the most frequently affected of all joints. As the United States' population ages along with the increasing trends in obesity prevalence in other parts of the world, it is expected that the burden of OA on the population, healthcare system, and overall economy will continue to increase in the future without making major improvements in managing knee OA. Numerous therapies aim to reduce symptoms of knee OA and continued research has helped to further understand the complex pathophysiology of its disease mechanism attempting to uncover new potential targets for the treatment of OA. This review article seeks to evaluate the current practices for managing knee OA and discusses emerging therapies on the horizon. These practices include non-pharmacological treatments such as providing patient education and self-management strategies, advising weight loss, strengthening programs, and addressing biomechanical issues with bracing or foot orthoses. Oral analgesics and anti-inflammatories are pharmacologicals that are commonly used and the literature overall supports that some of these medications can be helpful for managing knee OA in the short-term but are less effective for long-term management. Additionally, more prolonged use significantly increases the risk of serious associated side effects that are not too uncommon. Diseasemodifying osteoarthritis drugs are being researched as a treatment modality to potentially halt or slow disease progression but data at this time is limited and continued studies are being conducted to further investigate their effectiveness. Intra-articular injectables are also implemented to manage knee OA ranging from corticosteroids to hyaluronans to more recently plateletrich plasma and even stem cells while several other injection therapies are presently being studied. The goal of developing new treatment strategies for knee OA is to prolong the need for total knee arthroplasty which should be utilized only if other strategies have failed. High tibial osteotomy and unicompartmental knee arthroplasty are potential alternatives if only a single compartment is involved with more data supporting unicompartmental knee arthroplasty as a good treatment option in this scenario. Arthroscopy has been commonly used for many years to treat knee OA to address degenerative articular cartilage and menisci, however, several high-quality studies have shown that it is not a very effective treatment for the majority of cases and should generally not be considered when managing knee OA. Improving the management of knee OA requires a multi-faceted treatment approach along with continuing to broaden our understanding of this complex disease so that therapeutic advancements can continue to be developed with the goal of preventing further disease progression and even potentially reversing the degenerative process.

Management of psoriasis patients with hepatitis B or hepatitis C virus infection

The systemic therapies available for the management of Psoriasis(PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs(c DMARDs) or biological ones(b DMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus(HBV) and hepatitis C virus(HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen(anti-HBs Ag), HBs Ag, and antibody to HCV(anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a(Cy A) or b DMARDs(etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBs Ag and transaminases dosing can be monitored every 3 mo. Concerning PsO patients with chronic HCV infection their management with immunosuppressive drugs is less problematic as compared to those infected by HBV.In fact, HCV reactivation is an extremely rare event after administration of drugs such as CyA or tumor necrosis factor-α inhibitors. As a rule, these patients can be monitored measuring HCV RNA load, and ALT, aspartate transaminase, gamma-glutamyl-transferase, bilirubin, alkaline phosphatase, albumin and platelet every 3-6 mo. The present article provides an updated overview based on more recently reported data on monitoring and managing PsO patients who need systemic antipsoriatic treatment and have HBV or HCV infection as comorbidity.

From regenerative strategies to pharmacological approaches:can we fine-tune treatment for Parkinson's disease?

Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide.Clinically,it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons.Current treatment is focused on mitigating the symptoms through the administration of levodopa,rather than on preventing dopaminergic neuronal damage.Therefore,the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson's disease.For instance,N-acetylcysteine,a natural compound with strong antioxidant effects,has been shown to modulate oxidative stress,preventing dopamine-induced cell death.Despite the evidence of neuroprotective and modulatory effects of this drug,as far as we know,it does not induce per se any regenerative process.Therefore,it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation,as stem cell-based strategies.Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson's disease,given its ability to modulate cell viability/preservation of dopaminergic neurons.Such approach represents a shift in the paradigm,showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson's disease.Thus,in this review,we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases,like Parkinson's disease.

Treatment strategies for multiple sclerosis:When to start,when to change,when to stop?

Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.

Hepatitis B virus reactivation in rheumatoid arthritis

Rheumatoid arthritis(RA)is an autoimmune disease characterized by proliferative synovitis,which can cause cartilage and bone damage as well as functional limitations.Disease-modifying anti-rheumatic drugs have significantly improved the prognosis of RA patients.However,people with RA,when combined with hepatitis B virus(HBV)infection,may experience reactivation of HBV during treatment with anti-rheumatic drugs.The outcome of HBV reactivation(HBVr)varies from liver inflammation to liver failure,while insufficient HBV screening in RA patients has been reported in various countries.Therefore,it is necessary to identify patients at high risk before starting immunosuppressive therapy.The immune response plays an important role in anti-HBV infection.However,most anti-rheumatic drugs exert an inhibitory effect on the body’s immune system,resulting in HBVr.Therefore,it is necessary to conduct a comprehensive evaluation based on host factors,viral factors,and drug factors.In this paper,we summarize the mechanism of HBVr,the risk of HBVr caused by anti-rheumatic drugs,and the appropriate diagnosis and treatment process for RA patients so that clinicians can have a more comprehensive understanding of HBVr in RA patients.

Hepatitis B virus infection reactivation in patients under immunosuppressive therapies:Pathogenesis,screening,prevention and treatment

With a 5.3%of the global population involved,hepatitis B virus(HBV)is a major public health challenge requiring an urgent response.After a possible acute phase,the natural history of HBV infection can progress in chronicity.Patients with overt or occult HBV infection can undergo HBV reactivation(HBVr)in course of immunosuppressive treatments that,apart from oncological and hematological diseases,are also used in rheumatologic,gastrointestinal,neurological and dermatological settings,as well as to treat severe acute respiratory syndrome coronavirus 2 infection.The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition.The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence.The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed.The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status.Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.

Precautions before starting tofacitinib in persons with rheumatoid arthritis

Tofacitinib is an immunosuppressive and disease-modifying therapy in rheumatoid arthritis.It may result in many infections flaring up.It is important to take precautions of all kinds(cardiovascular,malignancy,infections etc.)before starting tofacitinib.In this article,we have highlighted important steps where we need to take precautions before starting tofacitinib.

Use of biologic agents for rheumatic diseases in pregnancy

Biologic agents have ushered a new era in the treatment of inflammatory rheumatic diseases.In recent years,several biologic agents have been approved by food and drug administration and have significantly improved outcomes for patients with immune mediatedinflammatory disorders including rheumatic and inflammatory bowel diseases.The most common used biologic therapeutic agents are tumor necrosis factor inhibitors(etanercept,infliximab,adalimumab,certolizumab pegol,and golimumab),an interleukin(IL)-6 inhibitor(tocilizumab),an IL-1 receptor antagonist(anakinra),an anti-CD-20 antibody(rituximab),and a T cell costimulation modulator(abatacept).Their use during pregnancy has been controversial because of absence of controlled studies which have enrolled pregnant women.This brief overview provides published data on use of biologic agents for the treatment of rheumatic diseases in pregnancy.

Treatment Adherence of Patients with Rheumatoid Arthritis during COVID-19 Pandemic

India is no exception to the economic setback due to coronavirus disease 2019 (COVID-19). Loss of jobs and income dramatically impacts the health care cost of chronic disease management. Rheumatoid arthritis is a chronic condition with a high-cost implication. With the outbreak of COVID-19, there is uncertainty about continuing immunosuppressive therapy for rheumatoid arthritis for several reasons. In this milieu, we undertook a prospective observational study to observe the use of Janus Kinase (JAK) inhibitors in a hospital-based rheumatology service in Eastern India during the pandemic period (21 March 2020 to 31 July 2020). Forty-two patients with rheumatoid arthritis were receiving treatment with JAK inhibitors. Twenty-four patients visited the Outpatient Department (OPD) during the COVID-19 pandemic. All of them were COVID-negative, but few of the patients had influenza-like symptoms. Patients faced up to a 25% reduction in their annual income during the COVID-19 pandemic. Of 24 patients, four patients had stopped treatment with JAK inhibitors owing to financial constraints or initial non-availability of medications during the lockdown. In this study, adherence to JAK inhibitors was substantially high even in the face of income curtailment during the COVID-19 pandemic.

Remission is not maintained over 2 years with hematopoietic stem cell transplantation for rheumatoid arthritis:A systematic review with meta-analysis

BACKGROUND Hematopoietic stem cell(HSC)transplantation(HSCT)is being accepted as a standard of care in various inflammatory diseases.The treatment of rheumatoid arthritis(RA)has been closely evolving with the understanding of disease pathogenesis.With the rising resistance to the traditional disease-modifying antirheumatic drugs and targeted biological therapy,researchers are in pursuit of other methods for disease management.Since the ultimate goal of the ideal treatment of RA is to restore immune tolerance,HSCT attracts much attention considering its reparative,paracrine,and anti-inflammatory effects.However,a systematic review of studies on HSCT in RA is lacking.AIM To investigate the role of HSCT in the management of RA.METHODS A detailed search of PubMed,Scopus,EMBASE,Cochrane,and the Web of Science databases was made to identify the relevant articles till September 2020 following Cochrane and PRISMA guidelines.We extracted data including the number of patients,source of hematopoietic stem cells,their mobilization and conditioning regimens,results,and complications from the eligible studies.Results were dichotomized into success(ACR 50/70)and failure(ACR 20)based on the improvement from baseline characteristics.The methodological quality of the included studies was also assessed.Analysis was performed using OpenMeta[Analysis]software.RESULTS We included 17 studies(1 randomized controlled trial,11 prospective,and 5 retrospective studies)with 233 patients for analysis.HSCT provided a significantly beneficial overall improvement in the clinical grades of ACR criteria(Z=11.309,P<0.001).However,the remission was noted only till 24 mo and later on the significance of the result was lost(Z=1.737,P=0.082).A less than 1%treatmentrelated mortality was noted from the included studies.No major drug-related toxicities were noted in any of the included studies.All patients who underwent allogeneic HSCT received immunosuppression in the conditioning regimen to counteract the graft-vs-host reaction which made them vulnerable to infections.It is noted that the source of hematopoietic stem cells did not play a role in altering the functional outcome and both autologous(Z=9.972,P<0.001)and allogenic(Z=6.978,P<0.001)sources produced significant improvement in the outcome compared to the pre-operative state despite having a significant heterogeneity among the studies reporting them(I2=99.4,P<0.001).CONCLUSION Although the available literature is encouraging towards the use of HSCT in refractory cases with significant improvement from baseline till 2 years,the inclusion of HSCT into the standard of care of RA needs further exploration.

What is the best biological treatment for rheumatoid arthritis? A systematic review of effectiveness

AIM:To evaluate the effectiveness of the biological disease-modifying antirheumatic drugs(b DMARD) in the treatment of rheumatoid arthritis through a systematic review of observational studies.METHODS:The studies were searched in the Pub Med,EMBASE,Cochrane Controlled Trials Register and LILACS databases(until August 2014),in the grey literature and conducted a manual search.The assessed criteria of effectiveness included the EULAR,the disease activity score(DAS),the Clinical Disease Activity Index,the Simplified Disease Activity Index,the American College of Rheumatology and the Health Assessment Questionnaire.The meta-analysis was performed with Review Manager 5.2 software using a random effects model.A total of 35 studies were included in this review.RESULTS:The participants anti-tumor necrosis factor inhibitors(TNF) nave,who used adalimumab(P = 0.0002) and etanercept(P = 0.0006) exhibited greater good EULAR response compared to the participants who used infliximab.No difference was detected between adalimumab and etanercept(P = 0.05).The participants who used etanercept exhibited greater remission according to DAS28 compared to the participants who used infliximab(P = 0.01).No differences were detected between adalimumab and infliximab(P = 0.12) or etanercept(P = 0.79).Better results were obtained with b DMARD associated with methotrexate than with b DMARD alone.The good EULAR response and DAS 28 was better for combination with methotrexate than b DMARD monotherapy(P = 0.03 e P < 0.00001).In cases of therapeutic failure,the participants who used rituximab exhibited greater DAS28 reduction compared to those who used anti-TNF agents(P = 0.0002).The participants who used etanercept achieved greater good EULAR response compared to those who did not use that drug(P = 0.007).Studies that assessed reduction of the CDAI score indicated the superiority of abatacept over rituximab(12.4 vs +1.7) and anti-TNF agents(7.6 vs 8.3).The present systematic review with meta-analysis found that relative to anti-TNF treatmentnave patients,adalimumab and etanercept were more effective when combined with methotrexate than when used alone.Furthermore,in case of therapeutic failure with anti-TNF agents;rituximab and abatacept(non anti-TNF) and etanercept(as second anti-TNF) were more effective.However,more studies of effectiveness were found for the rituximab.CONCLUSION:The best treatment for treatment-nave patients is adalimumab or etanercept combined with methotrexate.For anti-TNF therapeutic failure,the best choice is rituximab,abatacept or etanercept.

Evolution of treatment options for juvenile idiopathic arthritis

A recent study published in World J Clin Cases addressed the optimal non-steroidal anti-inflammatory drugs(NSAIDs)for juvenile idiopathic arthritis(JIA).Herein,we outline the progress in drug therapy of JIA.NSAIDs have traditionally been the primary treatment for all forms of JIA.NSAIDs are symptom-relief medications,and well tolerated by patients.Additionally,the availability of selective NSAIDs further lower the gastrointestinal adverse reactions compared with traditional NSAIDs.Glucocorticoid is another kind of symptom-relief medications with potent anti-inflammatory effect.However,the frequent adverse events limit the clinical use.Both NSAIDs and glucocorticoid fail to ease or pre-vent joint damage,and the breakthrough comes along with the disease-mo-difying antirheumatic drugs(DMARDs).DMARDs can prevent disease pro-gression and reduce joint destruction.Particularly,the emergence of biologic DMARDs(bDMARDs)has truly revolutionized the therapeutics of JIA,compared with conventional synthetic DMARDs.As a newly developed class of drugs,the places of most bDMARDs in the management of JIA remain to be well estab-lished.Nevertheless,the continuous evolution of bDMARDs raises hopes of improving long-term disease outcomes for JIA.

Emerging Novel Therapeutic Approaches for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially Aβ and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren’s syndrome

Primary Sjögren’s syndrome(pSS)is a systemic autoimmune disease with high prevalence and possible poor prognosis.Though the pathogenesis of pSS has not been fully elucidated,B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients.It has long been identified that Janus kinases-signal transducer and activator of transcription(JAK-STAT)signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus.Recently,increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells.Signal transducer and activator of transcription 1(STAT1),STAT3,and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development,respectively or synergically.These results reveal the potential application of Janus kinase inhibitors for treatment of pSS,which may fundamentally improve the quality of life and prognosis of patients with pSS.

SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins

Glial cell line-derived neurotrophic factor(GDNF),a disease-modifying drug for Parkinson’s disease(PD)is in Phase 2 clinical trials(EudraCT number:2011-003866-34),however it is administered by direct intrastriatal delivery via stereotaxy,which is accompanied with intracranial infection,brain tissue damage,and other complications.In addition,because of complex administration routes,clinical trials of GDNF have yielded contrary results,largely due to differences in dose and concentration brought by intracranial device.Herein,a small molecular agonist SC79 was screened to open blood-brain barrier(BBB)and promote GDNF liposomes to get into brain.SC79 reversibly reduces the expression of claudin-5,one of dominant tight junctions of BBB.Animal study showed SC79 promoted liposomes to enter into brain parenchyma 2.43 times more than that of the control.Motor deficits of PD mice receiving SC79 and brain-targeted GDNF liposomes were recovered by 36.70%and tyrosine hydroxylase positive neurons in striatum were restored by 39.90%.Our combination therapy effectively avoids the side effects such as secondary infection and uneven delivery caused by intracranial injection,improving patients’compliance and providing valuable research ideas for the clinic.