Biological therapy for ulcerative colitis:An update

Of the diverse biological agents used for patients with ulcerative colitis, the anti-tumor necrosis factor-α agents infliximab and adalimumab have been used in large-scale clinical trials and are currently widely used in the treatment of inflammatory bowel disease patients. Recent studies have indicated that golimumab, oral tofacitinib and vedolizumab reportedly achieved good clinical response and remission rates in ulcerative colitis patients. Thus, we believe that the detailed investigation of various studies on clinical trials may provide important information for the selection of appropriate biological agents, and therefore, we have extensively reviewed such trials in the present study.

Frequency and prognostic role of mucosal healing in patients with Crohn's disease and ulcerative colitis after one-year of biological therapy

AIM: To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’s disease (CD) and ulcerative colitis (UC).

Rare extraintestinal manifestations of ulcerative colitis treated with dual biologic therapy:A case report

BACKGROUND Ulcerative colitis(UC)is an idiopathic,chronic inflammatory bowel disease(IBD)most often located in the rectum,but may involve the entire colon.Extra intestinal manifestations(EIMs)occur with varying frequency depending on the affected organ.The most common ones are musculoskeletal EIMs,affecting up to 33%-40%of IBD patients.These include,among others,inflammatory back pain,tendinitis,plantar fasciitis and arthritis.Only a few case reports in literature discuss Achilles tendinitis.CASE SUMMARY This report describes a patient with UC and Achilles tendinitis in whom after many unsuccessful attempts of treatment with sulfasalazine,mesalazine,glucocorticosteroids,infliximab and tofacitinib,a complete UC remission and resolution of Achilles tendinitis were achieved with the use of dual biologic therapy(DBT)-ustekinumab and adalimumab(ADA).CONCLUSION This case mentions rare EIMs of UC and suggests that DBT may be an alternative for patient with ulcerative colitis and EIMs.

Biological therapy for ulcerative colitis

Ulcerative colitis(UC)is a major form of inflammatory bowel disease(IBD)worldwide.Better understanding of the pathogenesis of UC has led to the development of novel therapeutic agents that target specific mediators of the inflammatory cascade.A number of biological agents have been approved by the U.S.Food and Drug Administration(FDA)for the treatment of UC and several more are currently in various phases of drug development.The commonly used agents include TNFa antagonists(e.g.infliximab,adalimumab,and golimumab)and anti-integrin agents(vedolizumab).These biological agents have profoundly influenced the management of UC patients,especially those with refractory disease.This paper reviews the currently available knowledge and evidence for the use of various biological agents in the treatment of UC.

Optimizing the use of biological therapy in patients with inflammatory bowel disease

Biological therapy revolutionized the treatment of inflammatory bowel disease(IBD)during the last decade.These monoclonal antibodies,which target tumor necrosis factor(TNF),integrins or IL12/23,have been approved—or are in development for—both Crohn’s disease(CD)and ulcerative colitis(UC).Early use of these agents taught clinicians that induction and maintenance therapy,coupled with immunomodulator agents,reduced the immunogenicity of these agents,and led to sustained remission in many patients.More recent data has demonstrated that,through dose adjustments,optimizing serum drug levels may also provide more durable maintenance of remission,and improved mucosal healing.This review examines clinical practices that may enhance clinical outcomes from biological therapy in IBD.

Improving cancer therapy by combining cell biological, physical, and molecular targeting strategies

Successful cancer therapy depends on selective killing of tumor cells while sparing normal cells. Selectivity can be achieved through treatment strategies that target tumor cells. A recent report from the Li laboratory （1） describes an elegant strategy to selectively kill tumor cells by combining several targeting strategies based on cell biological, physical, and molecular （genetic） properties of tumor and normal cells that enhances tumor cell killing in vitro and in an in vivo tumor xenograft model. The idea of using a multiplex targeting approach is reminiscent of strategies in which several antibiotics are used to treat bacterial infections while minimizing the chance that rare antibiotic-resistant mutants will arise within a population.

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease

Biologic agents have now been used in the management of inflammatory bowel disease(IBD)for many years where experience,expertise and confidence in their use has developed over time.In the United Kingdom,there are well established guidelines and recommendations for both single agent biologic treatments,and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy.In recent times,there has been increasing interest and experience using dual biologic therapy(DBT)in IBD,primarily in difficult to treat and refractory cases with high disease burden.However,published data on use,experience and safety profiles is limited and large-scale studies remain low in number in this developing area.We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.

Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. rmhTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the 11th to 17th days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00±9.92 in the trial group, and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. Conclusion: The administration of rmhTNF in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor.

Access to biologicals in Crohn's disease in ten European countries

AIM To analyze access(availability, affordability and acceptability) to biologicals for Crohn's disease(CD) in ten European countries and to explore the associations between these dimensions, the uptake of biologicals and economic development.METHODS A questionnaire-based survey combined with desk research was carried out in May 2016. Gastroenterologists from the Czech Republic, France, Germany, Hungary, Latvia, Poland, Romania, Slovakia, Spain and Sweden were invited to participate and provide data on the availability of biologicals/biosimilars, reimbursement criteria, clinical practice and prices, and use of biologicals. An availability score was developed to evaluate the restrictiveness of eligibility and administrative criteria applied in the countries. Affordability was defined as the annual cost of treatment as a share of gross domestic product(GDP) per capita. Correlations with the uptake of biologicals, dimensions of access and GDP per capita were calculated.RESULTS At the time of the survey, infliximab and adalimumab were reimbursed in all ten countries, and vedolizumab was reimbursed in five countries(France, Germany, Latvia, Slovakia, Sweden). Reimbursement criteria were the least strict in Sweden and Germany, and the strictest in Hungary, Poland and Slovakia. Between countries, the annual cost of different biological treatments differed 1.6-3.3-fold. Treatments were the most affordable in Sweden(13%-37% of the GDP per capita) and the least affordable in the Central and Eastern European countries, especially in Hungary(87%-124%) and Romania(141%-277%). Biosimilars made treatments more affordable by driving down the annual costs. The number of patients with CD on biologicals per 100000 population was strongly correlated with GDP per capita(0.91), although substantial differences were found in the uptake among countries with similar economic development. Correlation between the number of patients with CD on biologicals per 100000 population and the availability and affordability was also strong(-0.75,-0.69 respectively). CONCLUSION Substantial inequalities in access to biologicals were largely associated with GDP. To explain differences in access among countries with similar development needs further research on acceptance.

Malignant solitary fibrous tumor in the central nervous system treated with surgery,radiotherapy and anlotinib:A case report

BACKGROUND Solitary fibrous tumor(SFT)of the central nervous system is rare.It is predominantly benign and rarely malignant.There is no established standardized treatment regimen for malignant intracranial SFTs.CASE SUMMARY We present a rare case of SFT in a 9-year-old girl with a space-occupying effect in the frontal-parietal lobes.She underwent craniotomy,and the mass was resected.Immunohistochemistry examination of the specimen showed that Ki-67 proliferation index staining was highly positive in 80%of tumor cells.Whole exome sequencing of the surgical tissue showed 38 somatic gene mutations and 1 gene amplification such as fibroblast growth factor receptor 4 or TP53.At 1.5 mo after surgery,head magnetic resonance imaging revealed that the tumor had recurred.The patient received 60 Gy and 30 fractions of intensity modulated radiotherapy.The patient then received anlotinib 8 mg po qd for 1-14 d of a 21 d cycle.Following this regimen,the patient achieved stable disease for>17 mo.Magnetic resonance imaging at 1.5 year after surgery showed that the tumor had not progressed.CONCLUSION This is the first reported case of SFT of the central nervous system treated with surgery,radiotherapy and anlotinib.This regimen may be an effective treatment option for malignant intracranial SFT patients.

Role of conventional therapies in the era of biological treatment in Crohn’s disease

Outstanding progress regarding the pathophysiology of Crohn's disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentrates on the results of randomized,placebo-controlled trials,and meta-analyses when available,that provide the highest degree of evidence. Current guidelines on the management of CD recommend a step-up approach to treatment involving the addition of more powerful therapies as the severity of disease and refractoriness to therapy increase. The advent of biological drugs has opened new therapeutic horizons for treating CD,modifying the treatment goals. However,the large majority of patients with CD will be managed through conventional therapy,even if they are a prelude to biological therapy.

Dual biologic therapy with ocrelizumab for multiple sclerosis and vedolizumab for Crohn's disease:A case report and review of literature

BACKGROUND Little is known about the safety and efficacy of using two or more biologics for the treatment of immune-mediated diseases,including Crohn’s disease(CD).CASE SUMMARY This case report and narrative review demonstrate the potential safety of dual biologic therapy(DBT)in a 45-year-old female with two separate immunemediated diseases.She had a history of multiple sclerosis for which she was receiving treatment with ocrelizumab,and she had been recently diagnosed with CD after presenting with diarrhoea.The CD diagnosis was confirmed radiologically,endoscopically,histologically,and biochemically.The patient received treatment with vedolizumab,a gut-specific inhibitor of theα4β7 integrin on leukocytes.No adverse reactions were observed for the duration of treatment.The safety of ocrelizumab and vedolizumab for the treatment of different immune-mediated diseases was demonstrated.CONCLUSION DBT may be a safe and effective option for the treatment of refractory disease or multiple immunemediated diseases.Newer biologics,which have improved safety profiles and gut specificity,may provide promising avenues for treatment.However,caution must be exercised in the appropriate selection of biologics given their inherent immunosuppressive properties,side effects,and efficacy profiles.Current evidence suggests that biologic therapy is not associated with a worse prognosis in patients with coronavirus disease 2019,but treatment decisions should be made in a multidisciplinary setting.Further research from controlled trials is needed to better understand the safety profile of DBT in CD.The immunopathological mechanisms underlying DBT also remain to be clarified.

Biologic therapy for Crohn’s disease over the last 3 decades

BACKGROUND Despite the overload of publications on Crohn’s disease(CD),no comprehensive analysis of biologic therapy for CD has been reported.AIM To determine knowledge gaps and identify areas of interest of biologic therapy for CD.METHODS The top 100 highest-cited original articles were identified from January 1991 to December 2020 in the Clarivate Analytics Web of Science Core Collection database.We conducted a bibliometric analysis of biologic therapy for CD based on total citations,summarized the bibliographic information of the articles related to CD biologic therapy,and explored the research hotspots.RESULTS The top 100 highest-cited original articles were identified with total citations ranging from 307 to 2978.The 2000s(Period II,n=66)yielded the most influential original articles and saw the most dramatic growth.Among the top 10 countries,including 8 European countries and 2 North American countries,the United States(n=37)and Belgium(n=20)contributed the most publications.Among the top 10 institutions,the University Hospital Gasthuisberg in Belgium(n=23),the University of Chicago in the United States(n=20),and the Mayo Clinic in the United States(n=17)published the most papers.Regarding authors,Rutgeerts P in Belgium(n=32),Sandborn WJ in the United States(n=23),and Feagan BG in Canada(n=18)published the highest number of studies.The cooperation relationships between the United States and Europe were most frequent.Gastroenterology(impact factor=22.682)published the most articles on biologic therapy for CD(n=32)with 17654 total citations.Anti-tumor necrosis factor biologics and monoclonal antibodies were the most studied topics.CONCLUSION The bibliometric analysis emphasized the key contributions to the development of the specialized field.These data would provide useful research insights into biologic therapy for CD for clinicians and researchers.

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.

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients

AIM:To investigate the correlation between the appearance of skin lesions and concentration of interleukin(IL)-17A,IL-23 and interferon-γ(IFN-γ)in Crohn’s disease(CD)patients during anti-tumor necrosis factor-α(TNF-α)therapy METHODS:A prospective study included 30 adult patients with CD of Caucasian origin(19 men and 11women;mean age±SD 32.0±8.6 years)during biological therapy with anti-TNF-αantibodies from January2012 to March 2013.Eighteen patients were treated with infliximab,seven with adalimumab and five withcertolizumab.Inclusion criteria were exacerbation of the underlying disease,Crohn’s Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies.Patients with a history of psoriasis,atopic dermatitis and other autoimmune skin lesions were excluded from the study.The control group consisted of 12 healthy subjects.A diagnostic survey was carried out,blood tests and careful skin examination were performed,and the serum levels of IL-17,IL-23 and IFN-γwere measured using an enzyme-linked immunosorbent assays technique.Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by antiTNF-αtherapy.RESULTS:Skin manifestations occurred in 18 of CD patients during the anti-TNF-αtherapy(60%),in the average time of 10.16±3.42 mo following the beginning of the 52-wk treatment cycle.Skin lesions observed in CD patients during biological therapy included psoriasiform lesions(44.4%),and eczema forms lesions(22.2%).In CD patients with drug induced skin lesions significantly higher levels of hemoglobin(13.3±1.5 g/dL vs 10.8±1.9 g/dL,P=0.018)and hematocrit(39.9%±4.5%vs 34.3%±5.4%,P=0.01),as well as a significantly lower level of platelets(268±62×103/μL vs 408±239×103/μL,P=0.046)was observed compared with CD patients without skin manifestations.The concentrations of IL-17A and IL-23in CD patients with skin lesions developed under antiTNF-αtherapy were significantly higher compared to those in patients without lesions(IL-17A:39.01±7.03pg/mL vs 25.71±4.90 pg/mL,P=0.00004;IL-23:408.78±94.13 pg/mL vs 312.15±76.24 pg/mL,P=0.00556).CONCLUSION:Skin lesions in CD patients during bio-logical therapy may result from significantly increased concentrations of IL-17A and IL-23,which are strongly associated with TNF-α/Th1 immune pathways.

How to manage inflammatory bowel disease during the COVID-19 pandemic:A guide for the practicing clinician

Managing inflammatory bowel disease(IBD)during the coronavirus disease 2019(COVID-19)pandemic has been a challenge faced by clinicians and their patients,especially concerning whether to proceed with biologics and immunosuppressive agents in the background of a global outbreak of a highly contagious new coronavirus(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2).The knowledge about the impact of this virus on patients with IBD,although it is still scarce,is rapidly evolving.In particular,concerns surrounding medications’impact for IBD on the risk of acquiring SARS-CoV-2 infection or developing COVID-19,and potentially exacerbate viral replication and the COVID-19 course,are a current thinking of both practicing clinicians and providers caring for patients with IBD.Managing patients with IBD infected with SARS-CoV-2 depends on both the clinical activity of the IBD and the occasional development and severity of COVID-19.In this review,we summarize the current data regarding gastrointestinal involvement by SARS-CoV-2 and pharmacologic and surgical management for IBD concerning this infection,and the COVID-19 impact on both the patient's psychological functioning and endoscopy services,and we concisely summarize the telemedicine roles during the COVID-19 pandemic.

Advances in precision treatment of ovarian cancer

Ovarian cancer is one of the most common malignant tumors in female reproductive organs.Due to the lack of effective screening and early diagnosis methods,the vast majority of patients with ovarian cancer are in advanced stages once diagnosed.Precision therapy mainly includes immunotherapy,targeted therapy,biological therapy,and gene therapy.At present,precision therapy is increasingly used in the clinical treatment of ovarian cancer due to its advantages,such as fewer side effects and a high degree of killing.This article summarizes the recent advances in the precise treatment of ovarian cancer.

Historical evolution,overview,and therapeutic manipulation of costimulatory molecules

Co-stimulatory molecules are key mediators in the regulation of immune responses and knowledge of its different families,structure,and functions has improved in recent decades.Understanding the role of co-stimulatory molecules in pathological processes has allowed the development of strategies to modulate cellular functions.Currently,modulation of co-stimulatory and co-inhibitory molecules has been applied in clinical applications as therapeutic targets in diseases and promising results have been achieved.

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.

Progressive Symmetrical Erythrokeratoderma-Like Psoriasis: A New Case Report

Background: Psoriasis, a chronic, systemic, inflammatory disease with prominent skin involvement, affects approximately 2% - 4% of the world population. Common variants of psoriasis are plaque psoriasis, inverse psoriasis, guttate psoriasis, erythrodermic psoriasis, pustular form either palmoplantar pustular psoriasis or generalized pustular psoriasis, nail psoriasis, and psoriatic arthritis. Progressive Symmetrical Erythrokeratoderma (PSEK) is a rare genetic disorder, characterized by fixed, well-defined erythematous and hyperkeratotic plaques distributed predominantly on the elbows, knees, trunk, and dorsal surfaces of hands and feet. Clinically has the same presentation to psoriasis especially at early onset and could be confused with psoriasis but histopathological findings and progression of the psoriatic disease can differentiate between both conditions. Aim: To document a new variant of a severe, recalcitrant type of psoriasis with a history of recurrent attacks of exacerbations and partial remissions especially in lesions involving lower extremities that are clinically PSEK-like in presentation, but histopathologically consistent with psoriasis. Case report: A 12-year-old childhood male, known case of Down’s syndrome, presented to our clinic with a history of severely pruritic skin rashes involving the perioral area, corners of the mouth, bilateral elbows, dorsal hands, scrotum, and both lower extremities for 6 years duration. The rashes gradually progressed with time to form fixed lesions in the last 2 years. He was received multiple treatment modalities, including topical steroids, topical vitamin D derivatives, and narrowband UVB phototherapy without significant improvement and the lesions became more worsened over time. Conclusion: psoriasis can be presenting with a new variant of a severe, recalcitrant, and difficult to treat type in Down syndrome cases with a history of recurrent attacks of exacerbations and partial remissions especially in lesions involving lower extremities which are clinically PSEK-like in presentation, but histopathologically consistent with psoriasis. However, early diagnosis and strict management are important in controlling the severity of the condition.