Immunology and Biotherapies
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Biosimilars Savings: “...the Substance of Things Hoped For”

Biosimilars Savings: “...the Substance of Things Hoped For” | Immunology and Biotherapies | Scoop.it
Healio Rheumatology | In 2006, the European Medicines Agency approved Omnitrope, a biosimilar recombinant human growth hormone, as the first biosimilar. Over the subsequent decade, the EMA has approved additional biosimilars and, as of December 2017, 33 biosimilars were marketed in the European Union to treat a variety of conditions.Market competition in many European Economic Area countries has resulted in
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Immunology and Biotherapies
Page Ressources et Actualités du DIU immunologie et biothérapies
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Resources for DIU Immunologie et Biothérapies

DIU Immunologie et Biotherapies is a french diploma associating many french universities and immunology laboratories. It is dedicated to the involvement of immunology in new biotherapies, either molecular or cellular

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We choose Scoop.it as preferred curation tool to collect, select, comment informations flowing on the web in this rapidly evolving theme to keep teachers abreast of scientific knowledge and help students surf the wave...

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in Immunology also use http://www.scoop.it/t/immunology

in Mucosal Immunity http://www.scoop.it/t/mucosal-immunity

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in Allergy an Clinical Immunology http://www.scoop.it/t/allergy-and-clinical-immunology

in Autoimmunity http://www.scoop.it/t/autoimmunity

 

For further informantions on Immune monitoring of Immune therapies, go to

http://www.scoop.it/t/immune-monitoring-1

by MdC

 

Looking for cancer applications inside this topic, use

http://www.scoop.it/t/immunology-and-biotherapies?q=cancer

 

Looking for cytokines and chemokines, use

http://www.scoop.it/t/cytokines-et-chimiokines

 

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Intracerebral haemorrhage during alemtuzumab administration

Intracerebral haemorrhage during alemtuzumab administration | Immunology and Biotherapies | Scoop.it
Alemtuzumab is a monoclonal antibody that targets CD52, a protein expressed at high levels on T and B lymphocytes, and at lower levels on other components of the innate immune system.1 Alemtuzumab 12 mg per day is administered intravenously over five consecutive days, followed by a second course...
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Researchers characterize mechanism of action of CAR T cells

Researchers characterize mechanism of action of CAR T cells | Immunology and Biotherapies | Scoop.it
The scientific community has made great strides over the past decade in the development of a new class of cancer therapy called immunotherapy, a treatment that activates a patient's own immune system to target cancer cells.

Via Krishan Maggon
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Reprogramming pancreatic cells into insulin makers to treat diabetes | FierceBiotech

Reprogramming pancreatic cells into insulin makers to treat diabetes | FierceBiotech | Immunology and Biotherapies | Scoop.it
Scientists are keen to find methods for regenerating insulin-producing beta cells to treat diabetes. Now, researchers at the University of Geneva have converted other pancreatic cells into cells that can secret insulin, and they have shown promising results in treating mouse models of diabetes.
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Drug to Antibody Ratio (DAR) Analysis - Biopharmaceutical Characterization Services - ALFA CHEMISTRY

Drug to Antibody Ratio (DAR) Analysis - Biopharmaceutical Characterization Services - ALFA CHEMISTRY | Immunology and Biotherapies | Scoop.it
The scientists from Alfa Chemistry are specialized in offering our clients with a high quality customized drug/antibody ratio (DAR) analysis.
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Intradermal delivery of vaccine nanoparticles using hollow microneedle array generates enhanced and balanced immune response - ScienceDirect

Intradermal delivery of vaccine nanoparticles using hollow microneedle array generates enhanced and balanced immune response - ScienceDirect | Immunology and Biotherapies | Scoop.it
Abstract
Hollow microneedles can help overcome the skin permeation barrier imposed by the stratum corneum and facilitate transcutaneous delivery of nanoparticle delivery systems. In the present study, we investigated the use of the hollow microneedle array for intradermal delivery of polymeric nanoparticles (NPs) in rats. Compared to intravenous and subcutaneous routes of administration, intradermal delivery of polymeric NPs via a hollow microneedle array resulted in a unique pharmacokinetic profile, characterized by an early burst transit through the draining lymph nodes and a relatively limited overall systemic exposure. Based on high local lymphatic concentrations achieved, we investigated the use of this modality for vaccine delivery. A model antigen ovalbumin (OVA) and TLR agonists imiquimod and monophosphoryl Lipid A encapsulated in poly(d,l-lactide-co-glycolide) (PLGA) NPs were used as the vaccine formulation. Compared to soluble OVA-based vaccine, OVA loaded NPs demonstrated faster antibody affinity maturation kinetics. Moreover, antigen loaded NPs delivered via a hollow microneedle array elicited a significantly higher IgG2a antibody response and higher number of interferon (IFN)-γ secreting lymphocytes, both markers of Th1 response, in comparison to antigen loaded NPs delivered by intramuscular injection and soluble antigen delivered through hollow microneedle array. Overall, our results show that hollow microneedle mediated intradermal delivery of polymeric NPs is a promising approach to improve the effectiveness of vaccine formulations.

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TB episode following PD-1 blockade | Immunopaedia

TB episode following PD-1 blockade | Immunopaedia | Immunology and Biotherapies | Scoop.it
13th February Successful use of PD-1 blockade for cancer immunotherapy, has brought up the question as to whether this same therapy could be successful against
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IL1RL1 is dynamically expressed on Cbfb-MYH11 + leukemia stem cells and promotes cell survival

IL1RL1 is dynamically expressed on Cbfb-MYH11 + leukemia stem cells and promotes cell survival | Immunology and Biotherapies | Scoop.it
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Challenging the workhorse: Comparative analysis of eukaryotic microorganisms for expressing monoclonal antibodies - Jiang - - Biotechnology and Bioengineering - Wiley Online Library

Challenging the workhorse: Comparative analysis of eukaryotic microorganisms for expressing monoclonal antibodies - Jiang - - Biotechnology and Bioengineering - Wiley Online Library | Immunology and Biotherapies | Scoop.it
For commercial protein therapeutics, Chinese hamster ovary (CHO) cells have an established history of safety, proven capability to express a wide range of therapeutic proteins, and high volumetric productivities. Expanding global markets for therapeutic proteins and increasing concerns for broadened access of these medicines has catalyzed consideration of alternative approaches to this platform. Reaching these objectives likely will require an order of magnitude increase in volumetric productivity and a corresponding reduction in the costs of manufacture. For CHO‐based manufacturing, achieving this combination of targeted improvements presents challenges. Based on a holistic analysis, the choice of host cells was identified as the single most influential factor for both increasing productivity and decreasing costs. Here we evaluated eight wild‐type eukaryotic microorganisms with prior histories of recombinant protein expression. The evaluation focused on assessing the potential of each host, and their corresponding phyla, with respect to key attributes relevant for manufacturing, namely, i) growth rates in industry‐relevant media, ii) adaptability to modern techniques for genome editing, and iii) initial characterization of product quality. These characterizations showed that multiple organisms may be suitable for production with appropriate engineering and development and highlighted that yeast in general present advantages for rapid genome engineering and development cycles. This article is protected by copyright. All rights reserved.

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Applications of Machine Learning in Decision Analysis for Dose Management for Dofetilide; Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non-Small Cell Lung Cancer

Applications of Machine Learning in Decision Analysis for Dose Management for Dofetilide; Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non-Small Cell Lung Cancer | Immunology and Biotherapies | Scoop.it
Where dosing dreams are born: Developments in drug toxicity modelling and reinforcement learning in optimising drug dosing regimens...
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Cutting Edge: HDAC3 Protects Double-Positive Thymocytes from P2X7 Receptor–Induced Cell Death

Cutting Edge: HDAC3 Protects Double-Positive Thymocytes from P2X7 Receptor–Induced Cell Death | Immunology and Biotherapies | Scoop.it
Intricate life-versus-death decisions are programmed during T cell development, and the regulatory mechanisms that coordinate their activation and repression are still under investigation. In this study, HDAC3-deficient double-positive (DP) thymocytes exhibit a severe decrease in numbers.
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Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: A...

Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: A... | Immunology and Biotherapies | Scoop.it
Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard
treatment for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia
(Ph+ ALL) achieving complete remission after induction containing tyrosine kinase
inhibitors (TKIs).
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Ajuster les dosages de chimiothérapie grâce à l’intelligence artificielle

Ajuster les dosages de chimiothérapie grâce à l’intelligence artificielle | Immunology and Biotherapies | Scoop.it
Trouver la bonne dose de médicament par tâtonnement peut être une épreuve pénible pour des patients déjà éprouvés par la maladie. L’intelligence artificielle peut accélérer considérablement ce processus grâce à un nouvel algorithme créé par ...
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Monoclonal Antibody Treatment of RSV Bronchiolitis in Young Infants: A Randomized Trial. - PubMed - NCBI

Monoclonal Antibody Treatment of RSV Bronchiolitis in Young Infants: A Randomized Trial. - PubMed - NCBI | Immunology and Biotherapies | Scoop.it
Pediatrics. 2019 Feb 13. pii: e20182308. doi: 10.1542/peds.2018-2308.[Epub ahead of print]...
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Frontiers | The Impact of Immune Interventions: A Systems Biology Strategy for Predicting Adverse and Beneficial Immune Effects | Immunology

Frontiers | The Impact of Immune Interventions: A Systems Biology Strategy for Predicting Adverse and Beneficial Immune Effects | Immunology | Immunology and Biotherapies | Scoop.it
Despite scientific advances it remains difficult to predict the risk and benefit balance of immune interventions. Since a few years, network models have been built based on comprehensive datasets at multiple molecular/cellular levels (genes, gene products, metabolic intermediates, macromolecules, cells) to illuminate functional and structural relationships. Here we used a systems biology approach to identify key immune pathways involved in immune health endpoints and rank crucial candidate biomarkers to predict adverse and beneficial effects of nutritional immune interventions. First, a literature search was performed to select the molecular and cellular dynamics involved in hypersensitivity, autoimmunity and resistance to infection and cancer. Thereafter, molecular interaction between molecules and immune health endpoints was defined by connecting their relations by using database information. MeSH terms related to the immune health endpoints were selected resulting in the following selection: hypersensitivity (D006967: 184 genes), autoimmunity (D001327: 564 genes), infection (parasitic, bacterial, fungal and viral: 357 genes) and cancer (D009369: 3173 genes). In addition, a sequence of key processes was determined using Gene Ontology which drives the development of immune health disturbances resulting in the following selection: hypersensitivity (164 processes), autoimmunity (203 processes), infection (187 processes) and cancer (309 processes). Finally, an evaluation o
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JCI Insight - Mass cytometry identifies distinct CD4+ T cell clusters distinguishing HIV-1–infected patients according to antiretroviral therapy initiation

JCI Insight - Mass cytometry identifies distinct CD4+ T cell clusters distinguishing HIV-1–infected patients according to antiretroviral therapy initiation | Immunology and Biotherapies | Scoop.it
Research ArticleAIDS/HIVImmunology Free access | 10.1172/jci.insight.125442 Mass cytometry identifies distinct CD4+ T cell clusters distinguishing HIV-1–infected patients according to antiretroviral therapy initiation Yonas Bekele,1 Tadepally Lakshmikanth,2 Yang Chen,2 Jaromir Mikes,2 Aikaterini Nasi,1 Stefan Petkov,1 Bo Hejdeman,3 Petter Brodin,2,4 and Francesca Chiodi1 First published February 7, 2019 - More info

 

Abstract

 

Recent guidelines recommend antiretroviral therapy (ART) to be administered as early as possible during HIV-1 infection. Few studies addressed the immunological benefit of commencing ART during the acute phase of infection. We used mass cytometry to characterize blood CD4+ T cells from HIV-1–infected patients who initiated ART during acute or chronic phase of infection. Using this method, we analyzed a large number of markers on millions of individual immune cells. The results revealed that CD4+ T cell clusters with high expression of CD27, CD28, CD127, and CD44, whose function involves T cell migration to inflamed tissues and survival, are more abundant in healthy controls and patients initiating ART during the acute phase; on the contrary, CD4+ T cell clusters in patients initiating ART during the chronic phase had reduced expression of these markers. The results are suggestive of a better preserved immune function in HIV-1–infected patients initiating ART during acute infection.

 

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Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis - Industrial & Engineering Chemistry Research (ACS Publications)

Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis - Industrial & Engineering Chemistry Research (ACS Publications) | Immunology and Biotherapies | Scoop.it
Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis...
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Perform LCMS bioanalysis of antibody drugs using new nSMOL technology

Perform LCMS bioanalysis of antibody drugs using new nSMOL technology | Immunology and Biotherapies | Scoop.it
This application note demonstrates how nSMOL proteolysis can be conducted under static conditions and still fulfil the guideline criteria. Without the need of a dedicated shaking instrument, the nSMOL protocol can be integrated into automated assays and increase efficiency in your laboratory.
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Aluminum Ingestion Promotes Colorectal Hypersensitivity in Rodents

Aluminum Ingestion Promotes Colorectal Hypersensitivity in Rodents | Immunology and Biotherapies | Scoop.it
Irritable bowel syndrome (IBS) is a multifactorial disease arising from a complex
interplay between genetic predisposition and environmental influences. To date, environmental
triggers are not well known.
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5 Groundbreaking Treatments for Aging Pets

5 Groundbreaking Treatments for Aging Pets | Immunology and Biotherapies | Scoop.it
As our pets begin to age, the onset of senior-related health conditions can happen rapidly. This doesn’t mean your pet doesn’t have options. Conditions exacerbated by age, such as arthritis, anxiety and cancer, can be improved by veterinary treatments.
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An injectable bone marrow–like scaffold enhances T cell immunity after hematopoietic stem cell transplantation

An injectable bone marrow–like scaffold enhances T cell immunity after hematopoietic stem cell transplantation | Immunology and Biotherapies | Scoop.it
A bone marrow–like scaffold improves T cell regeneration after hematopoietic stem cell transplantation.
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Clustered stem cells become working insulin producers in potential cure for diabetes

Clustered stem cells become working insulin producers in potential cure for diabetes | Immunology and Biotherapies | Scoop.it
Medical scientists have made a promising breakthrough in diabetes research, describing a novel technology that converts stem cells into insulin-secreting beta cells by harnessing an often overlooked step in their maturation.
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Review article: managing the adverse events caused by anti‐TNF therapy in inflammatory bowel disease - Shivaji - - Alimentary Pharmacology & Therapeutics - Wiley Online Library

Review article: managing the adverse events caused by anti‐TNF therapy in inflammatory bowel disease - Shivaji - - Alimentary Pharmacology & Therapeutics - Wiley Online Library | Immunology and Biotherapies | Scoop.it
2 AIMS AND METHODS A MEDLINE and PubMed search was undertaken by (U.S, C.L) for articles pertaining to adverse effects of anti‐TNF therapy in IBD. After an initial title screen, all relevant articles were examined in full. The main aim of the review is to focus on management of adverse events caused by anti‐TNF therapy. For clarity, these AEs are discussed in categories as per systems, alongside recommended course of action including any further investigations or management. Where relevant, this manuscript also refers to international guidelines. 2.1 Noninfectious complications and management strategies 2.1.1 Hypersensitivity reactions Hypersensitivity reactions vary widely in presentation, ranging from acute infusion reactions to delayed hypersensitivity. Type I acute hypersensitivity reactions (IgE mediated) present as anaphylaxis Type II are cytotoxic; complement‐mediated Type III are immune‐complex related presenting as serum sickness Type IV are cell‐mediated delayed hypersensitivity; mediated by T lymphocytes Acute infusion reactions (IR) are defined as those which occur during or within 24 hours of the infusion. The symptoms vary and reactions can range from mild (flushing, dizziness, headache, itching, rash) to severe (anaphylactic‐like).2 Acute infusion reactions are relatively common, estimated to occur in up to 5% of infusions, with less than 1% of all infusions resulting in a severe reaction.3 Patients with antibodies to infliximab are at an increased risk of infusion reactions4 and case reports suggest hypersensitivity to adalimumab are also associated with adalimumab antibodies.5 A review by the Food and Drug Administration (FDA) reported that injection site reactions were more common with adalimumab6 with higher reporting odds ratio(ROR) in the 20‐29 years age group (ROR = 16.18). The ROR was seen to reduce with increasing age.6 Injection site reactions to golimumab in the PURSUIT study were low at 3.4% with no reported anaphylaxis or delayed hypersensitivity to 6 weeks.7 Delayed reactions (24 hours to 14 days) presenting with arthralgia, myalgia, fever, fatigue and rash are much rarer (<1%).3 The pathophysiology of immunological features are not completely understood.8 Management The management of infusion reaction (IRs) is generally similar regardless of which agent has caused it. Typically, symptoms improve substantially or resolve completely after infusion rate adjustments and treatment with paracetamol, antihistamines or corticosteroids are provided. Evidence to support the use of premedication with corticosteroids or antihistamines is limited, with patients still experiencing infusion reactions despite premedication9 and therefore should be considered on an individual basis. Injection site pain due to adalimumab can be reduced by using low volume formulations which are free from citrate buffers, with no change in efficacy.10 In severe acute reactions, it is recommended that infusion is stopped and focus should be on maintaining airway, circulation as per standard anaphylaxis guidelines.11 (Table 1) Delayed infusion reactions are typically managed by antihistamines, paracetamol and corticosteroids. A systematic review looked at management of infusion reactions and presented useful algorithms to manage mild, moderate and severe reactions.12 These algorithms are simple, and a pragmatic tool to use for the vast majority of reactions seen in clinical practice.12 After a hypersensitivity reaction, it is pragmatic to obtain therapeutic drug levels and anti‐drug antibody levels. Complication Diagnosis Management strategy Type 1 Hypersensitivity This is more common when antibody titres are high. Incidence is higher during reintroduction of drugs Clinical diagnosis Serum mast cell tryptase Detection of antibodies on serum analysis where available Mild reactions: Slow infusion rates Consider hydrocortisone injections as a preadministration medication Anaphylaxis reactions: Treat as per ALS pathway with adrenaline, steroids and anti‐histamines Type 2 Complement mediated Nonspecific symptoms Detection of antibodies on serum analysis where available Symptomatic treatment Consider stopping treatment Type 3 Immune‐complex mediated Serum sickness Difficult to detect on assays, immune complexes known to adhere to membranes Symptomatic treatment Consider stopping the drug and switch if antibodies are confirmed Type 4 T‐cell mediated Delayed hypersensitivity reaction (after 24 h up to 14 d postinfusion) Clinical diagnosis Symptomatic management Consider stopping drug anti‐TNF, anti‐tumour necrosis factor; ALS, advanced life support. 2.1.2 Haematological effects Leucopenia Neutropenia has been reported in anti‐TNFα treatment‐exposed patients, with up to 20% of patients developing neutropenia on at least one occasion.13 TNFα up‐regulates other proinflammatory cytokines, including interleukin‐1 (IL‐1), IL‐6, IL‐8, and granulocyte–macrophage colony‐stimulating factor, involved in the differentiation and maturation of haematopoietic progenitor cells.14 TNFα blockade could mediate bone marrow failure by inhibiting stem cell differentiation.15 However, the reduction in neutrophil count following TNFα inhibitor therapy is not seen for other cells from the same lineage (myeloid progenitor cell), specifically basophils, eosinophils and monocytes. The risk of neutropenia is significantly higher in patients with a low baseline neutrophil count or a previous history of neutropenia.13, 16 Thrombocytopenia Isolated thrombocytopenia following the use of anti‐TNF drugs17, 18 has been reported. There are multiple hypotheses as to the possible aetiology, including autoimmune platelet destruction secondary to antiplatelet antibodies, immune complexes triggering the complement cascade, another unknown autoimmune mechanism, or idiosyncratic reaction.18 Anaemia Anaemia is considered a marker of active disease in IBD and therefore clinicians need to first consider this as an aetiology. The incidence and prevalence of anaemia was approximately 19% and 28%, respectively, in a recent population based cohort study. Crohn's with stricturing disease and long‐standing UC were recognised as risk factors.19 One study showed only marginal improvement in anaemia after treatment with anti‐TNF therapy suggesting that disease activity in itself has a major role to play.20 In this section, anaemia directly attributable to biologics is discussed, which is rare. There are sporadic case reports of aplastic anaemia with infliximab, more commonly in patients with rheumatoid arthritis than IBD.21 A single case of infliximab induced autoimmune haemolytic anaemia (in a patient found to be anti‐nuclear antibody (ANA) positive 1:40) has also been reported.22 Management of haematological effects All patients starting anti‐TNF therapy should have a baseline complete blood count with repeat testing every three to six months. At the onset of neutropenia, the anti‐TNF should be withheld if the neutrophil count is deemed too low by the clinician. The patient should be left drug‐free until neutrophil counts recover and anti‐TNF therapy restarted when deemed clinically safe. Neutropenia can occur in patients managed with combination therapy with an anti‐metabolite and this should be borne in mind and should be discontinued first. A neutrophil count less than 1000 per mm3 should raise concern and <500 per mm3 should lead to discontinuation of incriminating drugs and close monitoring. Rare anti‐TNF induced systemic lupus erythematosus should be excluded and sargramostim is rarely necessary after drug discontinuation. Thrombocytopenia can be managed by drug cessation, corticosteroid therapy or rescue therapy with intravenous immunoglobulin (IVIG). Thrombocytopenia has been reported to be prolonged after cessation of therapy. In severe cases this could persist for up to 6 months and also preclude exposure to any further anti‐TNF agents.18 This is likely to be a class effect and rechallenge with same class could be risky and therefore discouraged.17 In severe cases, specialist haematology input is suggested. Anaemia in IBD is more commonly seen due to ongoing disease activity. Clinicians should first consider assessment for disease and strategies to control and manage anaemia secondary to disease as per guidelines. As anaemia related only to therapy is rare, there is no specific guidance in current literature regarding future therapy with anti‐TNF. Cessation of therapy would depend on careful physician‐patient discussion taking into account the severity of anaemia and alternative treatment strategies. Involving haematologist in refractory cases would be prudent. (Table 2). Complication Diagnosis Management strategy Leucopenia Neutropenia Blood count monitoring If <safety threshold: stop drug, monitor blood count Restart drug when counts are within normal range Monitor Consider G‐CSF Thrombocytopenia Blood count monitoring Establish temporal relationship to drug Secondary cases of low platelets to be excluded including concomitant drug therapy If <safety threshold: stop drug, monitor platelet count Consider IV immunoglobulins and steroids Consider switching to different class of biologic Anaemia Drug related anaemia is rare but aplastic anaemia can be serious Blood count monitoring Bone marrow aspiration in refractory cases If aplastic anaemia: withdraw and stop drug Refractory cases warrant specialist haematology assessment G‐CSF, Granulocyte‐colony stimulating factor. 2.1.3 Dermatological effects In addition to skin malignancies anti‐TNF therapy can cause a wide range of dermatological conditions. Most notably they include local skin irritation or reaction, increased skin infection rates, psoriasis, eczema, acne and alopecia. Other rare dermatological complications include erythema nodosum,23 granuloma annulare and interstitial granulomatous dermatitis. Although some of the above complications are also seen as extraintestinal manifestations of disease, temporal association with biologic therapy should help differentiate disease related complications from drug related complications. Psoriasis and psoriasiform reactions can occur directly as a result of anti‐TNF therapy, which interestingly is used by dermatologists to treat severe cases of psoriasis. Psoriasis is a relatively common side effect of anti‐TNF therapy, with 1.5%‐5% of patients developing this manifestation.24 It is seen most commonly in females, typically 2‐6 months following initiation of therapy.25 A nation‐wide cohort study reported incidence rates of anti‐TNF induced psoriasis in IBD at 0.5% per patient‐year.26 A more recent study shows a much higher incidence at 10.5%,27 but psoriasiform lesions are more common than psoriasis and have distinctive features. According to current evidence, females, smokers, and patients with fistulising disease appear to be at risk.27 In addition to anti‐TNF induced psoriasis, psoriasiform and drug‐induced psoriasiform lesions have been well‐recognised. Psoriasiform drug reactions can be distinguished histologically from psoriasis and resolve swiftly on cessation of drug therapy. Rechallenge results in recurrence of the lesions. The psoriasiform lesions could be secondary to infections and resolve on its treatment, though the infective origin of these are not always clear nor are their implications.25 The exact mechanism triggering de novo psoriasis remains unclear, although it has been postulated to be secondary to increased cutaneous expression of interferon alpha (IFNα). IFNα is released from dendritic cells to recruit T cells and proinflammatory cytokines IL‐12 and IL‐23. TNFα would normally block IFNα expression and so anti‐TNFα results in up‐regulation of IFNα.24 Higher levels of IFNα are seen in anti‐TNF induced psoriasis than idiopathic psoriasis.25 Management Management of psoriasis due to anti‐TNF depends on severity of symptoms. Milder cases of psoriasis can be treated clinically with topical therapy without cessation of anti‐TNF, however, more severe cases may require anti‐TNF withdrawal.24 About 80% of patients respond to a combined approach of steroids and biologics withdrawal.26 The use of another anti‐TNF agent may result in recurrence of psoriasis in majority of cases (52%).25 Ustekinumab has been used in the treatment of CD28 and psoriasis.29 There have been rare reports of paradoxical worsening of psoriasis with ustekinumab but not known to cause drug‐induced psoriasis.21 Ustekinumab is potentially an attractive option for treatment of refractory anti‐TNF induced psoriasis25 requiring withdrawal of primary drug. Methotrexate has been used but does not appear to be effective in all cases.26 It is a useful option to have in selected cases (Table 3). Complication Diagnosis Management strategy Psoriasis Relatively common (1.5%‐5% of patients on anti‐TNFs) Clinical diagnosis Histology of skin lesions Establish temporal relationship between initiation of biologic therapy and development of psoriasis Specialist involvement from dermatology In mild cases: topical steroid therapy In severe cases: stop drug and consider alternatives such as Methotrexate Ustekinumab for managing both conditions is a viable alternative Psoriasiform lesions Common Clinical diagnosis Consider skin infections causing the rash Consider stopping drug in severe cases. Responds well to cessation of drug therapy Treat skin infection as appropriate Erythema Nodosum Granuloma Annulare Interstitial Granulomatous Dermatitis Very rare Clinical diagnosis No clear evidence on management as these conditions are rare Specialist dermatology involvement is advised Usually not necessary to withhold or stop drug Clinician decision based on risk: benefit assessment anti‐TNF, anti‐tumour necrosis factor. 2.1.4 Autoimmune‐like disorders Autoimmune‐like disorders/syndromes are a group of conditions observed in patients on anti‐TNF therapy. This was first described in initial studies of infliximab in patients with rheumatoid arthritis.30 These disorders include a variety of conditions such as positive antibodies eg, anti‐nuclear antibodies, anti‐double stranded DNA antibodies (dsDNA) (commonly IgM type), on immunological testing, various systemic or organ‐specific autoimmune diseases as documented in the BIOGEAS registry, drug‐induced systemic lupus erythematosus (DIL) called lupus‐like syndrome, vasculitis, antiphospholipid syndrome, sarcoidosis, interstitial lung disease, optical neuritis, inflammatory ocular disease, multiple sclerosis (MS)‐like central nervous system demyelination, and peripheral neuropathies.31 William et al described anti‐TNF induced lupus (ATIL) based on the severity of symptoms displayed and suggested that ATIL is a distinct syndrome in itself32 and are likely to be different from drug induced lupus. In a pooled analysis across various diseases, studies which included patients with IBD showed that whilst ANA positivity was very common after anti‐TNF therapy (40%‐56%), asymptomatic anti‐nuclear antibodies or anti‐double stranded DNA antibodies require observation but not discontinuation of anti‐TNF. The full range of symptoms of ATIL was seen in only about <1% of patients.32 Most patients with full blown ATIL had fever, rash, arthritis and haematological abnormalities. A large case series was reported by Costa et al comparing drug‐induced lupus secondary to anti‐TNF and classic drug‐induced lupus.33 Both groups had similar systemic features and symptoms but there were some features that distinguished one group from the other. 72% of patients with anti‐TNF drug‐induced lupus had cutaneous manifestations compared to about 25% in classic drug‐induced lupus group. Classic drug‐induced lupus was not usually associated with antibodies to dsDNA and extractable nuclear antigen (ENA) or with complement consumption. 90% of anti‐TNF drug‐induced lupus patients were positive for anti‐dsDNA antibodies and >50% had anti‐extractable nuclear antigen antibodies and decreased serum complement levels.33 Management The management of autoimmune‐like disorders/syndromes secondary to anti‐TNF therapy requires a customised therapeutic approach according to severity of the induced autoimmune disease. ATIL should be considered a distinct condition and managed accordingly. There are features which could help distinguish this. The incidence/prevalence of dsDNA antibodies and hypocomplementaemia is greater in ATIL, whilst anti‐histone antibodies, the hallmark of classic drug‐induced lupus, are less commonly found.32 In patients with a positive ANA, it is not in itself an indication for discontinuation of therapy. In the presence of mild features, cessation of anti‐TNF therapy is probably sufficient. However, it can be continued in patients with isolated cutaneous lesions or immunological alterations in whom biologics are thought to be essential to treat underlying disease, with closer follow‐up. In patients with involvement of internal organs (kidney, lungs, nervous system), cessation of therapy is mandatory with addition of corticosteroids and/or immunosuppressive agents.30, 33 After discontinuation of the incriminating anti‐TNF the prognosis is generally very favourable. The presence of diagnosed SLE is a contraindication to anti‐TNF exposure. 2.1.5 Cardiac effects It was reported that worsening cardiac failure was a possible adverse event in a randomised controlled trial investigating the use of anti‐TNF therapy in cardiac failure.34 Majority of patients enrolled were New York Heart Association III (NYHA) at baseline and the group receiving high dose infliximab (10 mg/kg) were adversely affected with an increased likelihood of hospitalisation, high frequency of worsening heart failure, with the risk of adverse clinical events persisting for up to five months after cessation of therapy.34 The exact mechanism of heart failure with anti‐TNF use remains unclear. There have been case reports of second degree and complete heart block after infliximab therapy but these are rare.35 This is more likely to happen in rheumatological conditions as there may be underlying cardiac involvement. A single blind prospective study which included rheumatological conditions concluded that new‐onset cardiac arrhythmias, particularly ventricular tachyarrhythmia, developed during infliximab infusion, but their incidence did not achieve statistical significance.36 Acute coronary syndrome following infusion has been reported but this too is very rare.37 The rarer cardiac effects are based on reports with a very small number of patients, mostly from the rheumatology cohort who are at higher risk of having cardiac disorders. Management Current guidance recommends that use of anti‐TNF therapy is best avoided in those with NYHA III/IV heart failure.38 All patients who develop heart failure while on an anti‐TNF agent should discontinue therapy, conventional medication for treatment of heart failure started and specialty advice sought. An alternate class of agent should be considered for the primary disease process. It is still unclear whether infliximab can be used safely in patients with asymptomatic left ventricular dysfunction or mild symptoms of heart failure (NYHA class I/II).38 For patients commencing anti‐TNF therapy who have specific cardiac risk factors such as hypertension, valve disorders or ischaemic heart disease, our recommendation is that clinicians should get a baseline electrocardiogram to record QT interval among other features and clinically assess the patient for any features of pre‐existing heart failure that may preclude therapy. Not all studies have substantiated an association of anti‐TNF therapy with heart failure and this is rare in patients with IBD (Table 4). Complication Diagnosis Management strategy Cardiac failure Clinical diagnosis Objective assessments with investigations Avoid anti‐TNFs in NYHA III and IV heart failure If drug precipitates heart failure: stop the drug Treat for heart failure with diuretics and early specialist involvement Switch to another class of drugs Second and third‐degree heart block More commonly seen in the treatment of rheumatological conditions; less so with IBD 12 Lead ECG Cardiac monitoring Monitor patients for features of decompensation Specialist involvement for further management Stop drug and switch to another class Arrhythmias More commonly seen in the treatment of rheumatological conditions; less so with IBD 12 Lead ECG Cardiac monitoring Usually transient and does not need any specific management If transient episodes are self‐limiting: consider continuing drug If persistent: seek specialist cardiology opinion anti‐TNF, anti‐tumour necrosis factor; NYHA, New York Heart Association. 2.1.6 Neurological effects Demyelination Demyelination has been recognised as a complication of anti‐TNF therapy. A review of FDA adverse event recording system showed that among 772 reports of neurological complications, 18% of patients had IBD. About 36% of patients had received infliximab and peripheral neuropathy was the most commonly reported event.39 Demyelination can occur in central or peripheral nervous systems.40 It remains unclear as to whether the relationship is truly causal, or whether anti‐TNF triggers an existing tendency for demyelination. Management Patients who have a family history of demyelination disorders may be at higher risk and this should be considered before the therapeutic agent is chosen.41 It is standard guidance to avoid anti‐TNF therapy in patients with concomitant multiple sclerosis or history of optic neuritis. In patients who develop neurological deterioration and suspected demyelination during therapy, treatment with biologic agent should be discontinued41 and specialist neurology opinion should be sought. The clear relationship between demyelinating events and anti‐TNF can be difficult to establish as IBD may also be associated with demyelination. Treatment with corticosteroids, IVIG, and plasmapheresis are rarely necessary (Table 5). Complication Diagnosis Management strategy Demyelination Known to worsen demyelination in patients with multiple sclerosis Clinical diagnosis Nerve conduction studies MRI Stop drug and consider alternatives Seek specialist Neurology involvement Consider pulse therapy with high dose methylprednisolone Consider IV Immunoglobulin MRI, magnetic resonance imaging. 2.2 Infections and management strategies Biologics are strong immunosuppressive agents and can increase risk of infection depending on their mechanism of action. Tumour necrosis factor‐α (TNFα) is essential for activation, differentiation, and recruitment of several immunological cell types; it has a role in granuloma formation, maintenance of granuloma integrity,42 and host response to mycobacteria and intracellular organisms.43 A recent meta‐analysis found that anti‐TNF therapy was associated with a greater infection risk than placebo in treating UC but anti‐integrin therapy was not; neither class showed an increased infection risk over placebo in CD.44 Other studies have confirmed increased risk in both forms of IBD. A recent systematic review by Wheat et al concluded that at present there is no evidence of a higher odds of serious infection from the newly available biologic therapies such as vedolizumab and ustekinumab compared to anti‐TNFs.45 Feagan et al report that infections in patients exposed to ustekinumab for CD is no higher than placebo in UNITI trials46 and Wils et al reported only one serious pulmonary infection in a cohort of 122 ustekinumab exposed patients, followed up over 2 years.47 Bye et al reported an increased risk of Clostridium difficile infection with vedolizumab therapy but concomitant steroid and narcotic analgesics were identified as risk factors.48 2.3 Bacterial infections Patients receiving anti‐TNF therapy have been reported to acquire both common and uncommon bacterial infections. Common sites for infection include upper and lower respiratory tracts, skin and subcutaneous tissue, urinary tract and GI tract.49 2.3.1 Management Common infections are treated with oral antibiotics as per local guidelines. A pragmatic approach would be to have a lower threshold to start treatment and switch to intravenous drugs in the presence of systemic symptoms. In severe sepsis requiring prolonged antimicrobial treatment, anti‐TNF therapy may have to be withheld. Restarting therapy can be considered once patients are afebrile, white cell counts within normal range and relevant imaging (CT, MRI pelvis) show no evidence of infective source. (Table 6). Complication Diagnosis Management strategy Common bacterial infections Respiratory tract Clinical diagnosis Relevant investigations depending on symptoms Appropriate antibiotics based on site of infection Consider early therapy If any signs of sepsis: stop drug Restart biologics when good evidence of resolved infection. (WCC, imaging) Urinary tract Gastrointestinal Cellulitis Serious bacterial infections Listeriosis Serology CT/MRI of brain Lumbar puncture if meningitis suspected Appropriate antibiotics based on sensitivity Seek specialist microbiology advice Legionnaires’ disease Septic Arthritis Septicemia Tuberculosis (TB) Latent TB Re‐activation Risk assessment based on initial screening with Quantiferon or T‐Spot testing Thorough history and risk factor assessment Chest X‐ray If positive or indeterminate: involve specialists Treat as per ECCO guidelines and British Thoracic Society Guidelines Risk: Benefit analysis by clinician Consider alternative therapy ie, vedolizumab or ustekinumab WCC, white cell count. 2.3.2 Uncommon infections Several nonmycobacterial intracellular infections, including listeriosis caused by Listeria monocytogenes and legionnaires’ disease most often caused by Legionella pneumophilia, have been associated with anti‐TNF therapy.50 Listeria sepsis and meningitis have been described in patients receiving anti‐TNF drugs51 and in 2011, the FDA added a boxed warning about the risk of listeriosis and legionnaires’ disease for the entire class of TNFα inhibitors.52 There are a few case reports of listeriosis complicating anti‐TNF therapy. Listeriosis carries significant mortality, therefore requiring prompt diagnosis and aggressive treatment. The risk appears to be higher during the first year of therapy.53 Anti‐TNF should be discontinued till the patient recovers from listeriosis. 2.3.3 Management Suspicion of infection requires confirmatory testing and treatment using standard antibiotic regimes depending on pathogen isolated. Listeriosis is more likely to be seen in patients consuming mould‐ripened cheese regardless of whether it is from pasteurised or unpasteurised milk and also from cold smoked gravad fish.54 In one study from United States, unpasteurised milk and dairy products were noted to significantly increase the risk of infections caused by Escherichia coli, Salmonella, and Campylobacter.55 In view of this overall increased risk of infections, it is safer for patients to avoid consumption of unpasteurised milk whilst on anti‐TNF drugs. 2.4 Mycobacteria and tuberculosis Tuberculosis (TB) caused by mycobacterium bacilli is a serious infection which carries significant morbidity. TNFα is necessary for a Th1‐based cell‐mediated immune response important in activating macrophages to kill intracellular mycobacteria, and limit spread by formation of granulomas.56, 57 The majority of exposed immunocompetent hosts have latent TB (LTB) which can subsequently lead to reactivation of infection if there is compromise to the immune system, such as initiation of anti‐TNF drugs.58 It is therefore critical to identify and treat LTB prior to starting anti‐TNF therapy.58 An association between anti‐TNF therapy and development of TB was noted when the FDA MedWatch spontaneous reporting system demonstrated 70 TB cases in a median of 12 weeks after initial infliximab exposure, in 2001.59-68 Both extrapulmonary and disseminated TB are more common in patients treated with anti‐TNF therapy, compared with immunocompetent patients.59, 60 It has been hypothesised that the early occurrence of TB after infliximab may suggest reactivation of LTB rather than a de novo infection.60 Due to the high risk of reactivation, screening for TB is recommended prior to starting anti‐TNF. The diagnosis of LTB can be difficult and should include a combination of detailed history and supportive investigations. At present, IGRA (interferon gamma release assay) and TST (tuberculin skin test) are commonly used in most centres. In a study by Mariette et al which looked at how effective the available tests are, it was noted that when one of the IGRA tests replaced TST, it influenced the decision made by physicians, leading to 28% fewer patients receiving anti‐TB (ATB) prophylaxis.61 This is likely because IGRA tests are more specific. As per this study, IGRA does not appear to be affected by corticosteroid or immunosuppressant therapy.61 However, this may not always be the case as shown in an ex vivo study in which corticosteroids and infliximab reduced the performance of IGRA.62 At present, IGRA is possibly more reliable than the other options available. TST is less specific and can be less frequently positive due to corticosteroid or immunosuppressant therapy and this should be borne in mind. Based on their findings, Mariette et al proposed an algorithm for assessing patients, which is now generally applied prior to starting anti‐TNF therapy.61 All patients should undergo appropriate history ± chest X‐ray. For those with a positive history or X‐ray, treat with ATB prophylaxis. For those with negative history, check with IGRA test (authors recommend GOLD, followed by T‐SPOT if indeterminate). Those with negative results require no further screening. Those with positive results require ATB prophylaxis. Patients with indeterminate GOLD and T‐SPOT test should undergo TST testing. Negative results require no further action, but a positive TST should be treated with prophylaxis.61 In patients who have a positive TST and negative IGRA, the degree of clinical suspicion should guide management, based on history and chest X‐ray with a very low threshold to treat the patient. Generally, performing both TST and IGRA is not recommended. An initial indeterminate borderline IGRA can be followed up with TST and if the latter is positive the patient should be treated. The CDC recommend testing with either IGRA or TST, but a combination of both may be appropriate where clinical suspicion of LTB is high, or risk of subsequent LTB reactivation may result in a poorer outcome (such as those on immunosuppressants).63 2.4.1 Management Guidelines by European Crohn's and Colitis organisation (ECCO)26 and British Thoracic Society (BTS)58 on screening and management of TB are similar in principle, suggesting treatment of LTB prior to initiation of anti‐TNF therapy with a complete therapeutic regimen. If there is clinical suspicion ± radiographic changes suggestive of TB, patients should be referred for treatment of LTB.58 Other patients should undergo LTB screening tests. The optimal screening strategy for these patients is still debatable. After diagnosis of latent TB in a patient with IBD, appropriate treatment should be administered for at least 3 weeks prior to commencement of anti‐TNF therapy64, 65; however, if treatment with anti‐TNF therapy is considered very urgent simultaneous treatment for latent TB and IBD may be considered. Alternative therapies such as vedolizumab or ustekinumab may also be considered for UC or CD. Short latent TB therapies are increasingly considered such as rifampicin for 4 months or isoniazid plus rifampicin for 3 months as adherence to 9 months of daily isoniazid poses challenges.66, 67 Exposure to active TB during anti‐TNF therapy should lead to prompt re‐evaluation for latent or active TB. In case of active TB, anti‐TNF should be discontinued and active TB treated. If absolutely necessary, anti‐TNF may be resumed after at least 2 months of anti‐TB therapy with satisfactory response, though it may sometimes be resumed earlier if absolutely necessary. Increasingly other monoclonal antibodies such as ustekinumab or vedolizumab are being considered. Annual retesting for LTB in patients on anti‐TNF therapy depends on risk factors for exposure to TB and desirable in geographical areas with endemic TB. (Table 6) 2.5 Viral infections A majority of human viral infections are self‐limiting but some are capable of causing chronic infection (eg human immunodeficiency virus [HIV], hepatitis B virus [HBV], and hepatitis C virus [HCV]). There are viruses linked to malignancy, such as Epstein‐Barr virus (EBV) and human papilloma virus (HPV). EBV will be discussed in more detail in “malignancy” section of this text. 2.5.1 Varicella zoster virus (VZV) and Shingles This can present with severe or disseminated disease if contracted while on anti‐TNF therapy.68 In one study, the prevalence of prior varicella zoster virus (VZV) infection among IBD patients was greater than 90%69 and it was not noted that a significant number had a VZV IgG negative status. It is known that patients with IBD are at a higher risk of VZV infection and more so when on immunosuppressive therapy.70, 71 Herpes zoster or shingles is caused by reactivation of VZV. The incidence of shingles is again increased in patients with IBD, the elderly population at particular risk. In a study looking at herpes zoster in IBD, it was seen that patients with CD were at higher risk; age >45 years, treatment with corticosteroids for >2 weeks, thiopurine therapy were associated with increased risk of infection.72 Long et al reported similar findings and also noted that patients on anti‐TNF therapy for IBD are at higher risk of herpes zoster with an odds ratio of 1.81 (95% CI: 1.48‐2.21).73 2.5.2 Management Immunocompromised patients exposed to VZV should be treated with VZV immunoglobulin.74 Patients who contract VZV or shingles during a period of immunosuppression require antiviral therapy. If oral therapy is appropriate, valganciclovir should be considered as this provides higher oral bioavailability than aciclovir.65 (Table 7) Complication Diagnosis Management strategy Varicella Relatively common Clinical diagnosis Serology testing available Treat with varicella immunoglobulin Antimicrobial therapy with valganciclovir Chronic stable HBV Reactivation of chronic infection Screening for HBV mandatory Close monitoring of liver function and viral load Joint care with Hepatologist May require treatment with antivirals Biologics can be continued unless acute fulminant liver failure suspected Chronic active HBV on antiviral therapy Screening for HBV mandatory Close monitoring of liver function and viral load Continue antivirals Entecavir and tenofovir drugs of choice Hepatitis C Screening for HCV recommended prior to anti‐TNF therapy Close monitoring of LFTs and HCV RNA Load in HCV infected patients Joint care with Hepatologist Continue biologic with close monitoring No contraindication for therapy Cytomegalovirus (CMV) Check serology for CMV IgM and viral PCR Supported by tissue diagnosis with histology and immunohistochemistry Treatment with IV ganciclovir and switch to oral valganciclovir for total of 2‐3 wk Use foscarnet as per sensitivities If systemic CMV infection: consider stopping anti‐TNF Human immunodeficiency virus Close monitoring in addition to CD4+ counts Continue biologics when HAART established and CD4+ counts are above 350 Consider withholding biologic when CD4+ <200 Joint care with multidisciplinary decision approach anti‐TNF, anti‐tumour necrosis factor; HAART, highly active antiretroviral therapy; HBV, Hepatitis B virus; HCV, Hepatitis C virus; LFTs, liver function tests; PCR, polymerase chain reaction. Prevention of infection is possible due to availability of effective vaccines. It is recommended that all patients are screened for evidence of past infection prior to starting biologics or immunosuppressives including steroids. ECCO suggest that in seronegative patients two‐dose course of varicella vaccine should be given at least 3 weeks prior to commencement of therapy.65 If subsequent immunisation is necessary, it can be administered after a 3‐6 month cessation of all immunosuppressives as both the VZV and shingles vaccines are live vaccines,65 although there is emerging evidence that administration of live zoster vaccine to patients already on anti‐TNF therapy did not result in disease and there was expected immune response to the vaccine.73 2.5.3 Hepatitis B Tumour necrosis factor‐α (TNFα) and interferon (IFN)γ are released by cytotoxic T lymphocytes on antigen recognition of the hepatitis B virus, activating two viricidal pathways, plus antigen nonspecific T cells & macrophages.75 Reactivation of HBV may occur during anti‐TNF therapy, or on subsequent withdrawal (secondary to immune reconstitution). Reactivation of chronic HBV carriers (hepatitis B surface antigen (HBsAg) positive, undetectable HBV DNA, normal LFTs) after anti‐TNF therapy has been reported.76 Patients who have had HBsAg seroconversion following exposure to HBV [HBsAg negative, anti‐HBc (core antibody) positive and anti‐HBsAg antibody positive] have been successfully treated with anti‐TNF therapy without HBV reactivation during follow up.77 Chronic active HBV patients already successfully controlled with antiviral therapy prior to introduction of anti‐TNF show no deterioration in the viral load or liver enzymes.78, 79 A comprehensive review by Pattullo80 looked at incidence & prevalence of HBV reactivation in IBD when treated with immunosuppressants without HBV prophylaxis; risk stratification of patients was also done based on type of biologic therapy.80 The incidence of immunosuppression related HBV reactivation was noted to be about 36% in HBsAg positive patients. The overall prevalence of HBV in IBD ranged from 0.6%‐17% for HBsAg positive patients, and 1.6%‐42% for HBsAg negative/anti‐HBc positive patients. The risk estimate of HBV reactivation was reported to be moderate (1%‐10%) with anti‐TNF.80 2.5.4 Management All patients should be screened prior to initiation of therapy, although which patients should receive antiviral therapy remains unclear. Screening should be carried out checking for hepatitis B surface antigen, antibody to surface antigen, and anti HB core antibody levels and if HBsAg or anti‐HBc is positive, DNA quantification should be done.65 Chronic HBV carriers and those with HbsAg seroconversion should be considered for antiviral therapy and hepatology involvement. It is recommended that patients who are due to start biologics (moderate risk of reactivation) are given anti‐viral prophylaxis if they are HBsAg positive and continued for at least 6 months after completion of immunosuppressive therapy.80 In case of reactivation, it is recommended that one of the antivirals is started and continued for at least 6‐12 months after immunosuppressive therapy has been stopped. The antiviral medication of choice may depend on the patient's individual circumstances and the planned duration of immunosupression.81 Entecavir and tenofovir are now preferred anti‐virals in IBD patients due to their rapid onset of action, highest anti‐viral potency with low incidence of resistance.65 Whilst lamivudine is used, this has its limitations if long term therapy is required, as resistance can occur in up to 30% of patients after 1 year and 70% after 5 years.81 Peginterferon‐alpha‐2a (IFNα) is best avoided due to the risk of myelosuppression and also risk of exacerbating CD.65 2.5.5 Hepatitis C Tumour necrosis factor‐α (TNFα) appears to be involved in the pathogenesis of HCV, with patients with higher serum TNFα levels less likely to respond to anti‐viral therapy.82 TNFα blockade may increase reactivity of peripheral T cells to antigen stimulation.82 Biologics have an acceptable safety profile for use in patients with HCV and is not contraindicated in concomitant HCV infection. However, in the presence of acute HCV, anti‐TNF therapy is contraindicated.83 In the presence of chronic HCV, the decision to treat with anti‐TNF depends on liver synthetic function. It is best avoided in patients who are Child‐Pugh category B or C.83 HCV patients being treated with anti‐TNF therapy should have close monitoring of aminotransferases with consideration for discontinuation of treatment with continued elevations.82 The guidelines from ECCO suggest cautious use of antivirals due to drug interactions.65 Infection diagnosed whilst on anti‐TNF therapy does not necessarily require cessation of therapy.65 There is no data yet on the use of newer antivirals for HCV in the context of biologics use for IBD but there are no contraindications for their concurrent use. 2.5.6 Management The ECCO guidelines are equivocal about screening for HCV prior to use of immunosuppressive therapy.65 However, it would be prudent to screen patients who are likely to need biologics considering the high curative rates with newer anti‐viral drugs for HCV. All patients with HCV infection should be discussed and managed jointly with hepatology services, especially when biologics are indicated for IBD. During the course of therapy, close monitoring of liver functions is key. 2.5.7 HIV infection The interaction between TNFα and the human immunodeficiency virus (HIV) has been the subject of much scrutiny. The molecular pathway by which HIV expression is upregulated by TNFα is well described.84, 85 Despite these findings, use of anti‐TNF in HIV‐patients must be balanced with a potential increase in the risk of opportunistic infections in patients with an attenuated immune system. The evidence base for advice regarding use of biologics in patients with HIV and IBD is limited. Within a cohort study and several case reports, biologic therapy with infliximab in refractory IBD patients has been demonstrated to be effective in inducing disease remission with only a minority experiencing adverse effects.76-86 It is important to note that initial CD4+ count in patients included in these studies are >200 cells/mL. The ECCO guidelines65 also suggest that the HIV‐IBD cohort of patients are less predisposed to infection on highly active anti‐retroviral therapy (HAART) than if they did not receive HAART. In this cohort, adverse effects have presented as either a predisposition to infections, deranged CD4+ count or HIV viral loads. Abreu et al describe an HIV positive, thiopurine‐intolerant patient treated with infliximab for a UC‐flare unresponsive to steroids87 who had been on ART (emtricitabine/tenofovir/efavirenz) with undetectable HIV viral load & CD4+ count of 357/mmc prior to infliximab therapy. Although excellent disease response was achieved, he was diagnosed with listeriosis and was successfully treated. (CD4+ count 350/mmc). Infliximab was restarted with no clinical consequences. It is likely that these patients with IBD remain at increased risk of opportunistic infections.88 Other examples of adverse effects of biologics in HIV are reported in the rheumatology cohort.89 In one case series,90 a patient who was not on HAART therapy was observed to have an increase in viral load (22 148‐428 503 c/ml) following initiation of infliximab therapy. This required temporary cessation of infliximab and the rise was not observed at readministration. Within the limited evidence available, it is noted that patients do benefit from adequate disease response with no specific HIV‐related complications. Due to risk of AEs, it is recommended that screening for HIV is undertaken prior to treatment with biologics and patients with IBD recognised as HIV positive are managed by a multispecialty team. Generally, in the absence of other infections treatment of HIV infected patients with anti‐TNF is relatively safe. This group of patients must ideally be on HAART. A discussion about potential increased risk of infection, baseline blood tests including CD4+ count (ideally 200 cells/mL+), and HIV viral load is necessary. Close monitoring throughout duration of therapy is key. An increase in HIV viral load needs discussion with specialists and discontinuation of biologic may become necessary. Any overt sign of infection merits hospital admission to identify and treat the infection source and biologics paused. Restarting biologics should be discussed based on clinical aspects of each case. (Table 7) 2.6 Fungal infections Patients with IBD are known to be at an increased risk of fungal infections. This is due to multiple factors such as severity of disease activity, comorbidities, treatment with opioids, surgery, poor nutritional status, leucopenia and older age.91 Another factor is immunosuppressive therapy, important of which are anti‐TNFs. A risk factor analysis by one recent systematic review reported anti‐TNF therapy as the predominant factor associated with fungal infections.91 2.6.1 Aspergillosis Aspergillosis, caused by Aspergillus fumigatus is a serious pulmonary infection which warrants prompt diagnosis and treatment. Attenuation of the inflammatory pathway through TNFα blockade alters the cytotoxic immune response to fungal infections and in aspergillosis, it is involved in polymorphonuclear leucocyte activation in response to infection.92 The evidence is mostly from case reports. In 2001, a case of invasive pulmonary aspergillosis was reported in a patient with CD on anti‐TNF therapy.93 There have been other case reports since but overall, it appears to be a rare occurrence. This usually presents initially with a poorly productive cough and can progress to respiratory insufficiency; radiological changes are seen.93, 94 2.6.2 Management The definitive diagnosis is on culture of broncho‐alveolar fluid. The infection is treated with prolonged antifungal therapy based on sensitivities; amphotericin B or voriconazole or caspofungin is used. The condition carries very poor prognosis. Concomitant tuberculous cavity needs exclusion (Table 8). Complication Diagnosis Management strategy Candidiasis Commonly localised infections but systemic and invasive infection can be life threatening Serology, culture and molecular studies Localised infections: Topical therapy Invasive infections: Stop biologic IV Fluconazole Seek specialist advice Aspergillosis Pulmonary symptoms and invasive infection Serology, culture and imaging Stop biologics IV Anti‐fungal therapy (Consider IV voriconazole) Caspofungin is another option Specialist involvement Histoplasmosis Usually pulmonary infection Serology, culture and radiology Stop biologic therapy Treatment with either one of: Amphotericin B initially and step‐down therapy to an azole preparation Itraconazole Pneumocystis jirovecci Clinical diagnosis Culture, microscopic and molecular diagnosis Cotrimoxazole 960 mg BD, if severe infection, increase to 1.44 g BD Specialist involvement 2.6.3 Histoplasmosis This is another potential opportunistic infection reported in patients exposed to anti‐TNF treatment. In a case series of ten immunocompromised subjects from an area endemic with histoplasmosis, 9 contracted histoplasmosis shortly after commencing infliximab infusions. Clinical presentation can be varied and include pulmonary, extrapulmonary or disseminated disease symptoms which are nonspecific.95 2.6.4 Management Invasive fungal infections should be treated with systemic antifungals and all immunosuppressant medication should be reviewed. The FDA in 2008 have issued post market drug safety information alerting healthcare providers that invasive fungal infections and histoplasmosis in patients receiving anti‐TNF drugs are not being swiftly recognised, resulting in possible delays to patient therapy. The FDA recommends the involvement of infectious diseases specialists96 in the management of such cases (Table 8). 2.7 Other Opportunistic infections 2.7.1 Cytomegalovirus (CMV) Cytomegalovirus (CMV) infection (detected by serology) could be due to reactivation of latent infection during immunomodulator or biologic therapy, but usually is itself mild or asymptomatic even on immunosuppressants. However, CMV colitis, retinitis, pneumonia or severe CMV infection during treatment of IBD requires further assessment65 to plan management. Nevertheless, not all cases of CMV infection in anti‐TNF use progress to CMV disease.97 The diagnosis of CMV disease using histopathology with immunohistochemistry is highly sensitive and specific. This combined with CMV viral load (CMV DNA detected by PCR in serum and tissues) can provide most information about disease state.65 CMV viral loads of >250 copies/mg is a predictor for patients presenting with corticosteroid‐resistant disease.65 Cytomegalovirus disease manifesting as colitis is a recognised complication of IBD and should be screened for in those patients presenting with acute severe colitis.98 Typically, patients may have had previous exposure to immunosuppressive therapy and experienced prolonged corticosteroid therapy or corticosteroid‐refractory disease. CMV can also be a cause of chronic pouchitis.99 2.7.2 Management It is important that diagnosis is established swiftly. When considered as a differential diagnosis, testing for CMV viral load with PCR is recommended to look for CMV disease especially in ill patients with systemic manifestations. Histology and immunohistochemistry may be used to support the diagnosis of CMV colitis. Once diagnosed, ECCO recommend a 2‐3 week course of ganciclovir therapy for CMV disease, and immunosuppressants are withheld.65 However, a retrospective cohort case study of CMV‐positive colitides, identified that patients with milder colitis were less likely to be treated, and could respond to standard immunosuppressive therapy without additional treatment for CMV. CMV may be transiently reactivated and disappear without antiviral therapy. In one study it was noted that those with more severe disease were more likely to be treated with ganciclovir, and were more likely to require either rescue therapy or surgery, despite adequate treatment of CMV.100 CMV colitis complicating UC leading to acute severe colitis can be challenging to manage. A study by Kopylov et al reported the outcomes for patients with severe colitis. Patients received infliximab/ciclosporin with ganciclovir vs ganciclovir alone, and both groups had similar colectomy rates.101 In patients who test positive for CMV whilst on anti‐TNF therapy, there is evidence that anti‐TNF can be continued102 (Table 7). 2.7.3 Pneumocystis pneumonia (PCP) or Pneumocystis jirovecci pneumonia (PJP) This is a serious infection reported in patients after use of immunosuppressants. A large population based cohort study looked at risk of PJP in IBD patients.103 Although there is some evidence that the overall hazard risk of PJP in IBD is higher than normal population, the absolute risk of PJP is considered to be very low (0.03% in their cohort).103 In a large case series of PJP after infliximab use, mean onset of symptoms reported was 21 days although majority of patients were exposed to concomitant immunosuppressive therapy. Over a quarter (27%) of patients died104 in these reported series, so early recognition and therapy is paramount. ECCO guidance recommends that patients on triple immunotherapy with one being a calcineurin inhibitor or anti‐TNF should receive standard prophylaxis with Trimethoprim‐sulfamethoxazole (co‐trimoxazole) if tolerated. It should be considered in those on dual immunosuppression especially if one is a calcineurin inhibitor65 and in anti‐TNF regimens with associated corticosteroid use.65 However, pill‐burden and side effects are to be kept in mind. Cotrimoxazole is an effective option for prophylaxis and active infection. Clinicians should discuss with their local microbiology and infectious disease departments. Although more recent studies report very low risk, clinicians have to be vigilant throughout the course of treatment and decision on prophylaxis has to be on a case‐by‐case basis (Table 8). 2.7.4 Infection prevention and vaccination recommendations The main focus of the article is on management of adverse effects and our stress on prevention, though very important, is limited as these have been extensively addressed in ECCO guidelines. ECCO guidance recommends that prior to immunosuppression, detailed history and examination, including prior bacterial, viral, and fungal infections, particularly herpes, VZV, TB exposure, prolonged travel/stay or plans to travel to TB endemic or tropical areas and completion of childhood vaccination programmes are documented. Further advice should include cervical smear screening for women, food hygiene, and avoidance of raw and unpasteurised foods. Education on safe use and preparation of dairy & meat products can benefit patients at risk of listeria infection whilst on anti‐TNF therapy. Live attenuated vaccines must be avoided on immunomodulator or anti‐TNF therapy and ideally patients should receive annual inactivated influenza vaccine and pneumococcal vaccine as required. Prior to the onset of immunosuppression, consider vaccination with any outstanding routine vaccines plus HBV, VZV (if seronegative and no clinical history), and HPV.65 If patients require live vaccines during therapy, the risk: benefit assessment of vaccination should be undertaken. Patients are usually immunocompetent within 3‐12 months105 after cessation of therapy. Corticosteroid therapy alone is not considered to cause significant immunocompromise unless high doses (20 mg or higher) have been used continuously for more than 2 weeks.105 2.8 Malignancy Malignancies thought to be linked to immunosuppressive agents and anti‐TNF use include solid organ malignancies, nonmelanoma skin cancer (NMSC), melanoma, lymphoproliferative malignancies, and those with viral association such as EBV‐related lymphomas and HPV‐related cervical cancers, or dysplasia. However, difficulty remains in establishing a cause‐effect relationship. A possible association between anti‐TNF use and malignancy first arose from postmarketing reports to the FDA. There were 26 cases of lymphoma reported in patients with rheumatoid arthritis or CD disease treated with etanercept or infliximab.106 Further studies demonstrated an increased risk for solid organ and NMSC in patients treated with anti‐TNF and further immunosuppressive therapies.107 Many IBD patients are either on multidrug regimes or have had past exposure to thiopurines (or other immunosuppressants) prior to anti‐TNF usage. Historically most trial data are from the rheumatology population. A meta‐analysis derived from nine clinical trials of patients receiving anti‐TNF treatment or placebo identified a number needed to harm of 154 (95% CI: 91‐500) for 1 additional malignancy within a treatment period of 6‐12 months.108 The malignancy rates were significantly more common in those treated with higher doses (≥6 mg/kg of infliximab every 8 weeks or 40 mg of adalimumab alternate weeks).108 A more recent meta‐analysis of 74 randomised controlled trials concerning adalimumab and infliximab showed no overall relative risk (RR) increase on short‐term follow‐up for malignancy with the exception of NMSC which had a RR of 2.02 (95% CI: 1.11‐3.95).109 A 6‐year follow‐up study from the national Danish registers only identified three solid organ malignancies and one case of melanoma, with total follow‐up ranging from 0.1‐72.1 months.110 The Crohn's therapy, resource, evaluation, and assessment tool (TREAT) registry is collecting prospective data on large number of CD patients to evaluate the long‐term safety of CD therapies. Data published from the registry in 2006 showed mortality rates to be similar between infliximab and non‐infliximab patient groups after a short period of follow‐up (mean follow up 1.9 years).111 Subsequent data from the registry published in 2014 (with follow‐up of up to 7.6 years) has shown that none of immunosuppressants, infliximab, or combination therapy to be an independent risk factor for malignancy.112 However, the follow‐up period remains short and future analysis of the registry is likely to provide further evidence. The CESAME Study Group113 assessed the impact of thiopurine use on development of NMSC–comprised of basal cell carcinoma, squamous cell carcinoma, and lymphoproliferative disorders (increased risk found in the thiopurine group). Although a large number of patients were included, the risk of malignancy secondary to biologics could not be assessed due to relatively small number of patients on these drugs.114 A study by Long et al published in 2010 assessed risk of malignancy and concluded that IBD in itself increased risk of NMSC (incidence rate ratio IRR 1.64 95% CI: 1.51‐1.78) and a nested case‐control model showed an increased risk because of recent biologic use among patients with CD (adjusted OR 2.07, 95% CI: 1.28‐3.33)115; patients on combination therapy had the highest OR compared to medication‐free patients (OR 5.85 95% CI: 3.2‐10.8).115 Another study in 2012 reported that patients were at higher risk of melanoma when exposed to biologics and NMSCs were mainly related to thiopurine therapy.116 The most recent French national cohort study showed an increased risk of lymphoma in treatment exposed patients. When compared with unexposed patients, the risk of lymphoma was higher among those exposed to thiopurine monotherapy (aHR, 2.60; 95% CI: 1.96‐3.44; P < 0.001), anti‐TNF monotherapy (aHR, 2.41; 95% CI: 1.60‐3.64; P < 0.001), or combination therapy (aHR, 6.11; 95% CI: 3.46‐10.8; P < 0.001).117 There remains concern about cases of hepatosplenic T‐cell lymphoma (HSTCL) (a rare and aggressive form of non‐Hodgkin's lymphoma affecting predominantly young men) occurring following infliximab, adalimumab or thiopurine use. In a study published by Thai et al, they reported 22 cases of HSTCL in IBD and most were associated with thiopurine therapy either as monotherapy or in combination with anti‐TNF. Whilst a link is recognised, quantifying this risk to individual patients on current evidence is difficult.118 They also concluded that despite the risk, benefits of treatment far outweighed the risks.118 Secondly, observational studies have noted a potential predisposition to development of EBV related lymphoproliferative disorders in IBD patients, in particular those treated with thiopurines and anti‐TNF agents.65 Patients with EBV are predisposed to post‐transplant lymphoproliferative disorders (PTLD), where T‐cell immune surveillance is impaired.65 EBV related lymphomas may present in the gut, rather than nodal sites. Screening for EBV should ideally be considered, however there is no current vaccination for EBV naïve patients. In those developing EBV on therapy, treatment with antiviral medication and withdrawal of therapy should be considered.65 IBD itself does not appear to increase risk of lymphoma diagnosis.119 However, use of a thiopurine for IBD or combination therapy with an anti‐TNF may increase risk.119 Establishing any isolated effect of anti‐TNF on lymphoma development is challenging. In a meta‐analysis looking at lymphoma rates in CD patients treated with anti‐TNF, two thirds of all patients were also receiving immunomodulator therapies120; anti‐TNF treated patients appeared to have an increased risk of lymphoma (SIR 3.23 95% CI: 1.5‐6.9) compared to the expected population rate.120 The SIR was also increased when compared to previously studied patients on immunomodulator therapy alone (1.7 95% CI: 0.5‐7.1), however this did not reach statistical significance.120 There were too few patients treated with isolated anti‐TNF therapy to determine the individual risk of anti‐TNF usage on lymphoma development.120 2.8.1 Management principles in malignancy The association between various malignancies and anti‐TNF treatment remains unclear, but it is important that patients’ history of previous or pre‐existing cancer is carefully documented prior to initiation of biologic treatment. The use of biologics as monotherapy can be considered in patients with previous history of cancer. Axelrad et al noted that at 5 years after prior cancer diagnosis no significant difference in cancer free survival could be demonstrated between IBD treatment with anti‐TNF monotherapy, immunosuppressant monotherapy, anti‐TNF combined with thiopurine therapy, though numerically anti‐TNF monotherapy had the least cancer recurrence.121 In a meta‐analysis of 16 studies of immune mediated diseases, including eight studies involving IBD patients, similar rates of cancer recurrence were observed among individuals affected by previous cancer who received no immunosuppressives, anti‐TNF monotherapy, immunosuppressant therapy or combination therapies.122 Therefore, in patients with a history of cancer, recent or past, effective therapy for IBD can be used after consideration of risks and benefits and discussion with oncologists. ECCO guidelines also provide advice on managing IBD patients with previous history of malignancy.123 Generally, among biologics, monotherapy anti‐TNF, vedolizumab, or ustekinumab may all be used, but often thiopurines are avoided (Table 9). Complication Causative drug/s Diagnosis Management strategy Melanoma Anti‐TNF Clinical diagnosis Skin biopsy Stop drug Consider alternatives like Methotrexate or vedolizumab Dermatology involvement Nonmelanoma skin cancer Dual anti‐TNF +thiopurine therapy Clinical diagnosis Skin biopsy Stop drug Consider alternatives like Methotrexate or vedolizumab Dermatology involvement Lymphoma HSTCL PTLD Dual anti‐TNF +thiopurine therapy Cross sectional imaging Tissue biopsy Stop drug Consider switching drug class Other malignancies: Leukoencephalopathy Dual anti‐TNF +thiopurine therapy Clinical diagnosis Imaging Tissue biopsy Stop the drug Consider switching drug class Relevant specialist involvement anti‐TNF, anti‐tumour necrosis factor; HSTCL, hepatosplenic T‐cell lymphoma; PTLD, Post‐transplant lymphoproliferative disorder.
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Morphological deconvolution of beta-lactam polyspecificity in E. coli

Morphological deconvolution of beta-lactam polyspecificity in E. coli | Immunology and Biotherapies | Scoop.it
Morphological deconvolution of beta-lactam polyspecificity in E. coli Beta-lactam antibiotics comprise one of the earliest known classes of antibiotic therapies. These molecules covalently inhibit enzymes from the family of penicillin-binding proteins, which are essential to the construction of the bacterial cell wall. As a result, beta-lactams have long been known to cause striking changes to cellular morphology. The exact nature of the changes tend to vary by the precise PBPs engaged in the cell since beta-lactams exhibit a range of PBP enzyme specificity. The traditional method for exploring beta-lactam polyspecificity is a gel-based binding assay which is low-throughput and typically run ex situ in cell extracts. Here, we describe a medium-throughput, image-based assay combined with machine learning methods to automatically profile the activity of beta-lactams in E. coli cells. By testing for morphological change across a panel of strains with perturbations to individual PBP enzymes, our approach automatically and quantifiably relates different beta-lactam antibiotics according to their preferences for individual PBPs in cells. We show the potential of our approach for guiding the design of novel inhibitors towards different PBP-binding profiles by recapitulating the activity of two recently-reported PBP inhibitors. Quick Link to PDF NurtureToken New! Token crowdsale for this paper ends in Buy Nurture Tokens Authors Are you an author of this paper? Check the Twitter handle we have for you is correct. William J. Godinez (add twitter) Helen Chan (edit) Imtiaz Hossain (add twitter) Cindy Li (add twitter) Srijan Ranjitkar (add twitter) Dita Rasper (add twitter) Robert L. Simmons (edit) Xian Zhang (edit) Brian Y Feng (add twitter) Category Systems Biology Ask The Authors Ask the authors of this paper a question or leave a comment. Leave a comment. (Comment will appear here.) Ask a question. (Question will appear here and we'll notify an author via Twitter.) Read it. Rate it. #1. Which part of the paper did you read? Abstract Related Work Methods Results Discussion Conclusion #2. The paper contains new data or analyses that is openly accessible? True False #3. The conclusion is supported by the data and analyses? True False #4. The conclusion is of scientific interest? True False #5. The result is likely to lead to future research? True False Github User: None (add) Repo: None (add) Stargazers: 0 Forks: 0 Open Issues: 0 Network: 0 Subscribers: 0 Language: None Youtube Link: None (add) Views: 0 Likes: 0 Dislikes: 0 Favorites: 0 Comments: 0 Other Sample Sizes (N=): Inserted: Words Total: Words Unique: Source: Abstract: None 02/08/19 09:01PM 9,319 2,947 biorxiv Link to Abstract Tweets biorxiv_sysbio: Morphological deconvolution of beta-lactam polyspecificity in E. coli https://t.co/eg1S9q5Il0 #biorxiv_sysbio biorxivpreprint: Morphological deconvolution of beta-lactam polyspecificity in E. coli https://t.co/T5drhXK6Qg #bioRxiv Images Related
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Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft‐versus‐host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition - Fishe...

Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft‐versus‐host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition - Fishe... | Immunology and Biotherapies | Scoop.it
Cochrane Database of Systematic Reviews

 

Abstract

 

Background Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft‐versus‐host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune‐mediated disorders. GvHD is one of the first areas in which MSCs were clinically applied, and it is important that the accumulating evidence is systematically reviewed to assess whether their use is favoured.

 

Objectives To determine the evidence for the safety and efficacy of MSCs for treating immune‐mediated inflammation post‐transplantation of haematopoietic stem cells. Search methods We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2018, Issue 12), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), Web of Science: Conference Proceedings Citation Index‐Science (CPCI‐S) (from 1990) and ongoing trial databases to 6 December 2018. No constraints were placed on language or publication status. Selection criteria We included RCTs of participants with a haematological condition who have undergone an HSCT as treatment for their condition and were randomised to MSCs (intervention arm) or no MSCs (comparator arm), to prevent or treat GvHD. We also included RCTs which compared different doses of MSCs or MSCs of different sources (e.g. bone marrow versus cord). We included MSCs co‐transplanted with haematopoietic stem cells as well as MSCs administered post‐transplantation of haematopoietic stem cells. Data collection and analysis We used standard methodological procedures expected by Cochrane. We employed a random‐effects model for all analyses due to expected clinical heterogeneity arising from differences in participant characteristics and interventions.

 

Main results We identified 12 completed RCTs (879 participants), and 13 ongoing trials (1532 enrolled participants planned). Of 12 completed trials, 10 compared MSCs versus no MSCs and two compared different doses of MSCs. One trial was in people with thalassaemia major, the remaining trials were for haematological malignancies. Seven trials administered MSCs to prevent GvHD, whereas five trials gave MSCs to treat GvHD. In the comparison of MSCs with no MSCs, cells were administered at a dose of between 105 and 107 cells/kg in either a single dose (six trials) or in multiple doses (four trials) over a period of three days to four months. The dose‐comparison trials compared 2 x 106 cells/kg with 8 x 106 cells/kg in two infusions, or 1 x 106 cells/kg with 3 x 106 cells/kg in a single infusion. The median duration of follow‐up in seven trials which administered MSCs prophylactically ranged from 10 to 60 months. In three trials of MSCs as treatment for aGvHD, participants were followed up for 90 or 100 days. In two trials of MSCs as treatment for cGvHD, the mean duration of follow‐up was 13.4 months (MSC group) and 23.6 months (control group) in one trial, and 56 weeks in the second trial. Five trials included adults only, six trials included adults and children, and one trial included children only. In eight trials which reported the gender distribution, the percentage of females ranged from 20% to 59% (median 35.8%). The overall quality of the included studies was low: randomisation methods were poorly reported and several of the included studies were subject to a high risk of performance bias and reporting bias. One trial which started in 2008 has not been published and the progress of this trial in unknown, leading to potential publication bias. The quality of evidence was therefore low or very low for all outcomes due to a high risk of bias as well as imprecision due to the low number of overall participants, and in some cases evidence based on a single study. We found that MSCs may make little or no difference in the risk of all‐cause mortality in either prophylactic trials (HR 0.85, 95% CI 0.50 to 1.42; participants = 301; studies = 5; I2 = 34% ; low‐quality evidence) or therapeutic trials (HR 1.12, 95% CI 0.80 to 1.56; participants = 244; studies = 1; very low‐quality evidence), and no difference in the risk of relapse of malignant disease (prophylactic trials: RR 1.08, 95% CI 0.73 to 1.59; participants = 323; studies = 6; I2 = 0%; low‐quality evidence) compared with no MSCs. MSCs were well‐tolerated, no infusion‐related toxicity or ectopic tissue formation was reported. No study reported health‐related quality of life. In prophylactic trials, MSCs may reduce the risk of chronic GvHD (RR 0.66, 95% CI 0.49 to 0.89; participants = 283; studies = 6; I2 = 0%; low‐quality evidence). This means that only 310 (95% CI 230 to 418) in every 1000 patients in the MSC arm are expected to develop chronic GvHD compared to 469 in the control arm. However, MSCs may make little or no difference to the risk of aGvHD (RR 0.86, 95% CI 0.63 to 1.17; participants = 247; studies = 6; I2 = 0%; low‐quality evidence). In GvHD therapeutic trials, we are very uncertain whether MSCs improve complete response of either aGvHD (RR 1.16, 95% CI 0.79 to 1.70, participants = 260, studies = 1; very low‐quality evidence) or cGvHD (RR 5.00, 95%CI 0.75 to 33.21, participants = 40, studies = 1; very low‐quality evidence). In two trials which compared different doses of MSCs, we found no evidence of any differences in outcomes.

 

Authors' conclusions MSCs are an area of intense research activity, and an increasing number of trials have been undertaken or are planned. Despite a number of reports of positive outcomes from the use of MSCs for treating acute GvHD, the evidence to date from RCTs has not supported the conclusion that they are an effective therapy. There is low‐quality evidence that MSCs may reduce the risk of cGvHD. New trial evidence will be incorporated into future updates of this review, which may better establish a role for MSCs in the prevention or treatment of GvHD. Plain language summary Mesenchymal stromal cells to treat or prevent graft‐versus‐host disease in stem cell transplant recipients Review question In people who receive a stem cell transplant for a haematological condition, can an additional infusion of mesenchymal stromal cells (MSCs) prevent the development of graft‐versus‐host disease (GvHD)? In people who have already developed GvHD as a result of their stem cell transplant, can MSCs improve their clinical outcome? Background Patients with leukaemia or other blood disorders may be treated with blood stem cells from another person, but the immune cells in the graft can attack their tissues in a serious complication referred to as graft‐versus‐host disease (GvHD). Steroids are the standard treatment for GvHD, but if they are unable stop the damage then treatment options are limited.

 

 

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A case report of severe recurrent varicella in an ankylosing spondylitis patient treated with adalimumab – a new side effect after 15 years of usage | BMC Infectious Diseases | Full Text

A case report of severe recurrent varicella in an ankylosing spondylitis patient treated with adalimumab – a new side effect after 15 years of usage | BMC Infectious Diseases | Full Text | Immunology and Biotherapies | Scoop.it
Tumor necrosis factor-α (TNF-α) antagonists, most of which are monoclonal antibodies, became a widespread treatment for autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, psoriasis, psoriatic arthritis, hidradenitis suppurativa and uveitis.
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