MH_dev_160

DB00065 SUB in experimental alkali burns of the oesophagus in the rat . BACKGROUND : We aimed to investigate the efficacy of infliximab , a chimeric P01375 REA antibody , in the prevention of fibrosis in an experimental alkaline burn of the oesophagus in the rat . METHODS : Thirty-two Wistar albino rats divided into four experimental groups . Caustic oesophageal burn was induced by applying 37.5 % NaOH to the distal oesophagus . DB00065 SUB was given at a dose of 5 mg / kg via the intraperitoneal route . Group A ( sham ) animals were uninjured , group B had untreated oesophageal burns , group C had oesophageal burns treated with a single dose of infliximab on the first day , and Group D had oesophageal burns treated with infliximab on the first and 14th days . Efficacy of the treatment was assessed on the 28th - day by measuring stenosis index of the oesophagus and histopathological damage score , and biochemically by determining tissue hydroxyproline content . RESULTS : There was no significant difference between the Group B and the infliximab treated Groups C and D in means of tissue hydroxyproline content and histopathological damage scores . Stenosis index was not significantly different between the Group B , Group C , and Group D . CONCLUSION : Anti - P01375 REA treatment with infliximab does not ameliorate the degree of fibrosis in alkali burns of the oesophagus in the rat . Further evaluation of inflammatory and immunological events leading to stricture in alkaline oesophageal burns may provide new perspectives for the treatment of alkaline oesophageal burns .

Diffuse large B-cell lymphoma in a patient with rheumatoid arthritis treated with infliximab and methotrexate . DB00065 SUB is a tumour necrosis factor ( P01375 REA ) - alpha blocking drug classified as a biological response modifier . It has been suggested that the risk of malignancies , especially lymphomas , is increased in patients with rheumatoid arthritis ( RA ) treated with anti - P01375 REA antibody therapy . We present a case of malignant lymphoma during the treatment of RA with infliximab and methotrexate .

[ Inflammatory bowel disease : from sulfasalazine to biologics ] . The arrival of biologics , in particular anti-Tumor Necrosis Facteur ( P01375 REA ) , at the end of the nineties , revolutionnized treatment of inflammatory bowel diseases . Concomitantly , immunosuppressants ( thiopurines , methotrexate ) are used more widely and earlier in the disease course . DB00065 SUB and adalimumab are very effective in more than two-thirds of patients , including those with fistula . This efficacy is long lasting in one-third of patients . Main side-effects of anti - P01375 REA are opportunistic infections ( intracellular bacteria ) which should be prevented and diagnosed early . Anti - P01375 REA are safe in the long-term , however , there is a particular concern regarding the risk of hepatosplenic T cell lymphomas in young men receiving bitherapy with thiopurine and anti - P01375 REA . The old strategy of adapting the therapeutic response to severity of symptoms and disease activity has no impact on natural history of the disease and should be abandoned . Most authors now favour an aggressive therapeutic approach in selected patients , before they develop irreversible anatomic lesions . This new strategy may change natural history and will become safer with a better knowledge of side-effects of immunosuppressants and biologics and how to prevent them . Moreover development of new therapeutic agents may permit to avoid surgery in patients who do not respond to therapy .

Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn ' s disease . BACKGROUND : Tumour necrosis factor alpha is the key inflammatory cytokine involved in the pathogenesis of Crohn ' s disease . DB00065 SUB , a chimaeric monoclonal antibody of tumour necrosis factor-alpha is successfully used for the treatment of Crohn ' s disease , although the response to infliximab therapy differs among patients . The genetic background of the individual may partially explain the differences of the responsiveness . AIM : To investigate whether the polymorphisms in these genes are associated with the response to infliximab treatment as tumour necrosis factor-alpha exerts its biological activity through P01375 REA receptor superfamily 1A and 1B . METHODS : Eighty Crohn ' s disease patients were enrolled in the study and classified into responder and nonresponder according to the efficacy of infliximab treatment . Single nucleotide polymorphisms of P01375 REA receptor superfamily 1A ( rs767455 and rs4149570 ) and P01375 REA receptor superfamily 1B ( rs1061622 , rs1061624 and rs3397 ) were determined . RESULTS : The minor allele carrier of rs767455 showed a significant association with a lack of efficacy compared to the major genotype ( OR = 0.26 ; 95 % CI : 0.08- 0.91 ) . A P01375 REA receptor superfamily 1B haplotype inferred by rs1061624 and rs3397 also showed significant differences in the distribution between responder and nonresponder ( P = 0.01 ) . CONCLUSION : These results suggest that tumour necrosis factor receptor genotypes may be involved in the different responses to infliximab in Japanese patients with Crohn ' s disease .

New indications for treatment of chronic inflammation by P01375 REA blockade . The impressive anti-inflammatory effects of the tumor necrosis factor ( P01375 REA ) alpha blockers etanercept and infliximab have led to their use in multiple inflammatory diseases besides their original indication , rheumatoid arthritis ( RA ) . The well-studied clinical effects of both agents in RA are the reduction of signs and symptoms of joint inflammation as well as the arrest of bone destruction . DB00065 SUB has also been Food and Drug Administration-approved in the treatment of Crohn disease ; etanercept is now FDA-approved for juvenile chronic arthritis and psoriatic arthritis . Favorable initial clinical trials have been reported in other rheumatic diseases , including ankylosing spondylitis and adult Still disease . In addition , P01375 REA alpha blockade is being studied in the treatment of uveitis , myelodysplastic syndromes , and graft-versus-host disease . Studies in sepsis and septic shock have identified small subsets of patients that may benefit from P01375 REA alpha blockade , but broader use in septic patients has not improved survival . The P01375 REA alpha blockers have had relatively infrequent serious side effects , especially compared with the immunosuppressive and cytotoxic agents otherwise employed to treat these diseases . Further studies of optimal dosing , combination with other therapies , and long-term benefits and side effects will emerge from future trials .

Current and Future Anti - P01375 REA Therapy for Inflammatory Bowel Disease . Anti-tumor necrosis factor-alpha ( anti - P01375 REA ) therapy has become a very important modality in the treatment of patients with inflammatory bowel disease . A number of anti - P01375 REA medications have been investigated for this purpose , many via randomized controlled trials . DB00065 SUB , the most studied of these agents , has shown impressive efficacy in the treatment of luminal and fistulizing Crohn ' s disease , as well as ulcerative colitis . DB00051 and certolizumab have shown similar efficacy in Crohn ' s disease but have not yet been studied in ulcerative colitis . Less impressive results were seen in randomized controlled trials involving CDP - 571 , etanercept , or onercept for patients with Crohn ' s disease . Thalidomide and CNI - 1493 have been evaluated only preliminarily in small , open-label pilot studies in patients with Crohn ' s disease . The future of anti - P01375 REA therapy in inflammatory bowel disease is very bright , as exciting new developments continue to be made at a rapid pace .

Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 REA ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen-presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 REA - mediated NF-ĸB signaling of DCs remain poorly defined . METHODS : Bone-marrow ( BM ) - derived DCs ( BM-DCs ) were treated with P35367 REA inverse agonists to interrupt basal P35367 REA - mediated signaling . The crosstalk of P35367 REA - mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay , NF-ĸB subunit analysis using Western blotting and P01375 REA - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 REA signaling by inverse agonists significantly inhibited P01375 REA - α and P05231 REA production of BM-DCs . P35367 REA - specific agonists were able to enhance P01375 REA - α production , but this overexpression was significantly inhibited by NF-ĸB inhibitor . The P35367 REA inverse agonist ketotifen also suppressed cellular NF-ĸB activity , suggesting crosstalk between P35367 REA and NF-ĸB signaling in DCs . After comprehensive analysis of NF-ĸB subunits , c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs , which led to inhibition of the promoter activity of P01375 REA - α . Finally , adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c-Rel controls P35367 REA - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 REA - mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation .

DB00065 SUB treatment reduces complement activation in patients with rheumatoid arthritis . BACKGROUND : Tumour necrosis factor ( P01375 REA ) blocking agents decrease C reactive protein ( CRP ) levels in rheumatoid arthritis ( RA ) . It has been shown that CRP may contribute to complement activation in RA . OBJECTIVE : To assess the effect of intravenous infliximab treatment on complement activation , especially that mediated by CRP , in RA . METHODS : 35 patients with active RA ( 28 joint count Disease Activity Score ( DAS 28 ) > 4.4 ) were treated with intravenous injections of infliximab ( 3 mg / kg , at weeks 0 , 2 , 6 , 14 , and 22 ) . Clinical response and plasma levels of complement activation products , of CRP and of CRP-complement complexes , which are specific markers for CRP mediated complement activation , were assessed at the indicated time points up to 22 weeks . The relationship between CRP and CRP-complement complexes was analysed by paired t test between two time points and by generalised estimated equation , to test differences of variables over time . RESULTS : At 2 weeks after the first dose , infliximab significantly reduced overall P01024 REA and C4 activation and plasma levels of CRP and CRP-complement complexes were also significantly reduced at this time point . The effects of infliximab on CRP and complement continued throughout the observation period and were more pronounced in patients with a good response to infliximab treatment . CONCLUSION : Treatment with infliximab decreases plasma levels of CRP and CRP dependent complement activation products and concomitantly may reduce complement activation in RA . Complement activation may be among the effector mechanisms of P01375 REA in RA .

DB00065 SUB for treating axial spondylarthropathy in everyday practice . The advent of P01375 REA antagonists has had a revolutionary impact on the treatment of ankylosing spondylitis ( AS ) . However , whether the benefits recorded in controlled trials are replicated in everyday practice has not been extensively evaluated . OBJECTIVES : To evaluate the effectiveness of infliximab in patients with axial spondyloarthropathies , to identify factors associated with the treatment response , and to assess fulfillment of modified New York criteria and compliance with guidelines about using P01375 REA antagonists . METHODS : Retrospective review of patients given infliximab for axial spondyloarthropathy between 2001 and 2003 . Disease activity , motion limitation , laboratory tests , and the 6 - week response rate were recorded . RESULTS : Of the 86 included patients ( 48 women and 38 men , mean age , 44 + / - 11 years ) , 37 % responded to infliximab therapy . Uveitis and P02741 REA elevation at baseline predicted a response . Only 53 % of patients met modified New York criteria and only 23 % met ASAS criteria for starting P01375 REA antagonist therapy . CONCLUSION : DB00065 SUB was less effective in our patients with axial spondyloarthropathy than expected based on the results of controlled trials . However , many patients did not meet New York criteria for AS and / or ASAS criteria for P01375 REA antagonist therapy . Therefore , our results do not challenge the usefulness of P01375 REA antagonists in axial AS . Our patients were treated before the development of guidelines for P01375 REA antagonist therapy and before the introduction of magnetic resonance imaging as an evaluation tool in AS . Strict criteria should be used to decide when P01375 REA antagonist therapy is appropriate in patients with spondyloarthropathies .

DB00203 MEN attenuates inflammation and oxidative stress in pelvic ganglia neurons after bilateral cavernosal nerve damage . Erectile dysfunction is a common complication for patients undergoing surgeries for prostate , bladder , and colorectal cancers , due to damage of the nerves associated with the major pelvic ganglia ( P29372 ) . Functional re-innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype . O76074 REA inhibitors ( PDE 5i ) have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage ( BCNR ) by up-regulating the expression of neurotrophic factors in P29372 . However , little is known about the effects of PDE 5i on markers of neuronal damage and oxidative stress after BCNR . This study aimed to investigate the changes in gene and protein expression profiles of inflammatory , anti-inflammatory cytokines and oxidative stress related-pathways in P29372 neurons after BCNR and subsequent treatment with sildenafil . Our results showed that BCNR in Fisher - 344 rats promoted up-regulation of cytokines ( interleukin - 1 ( IL - 1 ) β , P05231 REA , P22301 REA , transforming growth factor β 1 ( TGFβ 1 ) , and oxidative stress factors ( DB02701 adenine dinucleotide phosphate ( NADPH ) oxidase , P05164 REA ( P05164 REA ) , inducible nitric oxide synthase ( P35228 REA ) , P01375 REA receptor superfamily member 5 ( P25942 REA ) that were normalized by sildenafil treatment given in the drinking water . In summary , PDE 5i can attenuate the production of damaging factors and can up-regulate the expression of beneficial factors in the P29372 that may ameliorate neuropathic pain , promote neuroprotection , and favor nerve regeneration .

Binding and functional comparisons of two types of tumor necrosis factor antagonists . Two tumor necrosis factor ( P01375 REA ) antagonists infliximab ( a chimeric monoclonal antibody ) and etanercept ( a p75 P01375 REA receptor / Fc fusion protein ) have been approved for treatment of rheumatoid arthritis . However , these agents have shown different degrees of clinical benefit in controlled clinical trials in other P01375 REA - mediated diseases such as Crohn ' s disease ( CD ) and psoriasis . We investigated whether structural differences between these two antagonists translate into different binding and functional characteristics . To study the binding of infliximab and etanercept to both the soluble and cell-surface transmembrane forms of P01375 REA , a variety of in vitro binding and cell-based assays were performed . Binding assays using ( 125 ) I-labeled P01375 REA showed that infliximab binds to both monomer and trimer forms of soluble P01375 REA ( sTNF ) , whereas etanercept binding is restricted to the trimer form . DB00065 SUB formed stable complexes with sTNF , whereas etanercept formed relatively unstable complexes , resulting in release of dissociated P01375 REA . KYM - 1D4 cell killing assays and human umbilical vein endothelial cell activation assays demonstrated that P01375 REA that had dissociated from etanercept was bioactive . DB00065 SUB also formed more stable complexes with the transmembrane form of P01375 REA expressed on transfected cells relative to analogous complexes formed with etanercept . Additionally , more infliximab molecules bound to the transmembrane P01375 REA with higher avidity than etanercept . Although both infliximab and etanercept inhibited transmembrane P01375 REA - mediated activation of human endothelial cells , infliximab was significantly more effective . The differences between infliximab and etanercept in their P01375 REA binding characteristics may help explain their differential efficacy in CD and psoriasis clinical trials .

Strategies targeting tumor necrosis factor in Crohn ' s disease . P01375 REA plays an important role in mediating the inflammation of Crohn ' s disease . Strategies aimed at reducing tumor necrosis factor in patients with Crohn ' s disease include the mouse / human chimeric monoclonal antibody infliximab , the humanized monoclonal antibody CDP 571 , the human recombinant tumor necrosis factor receptor fusion protein etanercept , and the small molecule thalidomide . DB00065 SUB is effective for treating active Crohn ' s disease , maintaining remission , and closing fistulas . Side effects occurring in patients treated with infliximab include human anti-chimeric antibodies , infusion reactions , formation of autoantibodies , and rarely drug induced lupus . CDP 571 is effective for treating active Crohn ' s disease , steroid sparing , and possibly for closing fistulas and maintaining remission . Side effects occurring in patients treated with CDP 571 include anti-idiotype antibodies , infusion reactions , and formation of autoantibodies . Pilot studies have suggested that etanercept and thalidomide may also be beneficial . Anti-tumor necrosis factor therapies are effective for the treatment for Crohn ' s disease .

DB00065 SUB treatment for refractory kawasaki disease in korean children . BACKGROUND AND OBJECTIVES : This was a multicenter study to evaluate the usefulness of the tumor necrosis factor-alpha ( P01375 REA ) blocker infliximab for treatment of Korean pediatric patients with refractory Kawasaki disease ( KD ) . SUBJECTS AND METHODS : Data from 16 patients throughout Korea who were diagnosed with refractory KD and received infliximab were collected retrospectively . RESULTS : Complete response to therapy with cessation of fever occurred in 13 of 16 patients . P02741 REA ( CRP ) concentrations decreased following infliximab infusion in all 14 patients in whom it was measured before and after treatment . There were no infusion reactions or complications associated with infliximab except in 1 case with acute hepatitis occurring during treatment followed by calculous cholecystitis 4 months later . Fifteen patients had coronary artery ( CA ) abnormalities before infliximab therapy . Three had transient mild dilatation and 9 had CA aneurysms , with subsequent normalization in 4 patients , persistent mild dilatation in 3 , persistent aneurysm in 2 , and there were 3 cases ( 2 with CA aneurysm , 1 with mild CA dilatation ) without follow-up echocardiography . CONCLUSION : The results of this study suggest that infliximab may be useful in the treatment of refractory KD , and it appears that there is no significant further progression of CA lesions developing after infliximab treatment . Multicenter trials with larger numbers of patients and long-term follow-up are necessary to assess the clinical efficacy and safety of infliximab in refractory KD .

Microglial activation , increased P01375 REA and P31645 expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 REA ) and the 5 - HT transporter ( P31645 ) in the pre-frontal area . Enhanced expression of 5HT ( 2A ) and P23219 REA in the pre-frontal area was observed in all stressed animals . In turn , indoleamine -2,3- dioxygenase ( P14902 REA ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti-inflammatory , and possibly , P01375 REA - targeted therapy for major depression .

Treatment with anti - P01375 REA antibody infliximab reduces serum P40933 REA levels in patients with rheumatoid arthritis . The aim of this study was to analyze the change of serum cytokines and pentosidine levels in patients with rheumatoid arthritis ( RA ) by infliximab treatment . Twenty-three patients with RA were studied for 30 weeks on the effects of infliximab treatment . Serum levels of P40933 REA , IL - 16 , Q16552 REA , and granulocyte-macrophage colony-stimulating factor ( GM - P04141 REA ) were measured with ELISA methods and pentosidine levels were determined using high-performance liquid chromatography , both at baseline and at 14 and 30 weeks after the initial treatment with infliximab . In addition , the patients also underwent physical and routine blood examinations . The higher levels of serum P40933 REA in RA patients before treatment with infliximab significantly decreased at 14 and 30 weeks after the initial treatment with infliximab , but serum IL - 16 , Q16552 REA , GM - P04141 REA , and pentosidine levels did not decrease . The serum Q16552 REA and GM - P04141 REA levels remained to be a limited detectable level at the pre - and posttreatment with infliximab . DB00065 SUB treatment significantly lowered the serum levels of P40933 REA in patients with RA . P40933 REA is one of the crucial cytokines affected by infliximab .

P01375 REA - alpha blockade for the treatment of acute GVHD . Despite posttransplantation immunosuppressive therapy , acute graft-versus-host disease ( GVHD ) remains a major cause of sickness and death . P01375 REA - alpha ( P01375 REA ) is implicated in the pathophysiology of GVHD at several steps in the process . DB00065 SUB is a genetically constructed immunoglobulin P55008 ( IgG 1 ) murine-human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of P01375 REA , blocking its interaction with receptors and causing lysis of cells that produce P01375 REA . In this study we retrospectively evaluated 134 patients who had steroid-refractory acute GVHD . Of these , 21 who received infliximab as a single agent were analyzed . The overall response rate was 67 % ( n = 14 ) , and 13 patients ( 62 % ) experienced complete response ( CR ) . Five patients ( 24 % ) did not respond , and 2 ( 10 % ) had progressive GVHD . None had a toxic reaction to infliximab . Ten patients ( 48 % ) had 18 fungal infections , including Aspergillus species in 7 and Candida species in 10 . Seventeen patients ( 81 % ) had bacterial infections , including 32 gram-positive and 8 gram-negative infections . Viral infections , primarily cytomegalovirus reactivation , occurred in 14 patients ( 67 % ) . The Kaplan-Meier estimate of overall survival was 38 % . In conclusion , infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD , particularly with gastrointestinal tract involvement . Survival after steroid-resistant acute GVHD continues to be problematic . The possibility of excessive fungal and other infections must be explored further .

Open-label trial of anti - P01375 REA in dermato - and polymyositis treated concomitantly with methotrexate . BACKGROUND / AIMS : To determine the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis and polymyositis . METHODS : A multicentre open-label controlled trial was conducted . Disease activity was assessed using patient ' s and physician ' s disease activity assessment , manual muscle testing ( MMT ) , handheld dynamometry , and serum CK . The primary objective was to assess the efficacy using MMT after a period of 26 weeks . RESULTS : The study was terminated prematurely because of a low inclusion rate and a high drop-out rate due to disease progression and the occurrence of an infusion reaction . The few patients who did reach the primary endpoint showed improvement in all aspects studied . CONCLUSION : DB00065 SUB combined with weekly methotrexate might be safe and well tolerated in a small subgroup of patients with drug-naive recent-onset myositis . At present , we do not advocate the use of this treatment because treatment response can not be predicted beforehand .

Are there predictors of Remicade treatment success or failure ? DB00065 SUB ( Remicade ) is an antitumor necrosis factor ( P01375 REA ) therapy effective in both induction and maintenance of remission in Crohn ' s disease . Identifying predictors of response or relapse to infliximab is important given the potential toxicities and cost of this therapy . Currently available data suggest that concurrent immunosuppressant therapy , certain clinical characteristics , biological and immunological markers , and gene polymorphism may correlate with response to infliximab . However , no single variable has been consistently shown or definitely proven in studies to be a predictor of response to infliximab to be of practical value in current clinical practice . Data from the literature in these areas are reviewed in this article , pointing to the need for additional research in this topic .

DB00065 SUB and insulin resistance . P01308 REA resistance is the most important pathophysiologic feature of obesity , type 2 diabetes mellitus and prediabetic states . P01375 REA , a proinflammatory cytokine , plays a pivotal role in the pathogenesis of inflammation-associated insulin resistance during the course of rheumatic diseases . Therapies aimed at neutralizing P01375 REA , such as the monoclonal antibody infliximab , represent a novel approach for the treatment of rheumatic diseases and allow to obtain significant results in terms of control of the inflammatory process . In this article we reviewed the scientific evidence published in the literature about a potential role of P01375 REA blockade in improving insulin resistance in non-diabetic rheumatic patients .

[ Autoimmune aspects of treatment with P01375 REA inhibitors ] . P01375 REA - alpha ( P01375 REA ) plays an important role in the pathogenesis of such diseases as rheumatoid arthritis , Crohn ' s disease , ankylosing spondylitis , psoriatic arthritis , and juvenile chronic arthritis . Recent years have brought improvement in the understanding of the pathogeneses of these diseases , resulting in the production of new groups of biological drugs , including , among others , anti - P01375 REA antibodies . The use of P01375 REA inhibitors has been a great advance in the treatment of patients with these inflammatory diseases . DB00065 SUB and adalimumab are monoclonal antibodies that bind to and neutralize the activity of P01375 REA . DB00065 SUB is a mouse / human chimera that joins the variable regions of a mouse antibody to the constant region of human IgG 1 . DB00051 is a fully human IgG 1 antibody . DB00005 is a dimeric fusion protein that joins the human p75 P01375 REA receptor to the Fc domain of human IgG 1 . The beneficial effects of the anti - P01375 REA monoclonal antibodies infliximab and adalimumab and the soluble receptor fusion protein etanercept in the treatment of rheumatoid arthritis , especially in patients resistant to other disease-modifying antirheumatic drugs ( DMARDs ) , are discussed . We observe stoppage of articular destruction during treatment with P01375 REA inhibitors . Soon after the introduction of this therapy it was found that these agents have a propensity for stimulating the production of autoantibodies and antibodies against themselves . In this review , recent studies analyzing the effect of P01375 REA blockade ( infliximab , etanercept , and adalimumab ) on the Q14201 , anti-dsDNA , and anticardiolipin antibody profiles in autoimmune diseases are discussed .

Endometriosis is sustained by tumour necrosis factor-alpha . Endometriosis is a common gynaecological disorder causing pain , infertility , and emotional distress . Evidence presented here suggests that abnormal production of tumour necrosis factor-alpha ( P01375 REA ) is required for the establishment and maintenance of endometriosis and also is responsible for the associated infertility through its effect on sperm motility and function and oocyte development . DB00065 SUB , which blocks P01375 REA function , could be used in the treatment of endometriosis to reverse the above effects .

DB00065 SUB can induce a prolonged clinical remission and a decrease in thyroid hormonal requirements in a patient with SAPHO syndrome and hypothyroidism . SAPHO syndrome is a rare entity that compromises the skeletal system ( arthritis-osteitis ) and is associated with various dermatological conditions such as palmoplantaris pustulosis ( PPP ) and acne . We present the case of a 39 - year-old man with invalidating arthritis derived from a SAPHO syndrome and hypothyroidism ( after radioiodine treatment for a Graves ' disease ) . Due to the severity and refractoriness of his disease , we decided to use infliximab . He showed a prompt and prolonged response of his joint and cutaneous manifestations after three doses of a tumor necrosis factor alpha ( P01375 REA ) blocker . Interestingly , he also decreased his levothyroxine requirements after P01375 REA blockade therapy .

DB00065 SUB therapy for sarcoidosis ( lupus pernio ) . Sarcoidosis is a chronic granulomatous disease of unknown aetiology in which the primary cytokine tumour necrosis factor ( P01375 REA ) - alpha appears to play a major role . Older immune-modulating drugs including corticosteroids , antimalarials and thalidomide , as well as cytotoxic drugs with immune modulatory effects , have been used to control disease . We present a patient with severe mutilating cutaneous sarcoidosis ( lupus pernio ) who had showed only partial response to courses of a wide spectrum of immune modulators and cytotoxic therapies , and who had developed significant side-effects due to prolonged high-dose corticosteroids . However , the patient ' s cutaneous disease responded rapidly to the P01375 REA inhibitor infliximab .

Hepatitis and Lupus-Like Syndrome during DB00065 SUB Therapy for Psoriasis . Biologics are very useful medications that changed the lives of many patients in the last decade . However , we still do not know about the long-term side effects of these drugs . DB00065 SUB is an anti - P01375 REA chimeric antibody widely used and approved for the treatment of many diseases . Lupus-like syndrome and hepatitis are among the uncommon side effects of infliximab . Most of the written literature was published for cases of rheumatology and gastroenterology . We report here a case of both hepatitis and lupus-like syndrome that occurred sequentially in the same patient and compare our finding with two case reports of the same side effects , drug and disease .

How safe is infliximab therapy during pregnancy and lactation in inflammatory bowel disease ? INTRODUCTION : DB00065 SUB has been approved for the treatment of patients with inflammatory bowel diseases ( Q9UKU7 ) . However , data regarding its safety during pregnancy and breastfeeding are scarce . AREAS COVERED : Relevant papers sourced from bibliographical searches ( MEDLINE ) up to June 2014 are reviewed . DB00065 SUB , as adalimumab , crosses the placenta from the end of the second trimester . The use of anti - P01375 REA agents after the second trimester leads to intrauterine exposure . Although infliximab during pregnancy in Q9UKU7 patients seems to be safe in the short-term , there are concerns about the consequences of the early exposition with this drug for the development of the newborn immune system . Accordingly , it has recently been suggested that anti - P01375 REA drugs should be stopped during , at least , the second trimester , when the mother is in remission ; this approach seems to be safe for the mother and minimizes fetal exposition to the drug . DB00065 SUB has been detected in breast milk in miniscule amounts . Case reports do not suggest toxicity ; however , the effects of exposure on the neonate merit further investigation . EXPERT OPINION : DB00065 SUB appears to be safe for the mother with Q9UKU7 and the newborn , at least in the short-term . DB00065 SUB is transferred in breast milk ; although its toxicity is unlikely , it can not be discounted without further long-term data .

DB00065 SUB downregulates interferon-gamma production in activated gut T-lymphocytes from patients with Crohn ' s disease . The tumour necrosis factor-alpha ( P01375 REA ) neutralizing antibody , DB00065 SUB ( Ifx ) , reduces disease activity in patients with active steroid-dependent or fistulizing Crohn ' s disease . The mechanisms underlying the effects of Ifx are not fully understood . This study aims to investigate if and how Ifx regulates the interferon-gamma ( P01579 REA ) production in human intestinal T-cells . Colonic T cells were expanded from 25 patients with Crohn ' s disease and ten healthy controls in an in vitro system , using medium supplemented with interleukin - 2 and interleukin - 4 but without exogenous antigen . The effect of Ifx was investigated in these in situ activated T cell cultures regarding the P01579 REA production , proliferation , transmembrane P01375 REA expression , cytolysis and apoptosis . T cell cultures from patients with Crohn ' s disease produced significantly higher levels of P01579 REA ( < 0.001 ) and P01375 REA ( P= 0.04 ) than T cell cultures from healthy controls . The production of P01579 REA was downregulated by Ifx in early T cell cultures ( P= 0.002 ) . Ifx bound to transmembrane P01375 REA of activated T cells without inducing complement-mediated cytolysis , apoptosis and without affecting proliferation . Besides its known P01375 REA neutralizing property , Ifx downregulates P27352 REA - gamma production in colonic T cell cultures . Colonic T cells express transmembrane P01375 REA that binds Ifx . The data suggest that Ifx reduces the level of at least two pro-inflammatory cytokines leading to lower disease activity .

DB00065 SUB chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes . Tumour necrosis factor alpha ( P01375 REA ) is believed to play a major role in apoptotic death of bone marrow cells in myelodysplastic syndromes ( P43034 REA ) . We explored the efficacy and safety profile of infliximab chimaeric anti - P01375 REA monoclonal antibody treatment in two P43034 REA patients . They both had low - / intermediate-risk P43034 REA , isolated anaemia and elevated circulating levels of P01375 REA . DB00065 SUB produced no adverse side-effects and resulted in sustained erythroid responses , one major and one minor . Laboratory studies indicated a remarkable decrease in the percentage of apoptotic stem cells in the bone marrow . This preliminary report indicates that infliximab may have an application as P43034 REA therapy and warrants further investigation .

A placebo-controlled , double-blind trial of infliximab for cancer-associated weight loss in elderly and / or poor performance non-small cell lung cancer patients ( N01C9 ) . PURPOSE : This study tested whether infliximab , a chimeric IgG 1kappa monoclonal antibody that blocks tumor necrosis factor ( P01375 REA ) alpha , improves / stabilizes weight loss in elderly and / or poor performance status patients with metastatic non-small cell lung cancer ( NSCLC ) . METHODS : This double-blind trial randomly assigned patients to infliximab / docetaxel ( n = 32 ) versus placebo / docetaxel ( n = 29 ) . The primary endpoint was > or = 10 % weight gain . RESULTS : Groups were balanced with respect to age , number of prior chemotherapy regimens , baseline weight loss , and performance status . No patient gained > or = 10 % baseline weight , and early evidence of the lack of efficacy prompted early trial closure . Appetite improvement was negligible in both arms . However , infliximab - / docetaxel-treated patients developed greater fatigue and worse global quality of life scores . Other outcomes , such as tumor response rate ( < 10 % in both groups ) and overall survival , were not statistically different between groups . There were no statistically significant differences in adverse events , although one death was attributed to infliximab . Genotyping for the P01375 REA alpha - 238 and - 308 polymorphisms revealed no clinical significance of these genotypes , as relevant to the loss of weight or appetite . CONCLUSIONS : This trial closed early because infliximab did not prevent or palliate cancer-associated weight loss . DB00065 SUB was associated with increased fatigue and inferior global quality of life .

Role of P20333 REA polymorphisms in the response of Crohn ' s disease patients to infliximab . DB00065 SUB ( IFX ) is a valid treatment for Crohn ' s disease ( CD ) , but a relevant percentage of patients do not benefit from this therapy . In the Japanese population , the response to IFX was associated with markers in the P01375 REA receptor superfamily 1A ( P19438 REA ) and 1B ( P20333 REA ) genes . We aimed to replicate the association previously described in the Japanese population and to ascertain the role of P01375 REA receptors as modulators of the response to IFX . We studied 297 white Spanish CD patients with a known response to IFX : 238 responders and 59 primary nonresponders . Four single nucleotide polymorphisms ( SNPs ) were analyzed : rs767455 in P19438 REA and rs1061622 , rs1061624 , and rs3397 in P20333 REA . Comparisons between groups were performed with chi-square tests or the Fisher ' s exact test . Different features ( sex , age , disease duration , smoking among others ) were evaluated as possible confounding factors . No significant association was found between the studied P19438 REA polymorphisms and response to IFX . In the P20333 REA gene , the haplotype rs1061624_A - rs3397_T was significantly increased in nonresponders : p = 0.015 , OR = 1.78 , 95 % CI 1.09- 2.90 ; and an increased frequency of rs1061622_G carriers was observed in patients with remission : p = 0.033 vs nonresponders and p = 0.023 vs patients with a partial response . Our results support a role of P20333 REA gene variants in the response to IFX in CD patients .

DB00991 MEN : kinetic and dynamic profile in the treatment of pain . DB00991 MENMAX DB00991 MEN ( 4,5- diphenyl - 2 - oxazolepropionic acid ) is a non-steroidal anti-inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . DB00991 MEN has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . DB00991 MEN ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 REA and P35354 REA isoenzymes , inhibition of nuclear translocation of NF-kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . DB00991 MEN and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .

[ Use of infliximab in ulcerative colitis ] . DB00065 SUB , a chimeric monoclonal anti-tumour necrosis factor alpha ( P01375 REA ) antibody has dramatically changed the management of various chronic inflammatory disorders such as Crohn ' s disease ( CD ) , rheumatoid arthritis , ankylosing spondylitis or psoriasis . This drug is well established for the treatment of CD in case of steroid-refractoriness , failure to respond to an immunosuppressant agent or fistulizing disease . The immunological concept that ulcerative colitis ( UC ) reflects primarily a T-helper cell type - 2 mediated disease prevented the earlier use of anti - P01375 REA agents in this disease . Promising initial pilot studies in steroid-refractory UC patients led to two large placebo-controlled trials in patients with moderate to severe UC . These studies clearly showed a benefit for infliximab treatment in UC with mucosal healing and improved life quality . DB00065 SUB therefore can be used in patients not responding adequately to steroids and / or immunosuppressants . Furthermore , one study showed evidence that infliximab might also be effective in severe , intravenous steroid-refractory UC . Therefore , infliximab might be used alternatively to cyclosporine A or tacrolimus in this patient group . DB00065 SUB has now been established as an additional treatment option in patients with chronic-active UC not responding to an immunosuppressive agent and / or in case of severe acute UC . Experienced gastroenterologists should be involved in the decision making for such a therapy to balance thoroughly the benefit / risk ratio for our patients .

[ Drug treatment of chronic inflammatory bowel diseases : current status and prospects ] . The medical treatment of inflammatory bowel disease is dependent on disease activity and bowel involvement . Severe Crohn ' s disease and ulcerative colitis are primarily treated with corticosteroids . Alternatively , if inflammation is localised in the right colon and ileum , budesonide may be used in view of its low systemic side effects . In distal colitis and perianal disease , topical therapy with steroids is very effective . In moderate disease preparations containing 5 - aminosalicylate ( DB00244 ) may be used . The latter are highly effective applied locally in distal disease . Steroids should be tapered down and whenever possible not used to maintain remission . In patients with ulcerative colitis , DB00244 is effective in maintaining remission , whereas this medication plays only a limited role in Crohn ' s disease . Refractory disease or patients with multiple flare-ups should be treated with azathioprine . DB00065 SUB , an anti - P01375 REA antibody , is a potent therapy for fistulising Crohn ' s disease or steroid-refractory disease . Other approved and experimental treatments are discussed .

DB00065 SUB therapy in pulmonary fibrosis associated with collagen vascular disease . OBJECTIVE : To study the potential effectiveness of tumor necrosis factor a ( P01375 REA ) inhibitor treatment for pulmonary fibrosis associated with a collagen vascular disease , CVD ( rheumatoid arthritis , RA and systemic sclerosis , SSc ) refractory to conventional treatment . METHODS : Four patients ( three men with RA , one woman with SSc ) were treated with infliximab . All patients received 3mg / kgr of infliximab at intervals 0 , 2 and 6 weeks , and then maintenance infusions every 8 weeks afterwards for at least a 12 - month period . Patients had active disease despite treatment with corticosteroids and other immunomodulatory agents . RESULTS : Treatment was well-tolerated from all patients . Pulmonary fibrosis remained stable during treatment in terms of symptoms , pulmonary function tests ( PFTs ) and High resolution computed tomography ( HRCT ) appearance . As expected , a clinical response was observed in joint symptoms in patients with RA as evaluated by the DAS 28 ( Disease Activity Score , the 28 joint version ) . CONCLUSION : This study suggests that inhibition of P01375 REA with infliximab may stabilize the progression of pulmonary fibrosis associated with CVD . Prospective , controlled trials are necessary to determine the efficacy of infliximab in pulmonary fibrosis associated CVD .

Episcleritis Related to Drug-Induced Lupus Erythematosus following DB00065 SUB Therapy : A Case Report . Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug . Herein , we describe a patient with distinct clinical manifestations of anti - P01375 REA - associated DILE related to infliximab therapy . The patient exhibited clinical and laboratory findings of lupus-like illnesses as well as ocular disorders , such as episcleritis . The main message is that the symptoms of DILE should not be overlooked , although sometimes other systematic conditions may underlie them . As a result , it is very important for the clinicians to evaluate the symptoms of DILE and manage appropriately these cases .

DB00203 MEN induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin , hemeoxygenase and vascular endothelial growth factor . This study was undertaken to investigate the effect of phosphodiesterase - 5 ( O76074 REA ) inhibitor , sildenafil , on angiogenic response in human coronary arteriolar endothelial cells ( HCAEC ) . The cells exposed to sildenafil ( 1-20 microM ) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin - 1 ( P10599 REA - 1 ) , hemeoxygenase - 1 ( P09601 REA ) and P15692 REA . DB00203 MEN induced P15692 REA and angiopoietin specific receptors such as P35968 REA , Tie - 1 and Tie - 2 . This angiogenic response was repressed by tinprotoporphyrin IX ( SnPP ) , an inhibitor of P09601 REA enzyme activity . DB00203 MEN below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis . DB00203 MEN along with SnPP inhibited both P15692 REA and Q15389 REA ( Ang - 1 ) protein expression . Therefore our results demonstrated for the first time that sildenafil is a very potent pro-angiogenic factor .

Expression of P20839 REA and P12268 REA after transplantation and initiation of immunosuppression . BACKGROUND : DB01024 MEN ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 REA + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high-performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 REA ( 50-88 % , P < 0.0005 ) and decreased P12268 REA ( 42-56 % , P < 0.0005 ) expression . In P01730 REA + cells , however , P12268 REA increased ( 15 % , P= 0.009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 REA and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow-up demonstrated higher P12268 REA expression in P01730 REA + cells pretransplant than nonrejecting patients ( median expression 1.26 vs . 0.87 respectively , P= 0.017 ) . CONCLUSIONS : Knowledge of changes in P20839 REA and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 REA in P01730 REA + cells pretransplant may be an indicator of immune activation .

Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn ' s disease . OBJECTIVE : Osteoporosis is a common complication of Crohn ' s disease ( CD ) . Glucocorticoid use and detrimental effects of inflammatory cytokines including tumor necrosis factor-alpha ( P01375 REA ) can lead to osteoporosis . The aim of this study was to assess the ability of treatment with the P01375 REA antagonist infliximab to increase bone formation as measured by surrogate markers of bone turnover in patients with active CD . METHODS : Sera from 38 prospectively enrolled CD patients were examined for levels of bone alkaline phosphatase ( BAP ) , N-telopeptide of type I collagen ( NTX ) , immunoreactive parathyroid hormone ( iPTH ) , calcium , and pro-inflammatory cytokines at baseline and 4 weeks following infliximab infusion . Crohn ' s Disease Activity Index ( CDAI ) , Inflammatory Bowel Disease Questionnaire ( IBDQ ) , and glucocorticoid dose also were collected . RESULTS : In this cohort , CDAI and IBDQ scores were significantly improved at week 4 ( P < 0.001 ) . DB00065 SUB therapy was associated with an increase in BAP , a marker of bone formation ( P= 0.010 ) , whereas NTX , a marker of bone resorption , was not increased ( P= 0.801 ) . Among 22 patients who were taking glucocorticoids , mean glucocorticoid dose decreased 36 % ( P < 0.001 ; -7.9 mg ) . CONCLUSIONS : Treatment with infliximab was associated with increased markers of bone formation ( BAP ) without increasing bone resorption ( NTX ) . This effect may be due to a beneficial effect of P01375 REA blockade on bone turnover , a beneficial effect on CD activity resulting in decreased glucocorticoid dose , or both . Studies of longer duration are needed to assess the effect of infliximab on bone mineral density .

Anti - P01375 REA - A therapy about infliximab and adalimamab for the effectiveness in ulcerative colitis compared with conventional therapy : a meta-analysis . BACKGROUND / AIMS : P01375 REA - α has an important role in the pathogenesis of ulcerative colitis ( UC ) . It seems that anti - P01375 REA - α therapy is beneficial in the treatment of UC . The aim was to assess the effectiveness of DB00065 SUB and Adalimamab with UC compared with conventional therapy . METHODOLOGY : The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC . RESULTS : DB00065 SUB had a statistically significant effects in induction of clinical response ( RR = 1.67 ; 95 % CI 1.12 to 2.50 ) of UC compared with conventional therapy , but those had not a statistically significant effects in clinical remission ( RR = 1.63 ; 95 % CI 0.84 to 3.18 ) and reduction of colectomy rate ( RR = 0.54 ; 95 % CI 0.26 to 1.12 ) of UC . And adalimumab had a statistically significant effects in induction of clinical remission ( RR = 1.82 ; 95 % CI 1.24 to 2.67 ) and clinical response ( RR = 1.36 ; 95 % CI 1.13 to 1.64 ) of UC compared with conventional therapy . CONCLUSION : Our meta-analyses suggested that DB00065 SUB had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy .

Usefulness of QuantiFERON ® - TB Gold test in psoriatic patients under treatment with tumour necrosis factor blockers . OBJECTIVE : DB00065 SUB is a human / mouse chimeric anti-tumour necrosis factor ( P01375 REA ) - α antibody that is effective in the management of psoriasis . Anti - P01375 REA treatments may reactivate latent tuberculosis infection ( LTBI ) ; therefore , screening for LTBI is mandatory before starting any anti - P01375 REA - α therapy . The aim of this study is to evaluate the usefulness of the QuantiFERON ® - TB Gold ( QFT-G ) test in psoriatic patients under treatment with infliximab . RESEARCH DESIGN AND METHODS : A retrospective study had been performed on patients affected by psoriasis who had been treated with infliximab from 2003 to 2012 at a single centre . MAIN OUTCOMES MEASURES : QFT-G was tested by a standard TB enzyme-linked immunosorbent assay , based on detection of interferon-γ release from sensitized leucocytes exposed to the synthetic Mycobacterium tuberculosis antigens at baseline and every 6 months until the end of treatment . RESULTS : A total of 140 patients were included . At baseline , 7 QFT-G tests were positive and 133 tests were negative . Of the 133 patients , 11 ( 8 % ) who were negative at baseline became QFT-G test positive during treatment . Of those 11 patients , 5 had a reversion during treatment . Of the 133 patients , 122 ( 92 % ) who were negative at baseline remained negative . CONCLUSIONS : It was found that the development of positive QFT-G tests , observed in 8 % treated with infliximab , was not associated with pulmonary or extra-pulmonary tuberculosis .

DB00065 SUB for treatment of resistant pyoderma gangrenosum associated with Crohn ' s disease . We present the case of an 18 - year-old woman with Crohn ' s disease manifested by diffuse abdominal pain , bloody diarrhea accompanied by arthralgia , and swelling of large joints . On the lateral aspect of her right ankle there was an hemorrhagic , necrotic bullous lesion measuring 3 x 4 cm , surrounded by cutaneous inflammation and erythema . Biopsy showed a neutrophilic abscess-like ulcerative skin inflammation , which was diagnosed as pyoderma gangrenosum . The patient was treated with high doses of parenteral methylprednisolone , but her condition failed to improve and infliximab , a P01375 REA blocking agent , was instituted . An immediate response of Crohn ' s disease was observed and , over the next 5 weeks , the ulcer on her right ankle also healed completely .

Anti - P01375 REA immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis . BACKGROUND : Because periodontitis presents many similarities with rheumatoid arthritis ( RA ) with regard to tumor necrosis factor-alpha ( P01375 REA ) - induced bone resorption , the benefits of P01375 REA blockade in RA prompted us to determine its efficacy in treating coexisting periodontitis . METHODS : Periodontal status was evaluated in 40 subjects with RA who were divided into two groups : Group I contained 20 subjects who had received infliximab every 6 weeks for > or = 22 months at the time of periodontal evaluation . The 20 subjects in group II were evaluated before their first infusion with infliximab . Nine subjects in group II had periodontitis . These subjects were reevaluated after they received nine infusions of infliximab . RESULTS : DB00065 SUB tended to aggravate gingival inflammation as indicated by differences in the modified gingival and papillary bleeding indices between subjects in groups I and II with coexisting periodontitis before and after treatment . DB00563 had no effect on periodontal status . Although the plaque index revealed that bacterial infection persisted , the probing depth was equal in groups I and II and equivalent before and after treatment in subjects with periodontitis , whereas attachment loss was decreased after infliximab treatment . CONCLUSIONS : Inflammation and destruction constitute two interrelated yet separate components of periodontitis in patients with RA . Therefore , P01375 REA blockade could be beneficial in the treatment of periodontitis .

DB00065 SUB reduces the cytokine-mediated inflammation but does not suppress cellular infiltration of the vessel wall in refractory Kawasaki disease . The aim of our study was to evaluate the efficacy of infliximab for the treatment of patients with refractory Kawasaki disease ( KD ) and investigate the dynamic changes of cytokines during infliximab treatment . We have performed a study of cytokine and proinflammatory molecule levels in 43 KD patients including 18 responders to IVIG , 14 nonresponders , and 11 patients treated with infliximab . We determined serum levels of soluble P01375 REA receptor I ( sTNFR I ) and P05231 REA , as well as P15692 REA , damage associated molecular pattern ( DAMP ) molecules ; myeloid-related protein ( MRP )8 / P06702 REA and P8 0511 sequentially . In eight patients , fever subsided immediately upon infliximab treatment . Four patients , who started infliximab after 12 d of illness , developed coronary artery lesions . Each of the cytokines was elevated before infliximab treatment in all patients . Although serum levels of proinflammatory cytokines decreased dramatically after infliximab treatment , DAMP molecules and P15692 REA and markers of local tissue damage were not suppressed . In contrast , in IVIG responders all cytokines decreased markedly after IVIG treatment . We show that infliximab is one of the adoptive therapies in refractory KD patients . Different behaviors of proinflammatory cytokines and DAMP molecules and P15692 REA after infliximab treatment suggest that infliximab is effective for suppression of cytokine-mediated inflammation , but could not completely block local vasculitis .

A one-hour infusion of infliximab during maintenance therapy is safe and well tolerated : a prospective cohort study . BACKGROUND : DB00065 SUB is a chimeric monoclonal antibody to tumour necrosis factor alpha ( P01375 REA α ) with efficacy in inducing and maintaining remission of inflammatory bowel disease , rheumatoid arthritis , ankylosing spondylitis and psoriasis . DB00065 SUB is generally administered over 2h with a further 1 - h postinfusion observation . This time interval has substantial impact on healthcare resources and is costly in terms of patient ' s time away from work . AIM : To examine the safety and tolerability of a 1 - h , relative to a 2 - h maintenance of infusion of infliximab , and to determine the effect of corticosteroid premedication and concurrent immunosuppressor use on infusion reaction rates . METHOD : A prospective cohort study with variable follow-up duration of 2165 consecutive infliximab infusions in 415 patients during 2009 was conducted . Diagnosis , infusion episode number , infusion rate , premedication , concurrent immunosuppressor therapy , the nature and the outcome of infusion reactions were examined . RESULTS : The majority of infusions ( 74 % ) were for management of inflammatory bowel disease . Infusion reactions clustered within the first eight infusions with subsequent sporadic reactions . The infusion reaction incidence rate per 1000 person days in 274 1 - h infusions from 54 patients and 1356 2 - h infusions from 256 patients were 0.08 and 0.28 respectively ( P= 0.07 ) . Poisson regression model confirmed that the concurrent use of immunosuppressor therapy was associated with a lower infusion reaction rate , whereas corticosteroid premedication was not . CONCLUSIONS : During maintenance therapy , infliximab infusion can be safely administered over 1h in patients with no past history of significant infliximab infusion reaction . Corticosteroid premedication had no impact on the infusion reaction rates .

P01375 REA alpha inhibition as treatment modality for certain rheumatologic and gastrointestinal diseases . With the development of biologicals that specifically target tumor necrosis factor ( P01375 REA ) alpha , our therapeutic approach to inflammatory diseases has dramatically changed . There are currently three anti-TNFalpha drugs available : etanercept , infliximab , and adalimumab . DB00005 is a recombinant fusion protein that can be used alone or in combination with other medications for conditions such as rheumatoid arthritis , juvenile rheumatoid arthritis , psoriatic arthritis , psoriasis , and ankylosing spondylitis . DB00065 SUB , a chimeric humanized monoclonal antibody and adalimumab , a fully human monoclonal antibody are approved for the treatment of rheumatoid arthritis , psoriasis , psoriatic arthritis , ankylosing spondylitis , and moderate to severe Crohn ' s disease . DB00065 SUB is also approved for ulcerative colitis . Another anti-TNFalpha drug , certolizumab pegol , was declined approval as treatment option for active Crohn ' s disease due to a lack of sufficient efficacy . Phase III studies for the treatment of rheumatoid arthritis patients are still pending . It is the goal of this review article to summarize various therapeutic indications , underlying studies , safety , and use during pregnancy , as well as future directions for anti - P01375 REA therapies .

DB00065 SUB induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane P01375 REA . BACKGROUND AND AIMS : Both infliximab ( chimeric anti-tumor necrosis factor [ P01375 REA ] - alpha antibody ) and etanercept ( p75 P01375 REA receptor / immunoglobulin G fusion protein ) are effective against rheumatoid arthritis , but only infliximab induces clinical remission in Crohn ' s disease . To clarify this difference in clinical efficacy , we investigated reverse signaling through transmembrane P01375 REA ( mTNF ) by these 2 anti - P01375 REA agents . METHODS : We stably transfected wild-type and cytoplasmic serine-replaced mutant forms of mTNF in human Jurkat T cells . Cells were stimulated with infliximab and etanercept and then analyzed for P16581 REA expression , reactive oxygen species accumulation , apoptosis , and cell cycle distribution by flow cytometry . P22301 REA and interferon-gamma were measured by enzyme-linked immunosorbent assay . Phospho-c-Jun NH2 - terminal kinase , Bax , Bak , P38936 REA ( P38936 REA / CIP 1 ) , caspase - 8 , and caspase - 3 were examined by immunoblotting . RESULTS : Both anti - P01375 REA agents induced P16581 REA expression , but only infliximab induced interleukin - 10 production , apoptosis , and G0 / P55008 cell cycle arrest . Apoptosis and cell cycle arrest were abolished by substitution of all 3 cytoplasmic serine residues of mTNF by alanine residues . DB00065 SUB induced accumulation of reactive oxygen species and up-regulation of Bax , Bak , and P38936 REA ( P38936 REA / CIP 1 ) proteins , suggesting the involvement of p53 activation . Moreover , phosphorylation of c-Jun NH2 - terminal kinase was necessary for infliximab-induced apoptosis and cell cycle arrest . CONCLUSIONS : We revealed the mTNF motifs and the downstream intracellular molecular events essential for reverse signaling through mTNF . The biologic effects of mTNF elicited by infliximab should be important action mechanisms of this potent anti-inflammatory agent in addition to the neutralization of soluble P01375 REA . These observations will provide insight into the novel role of mTNF in inflammation .

DB00065 SUB : mechanism of action beyond P01375 REA neutralization in inflammatory bowel disease . DB00065 SUB , a chimeric antibody to tumour necrosis factor-alpha ( P01375 REA ) , holds much promise for the treatment of patients with Crohn ' s disease . On the cellular level , infliximab affects survival and , as presented by Agnholt et al . in this issue of the journal , inhibits GM - P04141 REA ( granulocyte-macrophage colony-stimulating factor ) production by intestinal T lymphocytes . Future studies will reveal whether the pro-apoptotic effect of infliximab is linked to its inhibition of endogenous GM - P04141 REA expression in T cells . Treatment of Crohn ' s disease , a severe chronic intestinal disorder , may at times be challenging as it can be refractory to routine therapy . Among novel therapeutic strategies , agents that neutralize tumour necrosis factor-alpha ( P01375 REA ) are of particular interest because of the crucial role of P01375 REA in sustaining chronic mucosal inflammation . The exact mechanism of the anti - P01375 REA action , apart from direct activity that neutralizes cytokines , is not fully understood . Cellular effects of P01375 REA neutralizing treatment include an increased susceptibility to apoptosis of intestinal mucosal T cells . A novel pathway of anti - P01375 REA interaction with T cells has been presented in the current issue of this journal . Agnholt et al . have found that in-vivo or in-vitro administration of infliximab , a chimeric antibody to P01375 REA , resulted in a decreased production of GM - P04141 REA ( granulocyte-macrophage colony-stimulating factor ) by T cells . DB00065 SUB related down-regulation of P01375 REA induced GM - P04141 REA expression may be one of the mechanisms by which this drug increases the rate of apoptosis in T cells .

Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17-1 A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co-medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 REA ) induced cytotoxicity and P60568 REA - induced-ADCC . We found that dexamethasone markedly inhibited the P60568 REA induced cytotoxicity and the P60568 REA - induced-ADCC . DB00904 MEN , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 REA - induced-ADCC . The P01375 REA antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .

Clinical and biological consequences of immunization to infliximab in pediatric Crohn ' s disease . P01375 REA ( P01375 REA ) - alpha plays a critical role in the initiation and progression of Crohn ' s disease , a chronic inflammatory disorder of the gastrointestinal tract . DB00065 SUB , a chimeric monoclonal antibody blocking P01375 REA , has proven effective as an induction and maintenance therapy for refractory Crohn ' s disease in adult and pediatric patients . However , infliximab therapy induces the appearance of neutralizing anti-infliximab antibodies . In the pediatric cohort , we analyzed ( n = 28 ) sensitization occurred in 35.7 % patients and was associated with a loss of response to maintenance infusions . In two patients presenting high titers of anti-infliximab antibodies , severe infusion reactions were observed , possibly IgE-mediated , precluding further use of the medication . Serum concentrations of P01375 REA and infliximab were influenced by the presence of anti-infliximab antibodies . We propose that surveillance of circulating infliximab and / or P01375 REA concentration during maintenance therapy represents an indirect but reliable method to monitor anti-infliximab immunization .

DB00065 SUB as rescue medication for patients with severe ulcerative / indeterminate colitis refractory to tacrolimus . BACKGROUND : The calcineurin inhibitor tacrolimus and the anti - P01375 REA - antibody infliximab are established options in steroid-refractory ulcerative colitis ( UC ) . AIM : To evaluate the efficacy of infliximab-salvage therapy in patients with refractory UC failing to respond to tacrolimus . METHODS : Twenty-four patients were enrolled in this evaluation . Reasons for tacrolimus therapy were steroid-refractory disease in 19 patients and steroid-dependency in five patients . All patients receiving infliximab had tacrolimus-refractory active disease ( Lichtiger score > 10 ) and were treated with 5 mg / kg at weeks 0 , 2 and 6 and every 8 weeks thereafter , if tolerated . RESULTS : Six of 24 patients ( 25 % ) achieved remission following infliximab infusion and four of 24 ( 17 % ) had an initial response only , but underwent proctocolectomy later because of loss of response ( 3 ) or development of a delayed hypersensitivity reaction ( 1 ) . Fourteen patients ( 58 % ) completely failed to respond with 10 undergoing colectomy . Eight patients experienced side effects under infliximab , including two infectious complications ( herpes zoster and herpes pneumonia ) . CONCLUSIONS : DB00065 SUB offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus . This benefit has to be weighed against the risks of infectious complications .

Small molecular anti-cytokine agents . The recent successful introduction of the anti-cytokine biologicals DB00005 , DB00065 SUB , DB00051 , and DB00026 has stimulated the search for anti-cytokine small-molecules . A number of molecular targets have been identified for the development of such small molecular anti-cytokine agents . The focus of this review will be on those inhibitors of cytokine production , which target either p38 mitogen activated protein ( Q96HU1 ) kinase , P01375 REA converting enzyme ( P78536 REA ) , or IL - 1beta converting enzyme ( ICE ) . O75791 REA Q96HU1 kinase occupies a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like interleukin 1beta ( IL - 1beta ) and P01375 REA , and regulates their biosynthesis at both the transcriptional and translational level . P78536 REA and ICE are two proteases required for the processing of proTNF-alpha and proIL - 1beta , respectively into their mature , proinflammatory form . Since the mid - 1990s , a plethora of inhibitors of p38 Q96HU1 kinase , P78536 REA , and ICE has been characterized in vitro , and individual representatives from all three inhibitor classes have in the meantime been advanced into clinical trials . This review will highlight the correlation between effective inhibition at the molecular target and cellular activity in functional assays of cytokine , particularly P01375 REA and IL - 1beta , production . Structure-activity relationships ( SAR ) will be discussed regarding activity at the respective enzyme target , but also with regard to properties required for efficient in vitro and in vivo cellular activity ( e . g . , oral availability , solubility , cell penetration , etc . ) .

Successful infliximab treatment of posterior scleritis in a 13 - year-old child refractory to other immunosuppressive therapy . BACKGROUND : Posterior scleritis is a potentially blinding inflammatory disorder rarely seen in children . Standard care consists of systemic administration of steroids and immunosuppressants such as methotrexate or ciclosporin A . We describe the case of a young girl suffering from therapy refractory posterior scleritis successfully treated with the tumor necrosis factor ( P01375 REA ) inhibitor infliximab . METHODS : This study was an interventional case report . The medical chart of a 13 - year-old child treated with infliximab ( 5 mg / kg , 10 applications at a 4-8 week interval ) was reviewed for changes of visual acuity , fundoscopy , optic choherence tomography , ultrasound imaging , and adverse events . RESULTS : DB00065 SUB therapy ( 5 mg / kg , 10 applications at a 4-8 week interval ) led to a long-term remission of posterior scleritis after unsuccessful therapy with high dose prednisolone , methotrexate , and ciclosporin A . To date no side effects have been reported . CONCLUSIONS : Administration of infliximab may be considered under appropriate circumstances to treat children with posterior scleritis .

Potential use of P01375 REA - α inhibitors in systemic sclerosis . Systemic sclerosis ( SSc ) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin , vascular abnormalities and variable involvement of organs . P01375 REA - α has a central role in initial host response to infections and in the pathogenesis of various systemic immune-mediated diseases . Serum levels of P01375 REA - α are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension . Inflammatory arthritis can occur in patients with SSc . DB00065 SUB and etanercept may improve the inflammatory arthritis and disability in SSc . P01375 REA - α inhibitors reduce the systemic inflammation , improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and / or cerebrovascular events . Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections . Randomized controlled trials with P01375 REA - α inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc .

P05231 REA , P01579 REA and P01375 REA production by liver-associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 REA P01579 REA and P05231 REA by liver-associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time-dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 REA , P01579 REA and P01375 REA . These increases correlated with an increase in the numbers of P01730 REA + , CD8 + and CD25 + T cells in blood and P01730 REA + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 REA , P01579 REA and P01375 REA were constitutively produced by liver-associated P01730 REA + T cells when cultured . In Con A-stimulated cultures , liver-associated P01730 REA + T cells secreted increasing levels of P01375 REA in a time-dependent manner following Con A injection , but P01375 REA production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 REA + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A-induced liver damage is mediated by P01730 REA + T cells acting within the liver , at least in part through the secretion of P01375 REA , P01579 REA and P05231 REA .

Efficacy of infliximab in a patient with refractory idiopathic retroperitoneal fibrosis . Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis ( Q969Q1 REA ) . However , relapses are frequent upon tapering of the glucocorticoid dose . A variety of traditional immunosuppressants have been proposed as steroid-sparing agents , but some patients fail to adequately respond to combined glucocorticoid and immunosuppressive therapy . We report a patient with Q969Q1 REA refractory to combined glucocorticoid and methotrexate therapy treated with the anti - P01375 REA - α monoclonal antibody infliximab . DB00065 SUB was administered at 5 mg / kg / bodyweight at week 0 , 2 , 6 and 8 - weekly thereafter for 3 consecutive years . Drug efficacy and safety were assessed clinically and by laboratory tests at treatment onset and subsequently before each infusion . In addition , 18FFluorodeoxyglucose ( DB09150 ) positron emission computerised tomography ( PET / CT ) and abdominal CT scans were used to monitor disease activity and response to treatment . DB00065 SUB therapy resulted in a satisfactory clinical and laboratory response paralleled by an improvement in imaging findings . No serious adverse events were noted . DB00065 SUB may be an effective and safe treatment for refractory Q969Q1 REA . A controlled study is required to confirm our findings .

DB00065 SUB does not activate replication of lymphotropic herpesviruses in patients with refractory rheumatoid arthritis . OBJECTIVE : The reactivation of human lymphotropic herpesviruses can be related to the intensity of immunosuppression . We analysed the risk of reactivation of lymphotropic herpesviruses in patients with refractory rheumatoid arthritis treated with an anti-tumour necrosis factor-alpha ( P01375 REA ) agent ( infliximab ) . METHODS : Fifteen patients were treated with infliximab ( 3 mg / kg ) at weeks 0 , 2 and 6 . Samples of both plasma and peripheral blood mononuclear cells ( PBMC ) were obtained before treatment ( week 0 ) and before each infusion at weeks 2 and 6 . Samples were analysed using a multiplex qualitative polymerase chain reaction ( PCR ) for lymphotropic herpesviruses . Quantification of cytomegalovirus ( CMV ) viral load ( copies / ml ) was performed using quantitative PCR . Reactivation was defined as the presence of viral DNA in plasma . Latent infection was defined as the presence of viral DNA in PBMC samples but not in plasma . RESULTS : On baseline , latent CMV infection was detected in eight patients ( 53.3 % ) , human herpesviruses - 6 ( HHV - 6 ) in two ( 13.3 % ) , Epstein-Barr virus ( EBV ) in seven ( 46.6 % ) , CMV + HHV - 6 in one ( 6.6 % ) , CMV + EBV in two ( 13.3 % ) and HHV - 6 + EBV in one ( 6.6 % ) . Viral reactivation related to infliximab treatment was not observed . There was only one patient who had HHV - 6 reactivation , but this was already detected in the baseline sample . CONCLUSIONS : DB00065 SUB treatment does not induce replication of human lymphotropic herpesviruses in patients with rheumatoid arthritis . Thus , herpesviruses prophylaxis would not be indicated in these patients .

P35367 REA antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three-way , double-blind , cross-over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : DB00341 MEN 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : DB00341 MEN affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .

How tumour necrosis factor blockers interfere with tuberculosis immunity . Tumour necrosis factor ( P01375 REA ) is a potent inflammatory cytokine that plays an important role in immunity to numerous bacterial infections , including Mycobacterium tuberculosis ( Mtb ) , the causative agent of tuberculosis ( TB ) in humans . DB00065 SUB , adalimumab , certolizumab pegol and etanercept are anti - P01375 REA agents used to treat a range of inflammatory / autoimmune diseases , such as rheumatoid arthritis . The use of some of these drugs has been linked to reactivation TB . In addition to blocking P01375 REA - mediated immune responses , some anti - P01375 REA drugs have been found to interfere with innate immune responses , such as phagolysosomal maturation and monocyte apoptosis , as well as cell-mediated responses , including interferon-gamma secretion by memory T cells , complement-mediated lysis of Mtb-reactive CD8 + T cells and increased regulatory T cell activity . This review summarizes some of the reported effects of P01375 REA blockers on immune cell responses in the context of the observed clinical data on TB reactivation in patients on anti - P01375 REA therapy .

Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders . TOPIC : To provide recommendations for the use of anti-tumor necrosis factor α ( P01375 REA - α ) biologic agents in patients with ocular inflammatory disorders . CLINICAL RELEVANCE : Ocular inflammatory diseases remain a leading cause of vision loss worldwide . Anti - P01375 REA - α agents are used widely in treatment of rheumatologic diseases . A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions . METHODS : A systematic review of published studies was performed . Recommendations were generated using the Grading of Recommendations Assessment , Development , and Evaluation group criteria . RESULTS : Numerous studies including controlled clinical trials have demonstrated that anti - P01375 REA - α biologic agents ( in particular infliximab and adalimumab ) are effective in the treatment of severe ocular inflammatory disease . Based on these studies , the expert panel makes the following recommendations . CONCLUSIONS : DB00065 SUB and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet ' s disease . DB00065 SUB and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis . DB00065 SUB and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis , panuveitis , severe uveitis associated with seronegative spondyloarthropathy , and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation . DB00065 SUB and adalimumab can be considered in these patients in preference to etanercept , which seems to be associated with lower rates of treatment success .

DB00065 SUB : a novel treatment for sight-threatening thyroid associated ophthalmopathy . We describe a patient with sight threatening thyroid associated ophthalmopathy ( DB01361 ) who was successfully treated with infliximab , an anti-tumour necrosis factor ( P01375 REA ) - a antibody .

Crohn ' s disease : a review of current treatment with a focus on biologics . Crohn ' s disease is a debilitating and expensive disease that is growing in incidence in both developing and developed countries . While conventional therapies , such as corticosteroids and immunosuppressants , continue to play a vital role in treating this condition , it is evident that many affected individuals do not respond to therapy or develop intolerable adverse effects . The addition of modern biological therapies to the Crohn ' s disease armamentarium is providing a change in expectations for disease outcome . DB00065 SUB and adalimumab are currently the only biological agents approved for induction and maintenance treatment in adults ( infliximab and adalimumab ) and children ( infliximab ) with Crohn ' s disease . Furthermore , infliximab has a beneficial effect on perianal fistulas . Other tumour necrosis factor ( P01375 REA ) - alpha inhibitors , such as certolizumab pegol , also demonstrate promising results in adults with moderate to severe active disease . In addition , adalimumab and certolizumab pegol have shown clinical efficacy in patients who are intolerant to or lose response to infliximab , suggesting that switching between agents may allow response to be maintained over time . The primary safety concerns with TNFalpha inhibitors include increased risk of serious infection ( including reactivation of tuberculosis ) , malignancy ( particularly lymphoma ) and demyelinating disease . Other agents in development include recombinant human anti-inflammatory cytokines , agents that target pro-inflammatory cytokines and granulocyte-macrophage colony-stimulating factors . Further prospective studies will provide interesting insight into different mechanisms by which factors involved in the pathophysiology of Crohn ' s disease can be modulated .

Correlation between elevation of serum antinuclear antibody titer and decreased therapeutic efficacy in the treatment of Behçet ' s disease with infliximab . BACKGROUND : DB00065 SUB , an anti - P01375 REA - α monoclonal antibody , administered to Behçet ' s disease ( BD ) patients in Japan with refractory intraocular inflammation , has shown excellent clinical results . However , some patients demonstrate a decreased response to infliximab during the course of the treatment . In the present study , we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody ( Q14201 ) titers in patients with BD who were undergoing infliximab therapy . METHODS : Seventeen patients ( 14 males and three females ) with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled . Their blood test results and clinical histories were obtained from medical records . RESULTS : One patient ( 5.9 % ) was Q14201 - positive prior to the initiation of infliximab , and 11 patients ( 64.7 % ) developed positive Q14201 during the therapy . The appearance of Q14201 was observed 6 months after the initiation of the infliximab therapy , and its titers gradually increased . None of the patients showed lupus symptoms . Five patients ( 29.4 % ) have suffered from ocular inflammatory attacks since the sixth month from the initiation of infliximab treatment and all of them were Q14201 - positive . In contrast , four patients ( 23.5 % ) who were Q14201 - negative experienced no ocular attacks during the follow-up period . CONCLUSIONS : Here we report the positive conversion and subsequent elevation of serum Q14201 titers in some patients with BD after the initiation of infliximab therapy . Since all recurrences of uveitis were shown only in the Q14201 - positive patients , serum Q14201 titer may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti - P01375 REA - α antibody therapies .

DB00065 SUB therapy in pediatric Crohn ' s disease : a review . Anti-tumor necrosis factor alpha ( P01375 REA - α ) therapy has re-defined our treatment paradigms in managing patients with Crohn ' s disease ( CD ) and ulcerative colitis . Although the ACCENT studies showed proven efficacy in the induction and maintenance of disease remission in adult patients with moderate to severe CD , the pediatric experience was instrumental in bringing forth the notion of " top-down " therapy to improve overall clinical response while reducing the risk of complications resulting from long-standing active disease . DB00065 SUB has proven efficacy in the induction and maintenance of disease remission in children and adolescents with CD . In an open-labeled study of 112 pediatric patients with moderate to severe CD , 58 % achieved clinical remission on induction of infliximab ( 5 mg / kg ) therapy . Among those patients who achieved disease remission , 56 % maintained disease remission on maintenance ( 5 mg / kg every 8 weeks ) therapy . Longitudinal follow-up studies have also shown that responsiveness to infliximab therapy also correlates well with reduced rates of hospitalization , and surgery for complication of long-standing active disease , including stricture and fistulae formation . Moreover , these children have also been shown to improve overall growth while maintaining an effective disease remission . The pediatric experience has been instructive in suggesting that the early introduction of anti - P01375 REA - α therapy may perhaps alter the natural history of CD in children , an observation that has stimulated a great deal of interest among gastroenterologists who care for adult patients with CD .