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      The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases

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          Abstract

          The management of RA, SpA, psoriasis and inflammatory bowel disease has significantly improved over the last decade with the addition of tumour necrosis factor inhibitors (anti-TNFs) to the therapeutic armamentarium. Immunogenicity in response to monoclonal antibody therapies (anti-drug antibodies) may give rise to low serum drug levels, loss of therapeutic response, poor drug survival and/or adverse events such as infusion reactions. To combat these, the use of concomitant MTX may attenuate the frequency of anti-drug antibodies in RA, SpA and Crohn’s disease. Although a similar effect to methotrexate has been observed with AZA usage in the management of Crohn’s disease, there is insufficient evidence to suggest that other DMARDs impact immunogenicity. In this article we review the evidence to date on the effect of immunomodulatory therapy when co-administered with anti-TNFs. We also discuss whether such a strategy should be employed in SpA and psoriasis, and if optimization of the MTX dose could improve biologic drug survival and thereby benefit disease management.

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          Immunoglobulin G4: an odd antibody.

          Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as 'Fab-arm exchange', results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.
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            Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression.

            Etanercept has been shown to improve the articular and cutaneous manifestations of psoriatic arthritis (PsA). In this study, we further evaluated the safety, efficacy, and effect on radiographic progression of etanercept in patients with PsA. Patients with PsA (n = 205) were randomized to receive placebo or 25 mg etanercept subcutaneously twice weekly for 24 weeks. Patients continued to receive blind-labeled therapy in a maintenance phase until all had completed the 24-week phase, then could receive open-label etanercept in a 48-week extension. Efficacy and safety were evaluated at 4, 12, and 24 weeks and at 12-week intervals thereafter. Radiographs of the hands and wrists were assessed at baseline and 24 weeks, at entry to the open-label phase, and after 48 weeks in the study. Etanercept significantly reduced the signs and symptoms of PsA and psoriasis. At 12 weeks, 59% of etanercept patients met the American College of Rheumatology 20% improvement criteria for joint response, compared with 15% of placebo patients (P < 0.0001), and results were sustained at 24 and 48 weeks. At 24 weeks, 23% of etanercept patients eligible for psoriasis evaluation achieved at least 75% improvement in the Psoriasis Area and Severity Index, compared with 3% of placebo patients (P = 0.001). Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was -0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001). Etanercept was well tolerated. Etanercept reduced joint symptoms, improved psoriatic lesions, inhibited radiographic progression, and was well tolerated in patients with PsA.
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              Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

              Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. Conclusion: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.
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                Author and article information

                Journal
                Rheumatology (Oxford)
                Rheumatology (Oxford)
                brheum
                rheumatology
                Rheumatology (Oxford, England)
                Oxford University Press
                1462-0324
                1462-0332
                February 2014
                14 August 2013
                14 August 2013
                : 53
                : 2
                : 213-222
                Affiliations
                1Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, 2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science Centre and 3The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
                Author notes
                Correspondence to: Hector Chinoy, Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK. E-mail: hector.chinoy@ 123456manchester.ac.uk
                Article
                ket260
                10.1093/rheumatology/ket260
                3894670
                23946436
                4e45d92c-9089-48d3-92b3-36f5cc39da9d
                © The Author(s) 2013. Published by Oxford University Press on behalf of the British Society to Rheumatology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 April 2013
                : 18 June 2013
                Page count
                Pages: 10
                Categories
                Reviews

                Rheumatology
                immunogenicity,biologics,azathioprine,disease-modifying anti-rheumatic drugs,methotrexate,anti-drug antibodies,anti-tnfs

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