Antibody profiles in patients treated with tumor necrosis factor-alpha antagonists : new findings /

Consultable des del TDXTítol obtingut de la portada digitalitzadaIt has been reported that patients with rheumatoid arthritis (RA), Crohn's disease (CD) and spondyloarthritis (SpA) treated with selective tumor necrosis factor-alpha (TNF-?) inhibitors develop autoantibodies such as antinuclear antibodies (ANA) and anti-double stranded DNA (anti-dsDNA) antibodies. TNF-? is a pro-inflammatory cytokine that is produced by multiple cell types, including blood monocytes, macrophages, mast cells and endothelial cells, and plays multiple complex functional roles within the immune system, including the stimulation of inflammation, cytotoxicity, the regulation cell adhesion and the induction of cachexia. There are therefore a number of potential mechanisms by means of which anti-TNF-? treatment could be beneficial in RA, CD and other diseases. RA is a chronic inflammatory disease that primarily affects the peripheral joints and often leads to tissue degradation and the destruction of bone and cartilage. As organic joint damage is irreversible, it is important to recognise and treat RA early with the aim of halting its progression. Clinical trials have demonstrated that TNF-? blocking agents are highly beneficial for most patients with RA refractory to classic treatment with disease-modifying antirheumatic drugs (DMARDs), but a significant number also fail to respond to anti-TNF-? therapy. No reliable predictive markers of a clinical response have been identified, although a recent report suggests that reduced rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody levels may be useful adjuncts when assessing treatment efficacy. A reduction in IgM-RF titres was initially described by Charles et al. in a small series of patients receiving infliximab, but the subsequent findings were inconsistent. Two recent studies have found decreased RF and anti-CCP antibody titres in RA patients treated with infliximab. In both cases, decrease paralleled the improvements in the disease activity scores, but one group reported a return to baseline levels when the follow-up was extended to 54 and 78 weeks. However, De Rycke et al. showed that RF, but not anti-CCP antibodies, is modulated by infliximab in RA and our findings support the existing evidence that RF and anti-CCP antibodies are independent autoantibody systems in RA. CD is a chronic inflammatory disease of the gastrointestinal tract whose variable clinical course is characterised by segmental transmural inflammation and granulomatous changes of unknown origin. Infliximab is a chimeric IgG1 monoclonal anti-TNF-? antibody that represents a significant advance in the treatment of CD. Controlled clinical trials have demonstrated its effectiveness in rapidly induces and maintains remission in patients with moderate/severe refractory CD, healing endoscopic lesions, and treating draining perianal (PA) fistulae in the short and long term. Moreover, audit data from North America and Europe have shown that its efficacy in clinical practice is comparable with that observed in clinical trials. Trials have shown that CD and RA patients develop ANAs and anti-dsDNA antibodies: according to the reported safety data, respectively 63.8% and 49.1% of patients develop newly positive ANAs during infliximab treatment, and respectively 13% and 21.5% develop newly positive anti-dsDNA antibodies. Two important papers have described the risk of immunogenicity induced by infliximab treatment in CD patients: Baert et al. showed that the development of antibodies against infliximab leads to infusion reactions and a shorter treatment response to treatment and, as concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response, concluded that it is necessary to combine methotrexate (MTX) and infliximab in order to reduce the risk of the appearance of anti-idiotypic autoantibodies; and Vermeire et al. found a cumulative 24-month incidence of ANAs in 71/125 patients (56.8%), almost half of whom developed ANAs after the first infusion and >75% became ANApositive after fewer than three infusions. However, lower percentages have been reported in patients treated with etanercept. Interestingly, these autoantibodies have been only anecdotally associated with clinical manifestations suggesting drug-induced systemic lupus erythematosus (SLE). It was thought that the absence of such an association was related to the IgM or IgA isotypes of anti-dsDNA antibodies, as well as low antibody affinity (in contrast with the widely accepted relationship between SLE and the high affinity IgG isotype). However, the occurrence of these autoantibodies is now considered a drug class-related side effect, despite the higher prevalence of ANAs and anti-dsDNA antibodies in patients treated with infliximab than in those treated with etanercept, and the absence of a flare when etanercept therapy was started in a patient with previous infliximab-induced SLE. Finally, anti-phospholipid antibodies (aPL), which are mainly detectable by means of anti-cardiolipin assay (aCL), have also been reported in RA patients receiving TNF-? blockers. In some cases, their appearance was related to concomitant infectious processes, but no clear correlation was found with the specific clinical manifestations of anti-phospholipid syndrome, although one paper suggests that they may predict a poor clinical outcome. The aim of this thesis is to evaluate prospectively the auto-antibody profiles of CD and RA patients treated with infliximab and adalimumab, and their relationships to clinical outcomes. In particular, the aim of the first one-year prospective study was planned to evaluated: a) the clinical efficacy of adalimumab; b) whether the prevalence and titres of RAassociated auto-antibodies, such as RF and anti-CCP antibodies correlate with treatment effect; and c) whether non organ-specific auto-antibodies are induced by adalimumab like other TNF-? blocking agents. The aim of the second study was evaluated: the frequency and correlation of autoantibody development at standardised timepoints in refractory/inflammatory and fistulising CD patients in a routine clinical setting. Finally, the findings were related to disease status before the start of infliximab treatment, the response to infliximab treatment and the onset of adverse clinical events. The first part of this thesis considers the role of TNF-? in RA and CD, and the efficacy of anti-TNF-? agents in inducing auto-antibodies (including two recent reviews by our group and a recently published case report); the second evaluates the mechanisms involved in auto-antibody development in CD and RA patients receiving anti-TNF-? treatment; and the third briefly summarises two original studies, together with their discussion and conclusions

Pain in systemic connective tissue diseases

Pain is frequent in patients with connective tissue diseases (CTDs), particularly those affected by systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) in which it is virtually ubiquitous and can have different causes. The SLE classi fi cation criteria include pain associated with musculoskeletal involve- ment, which are frequently the initial symptom of SLE and can include arthralgia, arthritis and/or myalgia. Chronic widespread pain, the cornerstone of fi bromyalgia (FM), is also frequently associated with CTDs. Chronic pain has a considerable impact on mental health, and the professional and family lives of patients. It can be due to many disorders, but there are few reports concerning its prevalence during the course of other diseases. It is essential to identify the origin of pain in CTDs in order to avoid dangerous over-treatment in patients with co-existing widespread pain. Effective pain management is a primary goal of patient care, although it has not been investigated in detail in patients with SSc

Building bridges between doctors and patients: the design and pilot evaluation of a training session in argumentation for chronic pain experts

Shared decision-making requires doctors to be competent in exchanging views with patients to identify the appropriate course of action. In this paper we focus on the potential of a course in argumentation as a promising way to empower doctors in presenting their viewpoints and addressing those of patients. Argumentation is the communication process in which the speaker, through the use of reasons, aims to convince the interlocutor of the acceptability of a viewpoint. The value of argumentation skills for doctors has been addressed in the literature. Yet, there is no research on what a course on argumentation might look like. In this paper, we present the content and format of a training session in argumentation for doctors and discuss some insights gained from a pilot study that examined doctors' perceived strengths and limitations vis-à-vis this training

The prevalence of fibromyalgia in the general population : A comparison of the American College of Rheumatology 1990, 2010 and modified 2010 classification criteria

Copyright © 2014 American College of Rheumatology. Funded by University of Aberdeen Development TrustPeer reviewedPostprin

Cost Effectiveness Analysis of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. A Systematic Review Literature

The cost effectiveness of treatments that have changed the “natural history” of a chronic progressive disease needs to be evaluated over the long term. Disease-modifying antirheumatic drugs (DMARDs) are the standard treatment of rheumatoid arthritis (RA) and should be started as early as possible. A number of studies have shown that they are effective in improving disease activity and function, and in joint damage. Our review was focused on revision and critical evaluation of the studies including the literature on cost effectiveness of DMARDs (cyclosporine A, sulphasalazine, leflunomide, and methotrexate). The European League Against Rheumatism (EULAR) recommendations showed that traditional DMARDs are cost effective at the time of disease onset. They are less expensive than biological DMARDs and can be useful in controlling disease activity in early RA

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence

Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks

The epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. This public health emergency has triggered a race to find medications to improve the prognosis of this disease. There is currently great interest in drug repositioning to manage SARS-CoV-2 infection, that is, the evaluation of the potential benefits of a drug that has already been proven safe and effective in humans for other approved indications. As interleukin-6 (IL-6) acts as a key driver of the inflammation associated with coronavirus disease 2019 (COVID-19), IL-6 and IL-6 receptor (IL-6R) inhibition appear to be promising targets for the treatment of COVID-19 patients. It is important to critically analyze the available evidence concerning the use of the available anti-IL-6 (siltuximab) and anti-IL-6R (tocilizumab and sarilumab) agents in COVID-19 patients, in terms of both benefit and risk. In this review, the pathogenesis of the cytokine storm induced by COVID-19, the role of IL-6 in this cytokine storm, the rationale for the use of anti-IL-6 agents, and key information on potential benefits and safety monitoring of these biologicals in COVID-19 patients is discussed

Co-Occurrence and Characteristics of Patients With Axial Spondyloarthritis Who Meet Criteria for Fibromyalgia : Results From a UK National Register

The British Society for Rheumatology (BSR) Biologics Register in Ankylosing Spondylitis is funded by the BSR and they have receive funds for this from Pfizer, AbbVie and UCB. These companies receive advance copies of manuscripts and can provide comments but have no input into determining the topics for analysis, publication and no input into the work involved in this analysis. This analysis is part-funded by Arthritis Research UK (Grant No: 21378)Peer reviewedPublisher PD

Pharmacological treatment of fibromyalgia

Fibromyalgia syndrome (FM) is a condition of chronic and diffuse muscular pain affecting particularly middle aged women. The aetiology of FM is not completely understood and it is currently considered a disorder of pain regulation. The most efficacious compounds include the tricyclic drugs and mixed reuptake inhibitors. Recent works suggest that the anticonvulsant medications pregabalin and gabapentin are also effective. Moreover, two serotonin and norepinephrine- reuptake inhibitors-duloxetine and milnacipran show encouraging results in treating FM symptoms. The results of clinical trials of anti-inflammatory medications have been generally disappointing, but three RCTs have found that tramadol (with or without acetaminophen) is effective in FM