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

It 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