Gammaglobulins, autoantibodies, therapeutic antibodies and anti-drug antibodies in rheumatoid arthritis.
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting 0.3% of the French population 1 and 1% of the general population 2. Treatment options include disease-modifying anti-rheumatic drugs and targeted therapies, such as biologicals. However, the use of biologicals makes RA a very expensive disease to treat, at approximately €8000–10 000 per patient per year 3. RA is almost as expensive to treat as renal failure, and more expensive than cancer or diabetes. Furthermore, RA disease activity is associated with an increased risk of other diseases; for example, RA patients with high levels of disease are at higher risk (two- to threefold) of developing lymphoma when compared with healthy individuals 4. Antibodies play an important role in the pathogenesis of RA, as shown by a study using a mouse model deficient in the low-affinity inhibitory Fc receptor (FcγRIIB). Mice injected with human RA-associated antibodies developed polysynovitis; in contrast, no response was observed using control serum, or in mice which were not deficient in FcγRIIB 5. RA is also associated with the presence of anti-citrullinated protein antibodies (ACPAs); citrullinated proteins are those in which the enzyme peptidylarginine deiminase (PAD) has catalyzed the conversion of protein-bound arginine to citrulline via post-translational modification. The fibrinogen protein is particularly susceptible to citrullination, leading to the development of citrullinated fibrinogen (cFb), which has been shown to exacerbate disease in a mouse RA model 6. When human macrophages are incubated with cFb production of tumour necrosis factor (TNF) is induced 7, indicating a potential role for citrullination in the propagation of inflammation in RA. Known risk factors for RA include smoking, which has been shown to induce citrullination in the lungs 8. Citrullination can also be stimulated by the PAD-containing bacteria Porphyromonas gingivalis, which can be found in the oral cavity (where it has been implicated in various forms of periodontal disease 9), as well as by other enzymes in the colon. In addition, some people are genetically predisposed to secrete ACPAs. For example, the role of the normal human leucocyte antigen (HLA) is to present peptide antigens to the immune system; however, several HLA-DRB1 alleles share a common sequence motif (called the 'shared epitope') that binds citrullinated peptides, and are therefore associated with an increase in secretion of ACPAs 10. Therefore, a combination of environmental and genetic triggers can increase the risk of developing RA. ACPAs can aid in the diagnosis of RA, as assays for these autoantibodies have high specificity (> 95%) and sensitivity (50–60%). Moreover, these autoantibodies can be detected years before the patient exhibits any symptoms when the disease is in the early stages, providing a window of opportunity for early treatment, which is essential to avoid rapid joint destruction. Autoantibodies can also be used to predict a patient's response to treatment for RA. For example, data from a French registry have shown that patients testing positive for anti-cyclic citrullinated peptide (anti-CCP) had a better response to treatment with abatacept [a fusion protein of human Fc fused to the extracellular domain of cytotoxic T lymphocyte antigen-4 (CTLA-4)] than patients without anti-CCP 11. Therapeutic monoclonal antibodies are an important element of the therapeutic strategy used to treat RA. A variety of mechanisms can be exploited, such as the inhibition of cytokines, T cells and B cells. The current treatment strategy for RA consists of methotrexate as first-line therapy. If this is unsuccessful, then combination therapy with methotrexate and a biological therapy should be considered, followed by third-line therapy with a change in biological therapy or Janus kinase/signal transducer and activator of transcription (JAK/STAT) kinase inhibitors. Biological therapy classes used in RA include inhibitors of cytokines such as anti-TNF [e.g. etanercept, a human recombinant receptor/Fc fusion protein; infliximab, adalimumab and golimumab, monoclonal antibodies (mAb); and certolizumab pegol, a PEGylated humanized Fab fragment] 12, anti-interleukin (IL)-6 receptor (e.g. tocilizumab, a humanized mAb which antagonizes the IL-6 receptor), CTLA-4-Ig (e.g. abatacept, an inhibitor of T cell co-stimulation) or anti-CD20 (e.g. rituximab, a chimeric mAb which depletes B cells). These therapies have a better efficacy to block radiographic progression of RA than methotrexate. Treatment with a combination of methotrexate and biological therapy is more effective than either therapy alone 13. In early RA, biological treatment results in an increased proportion of clinical remission. For example, a randomized, double-blind parallel treatment trial showed that early treatment with etanercept and methotrexate in combination was able to put 50% of patients into remission by week 52, compared with 28% of patients treated with methotrexate alone 14. Usually, anti-TNFs represent the first line of biological treatment in patients with insufficient response to methotrexate, with abatacept or tocilizumab as alternative options for these patients. However, due to a lack of data from strategy or head-to-head clinical trials it is not always clear which biological to use. Approximately 30% of patients fail to respond to their first biological, either by primary inefficacy or by loss of efficacy. In patients treated with anti-TNF monoclonal antibodies, this might be related to immunization against the therapeutic monoclonal antibody used. The development of anti-drug antibodies (ADAs) can decrease the circulating dose of the drug, increase infusion reactions and decrease efficacy. Patients who develop ADAs are more likely to discontinue treatment due to treatment failure. A long-term study of 272 RA patients receiving anti-TNF therapy showed that 28% developed ADAs 15. Three of 76 patients (4%) with ADAs achieved sustained remission, compared with 67 of 196 patients (34%) who did not develop ADAs. The development of ADAs was associated with lower adalimumab concentration. The strategy in patients with insufficient response to a first anti-TNF has not yet been defined. In a recent multi-centre, randomized controlled trial, patients who had an insufficient response to treatment with an anti-TNF were randomized to receive treatment with either a second anti-TNF (adalimumab, certolizumab, etanercept or infliximab) or a biological therapy from a different class (abatacept, rituximab or tocilizumab). Significantly more patients who were given an alternative biological reported a good or moderate response to treatment when compared with patients who received a second anti-TNF therapy 16. Therefore, it might be better to switch to a therapy with a different mechanism of action if initial treatment with an anti-TNF is unsuccessful. Unfortunately, biological therapies have been associated with increased risk of serious infections. In RA patients treated with rituximab, risk factors for serious infection include: chronic bronchopulmonary disease or cardiac insufficiency, extra-articular involvement and low IgG levels (< 6 g/l) before initiation of treatment 17. Real-world registry data show that, following rituximab treatment, approximately 12% of patients developed hypo-IgG (defined by at least one value below < 6 g/l) and more than 15% of patients had hypo-gammaglobulinaemia 18. In open extension phases of clinical trials, rates of serious infections remained low and stable over time at four to six events per 100 patient-years, and the number of patients exhibiting low IgG levels remained low across five courses of treatment 19. In conclusion, antibodies play a number of important roles in the pathogenesis, diagnosis, treatment and prediction of response to treatment in RA. Further work is needed to ensure that patients receive tailored treatment to produce the best outcomes and minimize the occurrence of adverse events. J.-E. G. has received scientific grants and honoraria from AbbVie, BMS, MSD, Pfizer and Roche.
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