Current Pharmaceutical Design - Volume 21, Issue 2, 2015

Rheumatoid arthritis (RA) is the most common autoimmune articular disorder. It is characterized by chronic inflammation and progressive joint destruction. As research traditionally focused on immune cells and cytokines, the role of stromal cells was addressed only to a limited extent. However, cell-cell interactions within the rheumatoid synovium alter the phenotype of synovial fibroblasts (SFs), which are nowadays considered as active and aggressive drivers in the destructive process of RA. SFs actively attach to and invade articular cartilage, thereby expressing increased amounts of adhesion molecules and proinflammatory and matrix-degrading mediators. Furthermore, RASFs stimulate synovial vascularization through the release of proangiogenic factors. As a result, angiogenesis supports the influx of immune cells into affected joints, thereby perpetuating inflammatory processes, and facilitates access of RASFs to the bloodstream, thus boosting dissemination of RA. Despite intensive research, early pathophysiological processes still remain largely unknown. In this respect, a prearthritic phase of RA is discussed. Early and intensive therapy is considered to be very effective and beneficial for long-term outcome. However, although innovative therapy and improved treatment strategies are applied to achieve clinical remission, failure of or only partial response to therapy remains common. Given that none of the currently approved therapies target RASFs, intensive research into new strategies is warranted. In this review, novel findings leading to the altered fibroblast phenotype in RA are discussed in terms of progressive inflammation and destruction. Potential novel therapeutic concepts are also addressed.

T cells play a role in the initiation and perpetuation of tissue inflammation that can lead to tissue destruction. With the discovery of a number of T helper subsets and their potential plasticity during disease it became clear that the T cell behaviour in autoimmune diseases is much more complex than the first Th1/Th2 concept. From experimental autoimmune arthritis models it became clear that the IL-23/IL-17 immune pathway is critical in the development of autoimmune arthritis and IL-17A has been recognized to be a key cytokine involved in initiation and perpetuation of chronic destructive arthritis. Functional studies using T cells and stromal cells from patients with RA revealed improvement of anti-TNF effects when combined with agents neutralizing IL-17A or agents suppressing Th17 cytokines production. Clinic trials will be needed to test whether these data from experimental settings can be translated to human arthritis. Different approaches are available or under investigation to target: (1) pathogenic T cell activity by inhibiting RORc or STAT3 or the costimulator pathway by CTLA4-Ig; (2) Th17 cytokine production by anti-IL-17A, anti-IL-22, or combination of anti-IL-17A/anti-TNF approaches; (3) Th17 polarization by neutralizing IL-23 using an anti-IL-23 specific antibody, IL-12/IL-23 by an anti-p40 antibody, or the IL-6 signaling pathway; (4) Th17 migration by interfering the CCR6-CCL20 interaction. The challenge is to bring the best to the clinic to further improve current therapy for patients with RA and to reach stable remission or even prevent the development of this disabling disease.

Treatment of patients with rheumatoid arthritis (RA) is rarely personalized, since predictors of disease course are lacking. The severity of RA can be measured objectively by radiographic progression. The most reliable way to measure radiographic progression is in a longitudinal cohort with serial time points, scoring on a quantitative scale, with a validated scoring method and trained readers. Current models used to predict radiographic progression are based on C-reactive protein and anti-citrullinated protein antibodies. Other biomarkers could increase the prognostic ability of these models. In this review, we evaluated the published (and partly nonpublished) data on genetic, serologic, and imaging biomarkers for the severity of joint destruction in RA. We evaluated variants in 10 genes (CD40, IL2RA, IL4R, IL15, OPG, DKK1, SOST, GRZB, MMP9, and SPAG16). In 5 variants (IL2RA, DKK1, GRZB, MMP9, and SPAG16), we found evidence of an association at the functional level. We evaluated several serological biomarkers, namely, autoantibodies (RF, ACPA, anti-CarP), markers related to inflammation (ESR, CRP), and proteinases or components of the extracellular matrix of bone and cartilage (MMP3, CTX-I, CTX-II, COMP, TIMP1, PYD, RANKL/OPG, CXCL13). Finally, we evaluated markers that can be visualized by ultrasound or MRI, including erosions, bone marrow edema, synovitis, and tenosynovitis. Several studies showed that bone marrow edema and synovitis on MRI are robust predictors of radiographic progression. Some studies showed that inflammation detected with ultrasound predicted radiographic progression. Future studies will reveal whether adding and combining all these different biomarkers will increase the accuracy of risk models predicting radiographic progression in RA.

The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment. In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slow— or even stop—irreversible structural changes. Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers. The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes. However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment. Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers. Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with premature mortality, severe morbidity, and functional impairment leading to considerable financial burden for both patients and society. Since disease progression and complications can differ from one patient to another, genetic markers are of potential relevance for identifying those individuals at a higher risk of more severe disease. RA is a complex polygenic disease. Cardiovascular (CV) disease due to accelerated atherogenesis is the most common cause of premature mortality in patients with RA. Several studies support the implication of genetic factors in the development of CV disease in RA. In addition to the strong association between alleles of the HLA-DRB1*04 shared epitope and both subclinical and clinically evident CV disease, genes implicated in inflammation and metabolism, such as TNFA, MTHFR, and CCR5, seem to be associated with a higher risk of CV disease in patients with RA. We propose the use of these genetic variants as molecular biomarkers that could help to predict disease outcome at diagnosis of RA and, therefore, to optimize the treatment and management of other risk factors from an early stage of the disease.

Methotrexate (MTX) is a first-line drug for the treatment of several rheumatic diseases. However, it is difficult to predict the response to this drug based on clinical manifestations. Although different mechanisms of action have been proposed for the antiinflammatory and immunosuppressive effects of MTX, the best characterized are blockade of the de novo synthesis of purines and pyrimidines, which inhibits DNA synthesis, and induction of adenosine release, which downregulates the effector functions of different immune cells. Thus, variants of the enzymes and other molecules involved in these metabolic pathways are expected to play a relevant role in the therapeutic effect or toxicity of MTX in patients with rheumatoid arthritis (RA). Accordingly, polymorphisms of the genes encoding these proteins have been widely associated with the response to or discontinuation of MTX. In addition, variants of the genes involved in the transportation of MTX inside and outside cells and in its metabolism have also been associated with the efficacy or toxicity of this drug in patients with RA. However, published results are contradictory, and no consensus regarding the best laboratory markers of MTX efficacy has been reached. Therefore, additional prospective studies with a large number of patients are necessary to identify the combination of genetic and nongenetic factors that can predict, with a reasonable level of confidence, the efficacy and toxicity of MTX in patients with RA.

Before the use of rituximab, the strongest accepted evidence for an association between B-cells and rheumatoid arthritis (RA) was that clinical disease was associated with serum autoantibodies. The ability to remove B-cells with rituximab has also revealed the relative importance of the different immunological parameters that underlie the clinical symptoms of RA. First, seropositive patients have a significantly more predictable and favorable clinical response to rituximab than seronegative patients. Second, the kinetics of the clinical response, with a delay of weeks or months after depletion, suggest that it is a B-cell product (autoantibody) and not B-cells per se that need to be reduced for remission to occur. Third, removal of B-cells from joints may not be closely associated with clinical improvement, although maintenance of plasma cell counts in joints has been associated with poorer responses. The requirement of ‘new’ B-cells generated from the bone marrow for relapse to occur suggests that selection of autoreactive B-cell clones in the periphery may also be necessary for their survival and differentiation into autoantibody-producing cells. The initial hypothesis suggested that the autoimmune response underlying the pathogenesis of RA was self-sustaining. This would seem to be confirmed, as relapse inevitably follows a variable period of reduced clinical symptoms induced by rituximab. In addition, a dominant role for autoantibodies seems to have strong support from clinical practice. In addition to their possible role in the pathogenesis of RA in the form of immune complexes, further investigation is necessary to determine whether autoantibodies contribute to perpetuation of changes in central B-cell tolerance in these patients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that involves synovial tissue and leads to joint destruction. There are currently 5 tumor necrosis factor (TNF) antagonists licensed for the treatment of RA. This review summarizes the predictors of response to TNF antagonists in RA. Demographic variables were found to predict response, although not consistently. The variables associated with poor clinical response were presence of radiographic joint erosions at baseline, poor functional capacity at baseline, presence of human antibodies against TNF chimeric antibodies, and increase in anti-DNA and antinuclear antibodies. In selected populations, polymorphisms of TNF, TNF receptor, and Fc γ receptor were related to clinical response. Expression of TNF and other inflammatory cytokines in synovial tissue was explored. The heterogeneity of study populations limits the generalizability of the results in most studies.

Safety is usually a secondary endpoint in clinical trials, and most observational studies on predictors focus on response, not toxicity. Research is clearly biased towards efficacy rather than safety, probably because of the difficulty in measuring toxicity arising from lack of standardization, low statistical power, missing data, misinterpretation, and confounding variables. An extensive search revealed very few studies on toxicity markers for the drugs used to treat rheumatoid arthritis. The literature contains many studies on predictors of the safety of methotrexate. Most analyze genetic markers, which are difficult to apply in daily practice. We found few studies on markers of toxicity for biologics. As many adverse events are related to patient characteristics, we recommend that clinicians understand the risk factors for the most common adverse events, especially infections and cancer, and manage risk on an individual basis. Moreover, patient involvement in monitoring safety is crucial.

Information from patients traditionally is regarded as “subjective,” in contrast to “objective,” “scientific” laboratory data. However, patient questionnaire scores for physical function are more significant to predict severe outcomes of rheumatoid arthritis (RA), such as work disability and mortality, than radiographs or laboratory tests. Furthermore, the 3 RA Core Data Set patient self-report measures of physical function, pain, and patient global estimate are as effective as radiographs or laboratory tests to distinguish active from control treatments in clinical trials. A multidimensional health assessment questionnaire (MDHAQ) has been developed in routine clinical care, to be completed by patients in 5-10 minutes and contribute to clinical decisions, in contrast to research questionnaires which may provide extensive information, but often are lengthy, unfeasible for routine care, and not designed to add to clinical care. RAPID3 (routine assessment of patient index data) is an index included on the MDHAQ which is calculated in 5 seconds, compared with almost 2 minutes for RA indices that require a formal joint count, such as DAS28 (disease activity score with 28-joint count) or CDAI (clinical disease activity index). MDHAQ with included RAPID3 scores appears as “scientific” as laboratory tests, formal joint counts, and indices such as DAS28 and CDAI, to assess patient status using standard, protocolized, quantitative measurement. MDHAQ/RAPID3 helps the patient prepare for the visit, enhances doctor-patient communication, and saves time for the physician. MDHAQ/RAPID3 is useful in all rheumatic diseases, and can be incorporated into routine clinical care with minimal extra work for physicians and staff. MDHAQ in no way prevents collection of formal joint counts, radiographs and other imaging studies, laboratory tests, or any other information regarded as important by a rheumatologist. MDHAQ provides quantitative, "scientific” data, rather than gestalt impressions, regarding patient status, change in status, prognosis, and outcomes of RA and all rheumatic diseases.

This paper presents a comprehensive review of research relating psychological domains with response to therapy in patients with rheumatoid arthritis. A holistic approach to the disease was adopted by incorporating not only disease activity but also dimensions of the impact of disease on patients’ lives. Psychological distress, including depression and anxiety, is common among patients with rheumatoid arthritis and has a significant negative impact on response to therapy and on patients' abilities to cope with chronic illness. Evidence regarding the influence of positive psychological dimensions such as acceptance, optimism, and adaptive coping strategies is scarce. The mechanisms involved in these interactions are incompletely understood, although changes in neuro-endocrine-immune pathways, which are common to depression and rheumatoid arthritis, seem to play a central role. Indirect psychological influences on therapeutic efficacy and long-term effectiveness include a myriad of factors such as adherence, placebo effects, cognition, coping strategies, and family and social support. Data suggest that recognition and appropriate management of psychological distress may improve response to treatment and significantly reduce disease burden.