Diagnosis and Treatment in Rheumatology

Malgorzata Wislowska

• Publisher: Bentham Science Publishers
• Year: 2018
• ISBN:
  9781681086552
• Topic: Médecine
• Subtopic: Rhumatologie, orthopédie et prothèses

Diagnosis and Treatment in Rheumatology is a clear and concise handbook of all rheumatic diseases. The book presents organized information about current diagnosis, treatment and statistics where available of diseases such as rheumatoid arthritis, spndyl

Rheumatoid Arthritis

Małgorzata Wisłowska

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease which affects around 0.5-1% of the population. RA is characterized by symmetric, erosive arthritis of the synovial joints and with various extra-articular features. The progressive destruction of the articular cartilage leads to deformation and loss of function of affected joints. The primary affected area is synovium, at the site where the “pannus” is developed. RA is characterized by a poor outcome, but the course may be varied. RA that is not controlled is associated with a reduction in life expectancy. The risk of atherosclerosis and lymphoma development is increased in RA . The etiopathogenesis of RA is partially understood, as it is a multifactorial disease and is determined by genetic as well as environmental factors. Class II major histocompatibility genes are responsible for about 30% of genetic susceptibility to RA. The autoantibody profile can be diagnostic, specifically rheumatoid factor (RA) and antibodies to cyclic-cytrullinated peptides (ACPA) more specific marker. RA is an economical burden for patients and society. Substantial advances have been made in the management at RA. Currently, methotrexate is the basic conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARD) in RA treatment. It may be used in combination with biologic drugs.

Following the introduction of the treatment recommendations for RA in 2016 by the EULAR, and the introduction of biological (b) DMARDs and targeted synthetic (ts) DMARDs in the management of RA, special consideration must be taken in the selection of therapy for patients who do not respond to standard treatment.

Keywords: Antibodies to cyclic-cytrullinated peptides (ACPA), Biological DMARDs, Disease-modifying antirheumatic drugs (DMARDs), Erosions, Erosive arthritis, Leflunomide, Methotrexate, Pannus, Rheumatoid arthritis, Rheumatoid factor (RA), Synovium, Targeted synthetic DMARDs.

INTRODUCTION

RA is a chronic inflammatory disease which affects around 0.5-1% of the population, the highest rate occurring in American-Indian populations showing between 5.3 to 6.8%, and the lowest occurrence has been shown in populations from South Africa, Nigeria and South-East Asia, with an occurrence rate of 0.2% to 0.3% [1]. RA is characterized by symmetric, erosive arthritis of the synovial joints and with various extra-articular features. Typical articular symptoms

include pain, stiffness and swelling. The progressive destruction of the articular cartilage leads to deformation and loss of function of affected joints. The primary affected area is synovium, at the site where the “pannus” is developed.

RA is usually characterized by a poor outcome, but the course may be varied. RA that is not controlled is associated with a reduction in life expectancy, which in some studies may be up to 6-7 years [1]. The risk of atherosclerosis and lymphoma development is increased in RA [2].

RA is an economical burden for both patients and society, which is calculated in terms of direct and indirect costs. Direct costs are where actual payments are made, e.g. treatment and hospitalization costs, while indirect costs are those resulting from loss of resources, e.g. loss of productivity.

Substantial advances have been made in the field of rheumatology in the past 20 years, particularly in the management at RA. Following the introduction of the treatment recommendations for RA in 2016 by the European League Against Rheumatism (EULAR) [3], and the introduction of biological (b) disease-modifying antirheumatic drugs (DMARDs) and targeted synthetic (ts) DMARDs in the management of RA, special consideration must be taken in the selection of therapy for patients who do not respond to standard treatment.

ETIOPATHOGENESIS

The etiopathogenesis of RA is only partially understood, as it is a multifactorial disease and is determined by genetic as well as environmental factors [4]. 50-60% of the risk of developing RA is due to genetics [5, 6]. The familial RA occurrences are about 10-30% of patients, in 12-15% of monozygotic twins and in 3-4% of dizygotic twins [7]. Genes play an important role in the susceptibility to RA. Class II major histocompatibility genes are responsible for about 30% of genetic susceptibility to RA [8]. Susceptibility to RA and disease severity, is connected particularly with the human leukocyte antigen (HLA) located on the short arm of chromosome 6 (6p21.3) [8]. The most important genetic associations are class II major histocompatibility genes, especially those containing a specific 5 amino acid sequence in the hypervariable region of HLA-DR. The susceptibility to RA is associated with the third hypervariable region of DRβ-chains, from amino acids 70 through 74 amino acid sequence which consists of glutamine – leucine – arginine – alanine – alanine (QKRAA) and is called “shared epitope” [8]. This epitope is found in DR4, DR14 and some DR1β chains.

The first non-HLA genetic association with RA is the protein tyrosine phosphatase-22 (PTPN22) candidate gene, which encodes a lymphoid-specific protein tyrosine phosphatase, that downregulates T cell receptor signaling. PTPN22 is a phosphatase that regulates the phosphorylation status of several kinases important to T cell activation [9].

The PADI (peptidylarguinine deiminase) genes are responsible for the post-translational modification of arginine to citrulline. An extended haplotype in the PAD 4 gene provides the most promising coding for RA [10].

Many other genes that are connected with immune regulation are also connected with RA, which is a polygenic disease.

RA is triggered by environmental factors, enhanced by genetic predisposition in combination with altered immune responses. For example Porphyromonas gingivalis, during periodontal diseases and tobacco smoking [11], encourages anti-cylic citrullinated peptide antibodies (ACPAs) production which has a crucial role in RA pathogenesis. Smoking is an important and proven risk factor, as it is connected with increased production of autoantibodies, especially ACPA and RF and with increased occurrence of extraarticular symptoms [11]. The polycyclic aromatic hydrocarbons (PAHs) present in tobacco smoke activate the aryl hydrocarbon receptor (AHR), which being a transcription factor, binds to response elements of xenobiotic (XRE), which regulates the expression of multiple genes [11].

The genetic associations of the HLA shared epitope alleles in the development of RA indicates that the disease is partially driven by T cells [12], and especially with CD4+T cells, which are a dominant cells type (add up to 30-50% all cells type) in the synovium of RA patients [13]. This subpopulation of T cells is capable of suppressing immune response [13].

For the development of RA a decrease in immunological self-tolerance is required. Human naïve CD4+T cells, depending on the cytokine environment in which they are currently in, divide into distinct cell subset, such as Th1, Th2, Th17 cells, regulatory T cells (Treg) and T follicular helper cells [14]. Th1 cells function to activate macrophages in ways that enhance microbial killing. Th1 cells are characterized by the profile of cytokines they produce INFγ. Th2 cells function in responses against parasitic infestations, and secrete cytokines such as IL-4, IL-5 and IL-13. IL-4 induces the production of IgG4 and IgE. Th2 cells play key roles in atopic and allergic disease. Th17 cells participate in host defense against fungal infections and extracellular bacteria. Th 17 cells are typical pro-inflammatory cells that promote inflammatory responses in tissues and the development of autoimmune diseases.

Specific populations of CD4+ T cells (Tregs or CD4+CD25+) express regulatory functions. These cells are required to maintain homeostasis of the immune system by preventing the activation of self-reactive lymphoid populations. Treg cells are involved in the inhibition of activation of the immune system and maintain immune homeostasis and tolerance to self-antigens.

Th17 and Treg cell differentiation pathways are interconnected, meaning that balance between them is important for correct immune homeostasis [15].

Th 17 cells through the production of proinflammatory cytokines such as IL-17, IL-1β, IL-6, IL-21, IL-23, TNFα and GM-CSF are necessary for the induction and maintenance of autoimmune tissue inflammation and contribute to the differentiation and proliferation of osteoclasts, which cause bone resorption [16]. Th17 cells can also produce IL-21, which is a major regulator of IgG production and T-dependent humoral responses [17].

The function of Treg during a phase of homeostatic control may predict if an autoimmune disease will occur. However, in the chronic inflammatory phase the increased number of Treg cells may even be negative. They may cause inhibition of the immune response, contributing to a change in inflammatory processes, leading to chronic autoimmune inflammation. Treg cells inhibit immunologic responses in many ways, including cytotoxic factors, anti-inflammatory cytokines (e.g. IL-10, TGFβ, IL-35), metabolic disruption or by changing the maturation and function of antigen presenting cells [14]. In RA, patients’ Treg cell count is higher in synovial fluid, comparing to peripheral blood, and there is still persistent inflammation in the joints. This means that these cells are not very effective in the control of inappropriate activation of the immune system [18]. Treg cells present in the RA synovial fluid may have an increased ability to suppress both T cell proliferation and production of proinflammatory cytokines (e.g. TNFα, INFγ), but disease is still able to progress [19]. This can be a result of interactions between Tregs and cytokines at the site of inflammation. Cytokines such as TNFα, IL-6, IL-15 and IL-1 present in the rheumatic joint are able to increase the number of infiltrating regulatory T cells and are able to impair their suppressive function [19]. The circulating Treg cells that can suppress proliferation of the effector T cells are unable to inhibit the proinflammatory cytokine secretion from activated T cells and monocytes [19]. Treg cells in the presence of pro-inflammatory cytokine-rich environment will change to pathogenic T cells [19].

Different extra – articular manifestations may be caused by abnormal systemic immune responses. The structure of the synovial va...