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Rheumatoid arthritis (RA) is best thought of as an inflammatory syndrome with autoimmune features with its predominant expression in synovial joints. It is the most common form of inflammatory polyarthritis. Current thinking favors the hypothesis that interplay between genetic factors, sex hormones, and possibly an infectious agent or another immune-activating agent initiates an autoimmune pathogenic mechanism that culminates in a disease with inflammatory and destructive features.
The 2010 ACR/EULAR classification criteria for RA
Joints Distribution (0–5)
1 Large joint
2–10 Large joints
1–3 Small joints (large joints not counted)
4–10 Small joints (large joints not counted)
>10 joints (at least one small joint)
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
Symptom Duration (0–1)
Acute Phase Reactants (0–1)
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
Once established, RA is characterized by deforming symmetrical polyarthritis associated with synovitis of joint and tendon sheaths, articular cartilage loss, and erosion of juxta-articular bone of varying extent and severity (Taylor 2006). IgM rheumatoid factor is detectable in the blood in a majority of patients. It is an autoantibody whose autoantigen is the Fc portion of IgG. The prevalence of rheumatoid factor increases with duration of disease in rheumatoid arthritis: at 3 months the prevalence is 33%, while at 1 year it is 75%. Up to 20% of RA patients remain negative for rheumatoid factor (also known as “seronegative rheumatoid arthritis”) throughout the course of their disease. Antibodies to cyclic-citrullinated peptides (anti-CCP) have a similar sensitivity to rheumatoid factor, but higher specificity (Taylor 2019b). As in the case of high-titer rheumatoid factor, anti-CCP antibodies are associated with persistence and destructiveness of rheumatoid arthritis and may precede the onset of clinical disease.
In a proportion of patients, systemic and extra-articular features may be observed during the course of the disease (and rarely prior to joint disease). These include anemia; weight loss; vasculitis; serositis; nodules in subcutaneous, pulmonary, and sclera tissues; mono-neuritis multiplex; and interstitial inflammation in lungs as well as in exocrine salivary and lacrimal tissue. However, these systemic manifestations occur relatively late in the disease progression.
RA is characterized by chronic inflammation of synovial joints with synovial proliferation and infiltration by blood derived cells, in particular, memory T cells, macrophages, and plasma cells, all of which show signs of activation. Prominent vasculature is a feature of RA synovitis that is observed as a fine network of vessels over the rheumatoid synovium at arthroscopic inspection of RA joints. Angiogenesis is evident on microscopic examination of synovial biopsies from the earliest stages of disease development. Formation of new blood vessels permits a supply of nutrients and oxygen to the augmented inflammatory cell mass and so contributes to the perpetuation of synovitis. In the chronic phase of disease, capillaries and post-capillary venules are particularly evident in the synovial sublining region. In histological sections mononuclear and polymorphonuclear leukocytes can sometimes be found in close apposition to vascular endothelium, probably in the process of margination and adhesion prior to migration into the inflamed tissue. The synovial tissue becomes markedly hyperplastic and locally invasive at the interface of cartilage and bone with progressive destruction of these tissues in the majority of cases. This invasive tissue is referred to as “pannus,” comprising mainly lining cells with the appearance of proliferating mesenchymal cells with very little sublining lymphocytic infiltration. The accompanying destruction of bone and cartilage is thought to be mediated by cytokine-induced degradative enzymes, notably the matrix metalloproteinases. Although RA has its principal manifestation in joints, there is also evidence of systemic involvement, for example, the upregulation of acute phase proteins, and a wide variety of extra-articular features may develop. These occur predominantly in patients who are rheumatoid factor positive and carry the HLA-DR4 gene.
Genetic factors were originally implicated in the etiopathogenesis of RA following the discovery that in population studies, there is a slight increase in the frequency of RA in first-degree relatives of patients with this disease, especially if seropositive for rheumatoid factor. In hospital-based population studies of identical twins, concordance rates of disease are around 30%, compared with 5% in nonidentical twins. The figures are lower in community-based studies and, although still supportive of the concept of a genetic contribution, argue against the proposition that RA is the result of a dominant single-gene disorder. These and other epidemiological studies have led to the conclusion that RA is a polygenic disease and that non-inherited factors are also of great importance (Kurkó et al. 2013).
Genes encoding particular class II human leukocyte antigens (HLA) are among candidates for involvement in predisposition to RA. This discovery came about with the observation that 60–70% of Caucasian patients with RA are HLA-DR4 positive by cellular or serological techniques compared with 20–25% of control populations. Furthermore, patients with more severe RA, especially those with extra-articular complications such as vasculitis and Felty’s syndrome, are even more likely to be HLA-DR4 positive than patients with less severe disease confined to joints.
Class II HLA molecules are expressed on the surface of antigen-presenting cells. They play a key role in presentation of processed linear peptide antigens of at least nine amino acids to T cells. Antigen is bound to the HLA-binding cleft formed by the α and β chains of the HLA class II molecule. This trimolecular HLA–antigen complex binds in turn to the variable portion of the T-cell receptor.
Nucleotide sequencing of HLA-DR β 1 exons coding amino acid residues 70–74 has revealed that HLA-DR4 subtypes Dw4, Dw14, and Dw15 share similarities with each other (with a conservative substitution of glutamine with lysine at position 71 in Dw4) and with HLA-DR1. The sequence predicts susceptibility to RA and is associated with RA in 83% of Caucasian patients in the United Kingdom. In contrast, negative associations are observed in individuals who are DR4w10, in whom the charged basic amino acids glutamine and arginine in positions 70 and 71 are replaced by the acidic amino acids aspartic and glutamic acid. In Dw13 individuals, in whom a negative association is also observed, arginine is substituted for glutamic acid in position 74. Molecular modelling studies suggest that amino acid residues 70–74 are located in the α-helix forming the wall of the peptide-binding groove and thus likely to be involved in antigen binding and subsequent interaction with T-cell receptors (Kurkó et al. 2013). Acidic substitutions could profoundly alter protein structures and thereby alter affinity for peptide antigens. However, molecular mechanisms accounting for susceptibility to RA remain to be elucidated. Possibilities include permissive binding of specific peptides such as those on autoantigens or on environmental antigens, initiation of disease by specific binding of superantigens to HLA molecules, or modulation of the T-cell repertoire by selection or tolerance. HLA and some non-HLA genes have been linked to autoimmunity to citrullinated proteins (anti-CCP) as well as smoking. Smoking, oral microbiota, and possibly other environmental and lifestyle-related factors may trigger the development of anti-CCP in some patients. It has been hypothesized that the severity of disease and extra-articular complications are related to homozygosity and the density of disease-associated MHC molecules that critically influence the selection of the T-cell repertoire and tolerance to antigens.
Cytokines are small, short-lived proteins and important mediators of local intercellular communication. Cytokines mediate both innate and adaptive immune cellular responses and play a key role in integrating responses to a variety of stimuli that contribute to inflammation and joint injury that characterize RA pathology. Much of the activity of key cytokines in RA pathology is paracrine in nature. By binding their cognate receptors on target cells in their immediate vicinity, these molecules participate in many important biological activities including cell proliferation, activation, death, and differentiation. In experimental systems, some cytokines are proinflammatory, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF); others, such as interleukin-10 (IL-10) and transforming growth factor β (TGFβ), exert predominantly anti-inflammatory effects. However, it is now known that many cytokines, for example, interferon γ (IFNγ), with chiefly proinflammatory activity can also in some instances have anti-inflammatory properties. Similarly, IL-10 and TGFβ may also exhibit proinflammatory properties under certain experimental conditions. Interleukin-6 (IL-6) does not have a classical proinflammatory action but has been implicated in the process of erosion of bone in inflammatory arthritis. Paracrine or autocrine pathways involving cytokines with either pro- or anti-inflammatory activity form complex networks determining whether chronic inflammation results. Following engagement with receptors on the surface of responder cells, cellular responses are mediated by an intracellular cascade of phosphorylation steps through a number of distinct signaling pathways. As understanding of cytokine signaling has advanced, various intracellular signaling molecules have been proposed as potential therapeutic targets. The Type I/II cytokines, which include IL-6, signal through the Janus kinase (JAK) enzymes comprising a family of four intracellular tyrosine kinases. The only targeted small molecule therapies to be approved for RA to date are JAK inhibitors.
Role of Cytokines in the Pathogenesis of RA
Cytokines derived from macrophages and fibroblasts are abundant in the rheumatoid synovium. These include IL-1, TNF, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-6, and numerous chemo-attractant cytokines known as chemokines. Many of these factors are of importance in regulating inflammatory cell migration and activation. By contrast, given the extent of synovial inflammation and lymphocytic infiltration, factors produced by T cells, for example, IFNγ, interleukin-2 (IL-2), and interleukin-4 (IL-4), are surprisingly sparsely expressed. However, there are a number of cytokines that cause co-stimulation of T helper cells including interleukin (IL)-7, IL-12, IL-15, and IL-18. There is a predominance of Th1 cell activity, as defined by IFNγ production, and low Th2 cell activity as defined by IL-4 production (Firestein and McInness 2017).
An extensive range of proinflammatory cytokines can be detected in RA synovial samples, regardless of differences in donor disease duration, severity, or even conventional (non-biologic) drug therapy. Proinflammatory cytokines are spontaneously produced over several days in dissociated RA synovial membrane cell cultures comprising a heterogeneous population of cells. This occurs in the absence of extrinsic stimulation, suggesting that the cultures produce one or more soluble factors regulating prolonged cytokine synthesis. Addition of anti-TNF antibodies to these cell cultures was observed to strikingly reduce the production of other proinflammatory cytokines, including IL-1, GM-CSF, IL-6, and IL-8. In contrast, blockade of IL-1 by means of the IL-1 receptor antagonist results in reduced production of IL-6 and IL-8 but not that of TNF. These observations led to the concept that TNF occupies a dominant position at the apex of a proinflammatory cytokine network.
TNF is a pleiotropic cytokine with biological properties that include enhanced synovial proliferation, production of prostaglandins and metalloproteinases, as well as regulation of other proinflammatory cytokines. The predicted clinical success of anti-TNF therapy in RA was based on the demonstration of RA synovial tissue expression of TNF and its receptors, in vitro experiments employing dissociated synovial cell cultures, and preclinical in vivo studies. A number of independent in vivo studies demonstrated that antibody therapies blocking bioactivity of TNF, administered either during the induction phase of murine collagen-induced arthritis or, more importantly, after the onset of disease, were able to ameliorate clinical symptoms and prevent joint destruction. Furthermore, in a murine model, the overexpression of a human TNF transgene modified at its 3′ end to prevent degradation of its mRNA was associated with the development of a destructive form of polyarthritis 4–6 weeks after birth. This could be prevented by administration of a human TNF-specific mAb.
A major emphasis in the management of RA over recent years has been on early diagnosis and treatment, before the onset of erosions, in order to best realize opportunities to achieve and sustain the ideal goal of remission and to prevent joint damage and disability. The heterogeneity of presentation of RA and subsequent disease course is such that pharmacological treatment will need to be adapted to the needs of the individual. Optimum suppression of inflammation is considered the most effective means to achieve optimal outcomes. In early RA, treatment is initiated with a csDMARD, most commonly methotrexate, unless contraindicated. Methotrexate can be administered either orally or parenterally and has a large dose-titratable range. Because of these features, as well as its efficacy, safety, and cost-effectiveness, methotrexate holds a unique place in the management of RA (Taylor et al. 2019). Methotrexate monotherapy is recommended as an initial pharmacological strategy, but it can also be used as an “anchor drug” in combination with another csDMARDs or targeted therapies. Symptomatic benefit following initiation of csDMARDs tends to be relatively slow in onset, often taking many weeks. Short-term glucocorticoids are often used as a “bridging” therapy when a more slowly acting oral csDMARD is initiated so that rapid suppression of synovitis can be achieved before the slower benefits of the csDMARD are expressed. Corticosteroids can be used effectively in a range of dose regimens and routes of administration but should be tapered as rapidly as clinically feasible.
There have been unprecedented advances in our understanding of the pathophysiology of RA over the last few decades which have been translated into a broad range of efficacious, so-called targeted, therapies directed against relevant cells and molecules contributing to disease pathogenesis. These include parenterally administered biologic DMARDs (bDMARDs) and orally available targeted synthetic DMARDs (tsDMARDs). bDMARDs are protein-based drugs derived from living organisms that are designed to either inhibit or augment specific component of the immune system.
The first bDMARDs to be approved were TNF inhibitors. The first generation of bDMARDs, referred to as bio-originators, was approved with finite patent life. Following patent expiry of the earliest bio-originator bDMARDs, biosimilars have emerged. A biosimilar is a biological medicinal product that is highly similar to an already authorized original biological medicinal product (reference medicinal product or bio-originator) in terms of quality, safety, and efficacy, based on a comprehensive comparability exercise. Following their introduction to the clinic, in many health-care economies high procurement costs of bio-originator bDMARDs limited their access to patients meeting eligibility criteria. In the case of the class of anti-TNF bDMARDs, bio-originators included three monoclonal antibodies (infliximab, adalimumab, and golimumab), a TNF receptor fusion protein (etanercept), and a pegylated antibody-binding fragment (certolizumab). There are now several biosimilars of infliximab, etanercept, and adalimumab which are introducing cost competition and may potentially widen patient access to the anti-TNF bDMARD class. Another class of bDMARDs directed against cytokines comprise antibodies directed against interleukin-6 receptor (IL6R). Two bio-originator anti-IL6R mAbs have been approved, tocilizumab and sarilumab.
An entirely different treatment approach to the blockade of pro-inflammatory cytokines is the targeting of cells implicated in the persistence of RA. At present there are two other classes of bDMARD with specificity for cellular targets, namely, cell surface molecules associated with B cell subsets, most notably CD20, and co-stimulation molecules expressed on antigen-presenting cells that recognize cognate ligands on T cells. There is one approved bio-originators directed against the CD20 antigen expressed on a B cell subset, rituximab, and there are now approved biosimilars. The bio-originator abatacept is the only representative of the final class of currently approved bDMARD. It is an inhibitor of the CD28-CD80/86 co-stimulatory signal necessary for T cell activation comprising a fusion protein composed of the Fc region of the human IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).
In contrast to bDMARDs, which are large molecular weight proteins that must be injected and are incapable of penetrating the lipid bilayer of cell membranes, tsDMARDs are low molecular weight, orally available, “small molecules.” The only tsDMARDs currently available for the treatment of RA are JAK inhibitors or “jakinibs,” multi-cytokine inhibitors that can cross the cell membrane to block activity of one or more cytoplasmic JAKs. Tofacitinib selectively inhibits JAK1 and JAK3 and was the first JAK inhibitor to be approved, initially with twice daily dosing. A modified release formulation for once daily use has since been developed. Baricitinib selectively inhibits JAK1 and JAK2 and is dosed once daily. Both drugs have undergone extensive clinical trials and demonstrated rapid improvements in symptoms and signs when used in combination with concomitant MTX, other conventional disease-modifying anti-rheumatic drugs (cDMARDs), or as monotherapy (Taylor 2019a) with benefits reported as early as 2 weeks. Both agents inhibit structural damage progression. Remarkably, in MTX inadequate responders, the combination of MTX and baricitinib 4 mg od demonstrated superiority for ACR20 responders and DAS28-CRP reduction over the standard of care biologic adalimumab used with background MTX. Other JAK inhibitors in development include upadacitinib and filgotinib, both with selectivity for JAK1. Both drugs have demonstrated efficacy in combination with MTX and as monotherapy in phase III trials.
In summary, the introduction to the clinic in the late 1990s of bDMARDs directed against TNF heralded the beginning of the era of targeted therapies. Other bio-originator bDMARDs with distinct mechanisms of action followed, and most recently, JAKs have been validated as a therapeutic target with the introduction of orally available small molecular therapies. This expansion of therapeutic options has contributed to a greatly improved outlook for people living with RA and set a high standard for symptom control and prevention of joint destruction.
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