cells Review Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis 1 2, 1, , Yen-Ju Lin , Martina Anzaghe y and Stefan Schülke * y 1 Paul-Ehrlich-Institut, Vice President’s Research Group 1: Molecular Allergology, 63225 Langen (Hesse), Germany; [email protected] 2 Paul-Ehrlich-Institut, Product Testing of Immunological Biomedicines, 63225 Langen (Hesse), Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-6103-775209 These authors have contributed equally to this manuscript. y Received: 23 January 2020; Accepted: 30 March 2020; Published: 3 April 2020 Abstract: Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs. Keywords: rheumatoid arthritis; autoimmunity; TNF; IL-6 1. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting the joints. It is characterized by a progressive symmetric inflammation of affected joints resulting in cartilage destruction, bone erosion, and disability [1]. While initially only a few joints are affected, in later stages many joints are affected and extraarticular symptoms are common (see below) [2]. With a prevalence ranging from 0.4% to 1.3% of the population depending on both sex (women are affected two to three times more often than men), age (frequency of new RA diagnoses peaks in the sixth decade of life), and studied patient collective (RA frequency increases from south to north and is higher in urban than rural areas) [1–5], RA is one of the most prevalent chronic inflammatory diseases [1]. Clinically, the symptoms of RA significantly differ between early stage RA and insufficiently treated later stages of the disease. Early stage RA is characterized by generalized disease symptoms such as fatigue, flu-like feeling, swollen and tender joints, and morning stiffness; and is paralleled by elevated levels of C-reactive protein (CRP) and an increased erythrocyte sedimentation rate (ESR) [6]. In contrast, insufficiently treated RA displays a complex clinical picture with the occurrence of serious systemic manifestations such as pleural effusions, lung nodules and interstitial lung Cells 2020, 9, 880; doi:10.3390/cells9040880 www.mdpi.com/journal/cells Cells 2020, 9, 880 2 of 43 disease, lymphomas, vasculitis in small or medium-sized arteries, keratoconjunctivitis, atherosclerosis, hematologic abnormalities (e.g., anemia, leukopenia, neutropenia, eosinophilia, thrombocytopenia, or thrombocytosis), joint malalignment, loss of range of motion, bone erosion, cartilage destruction, and rheumatic nodules (in detail reviewed in [1,2,7]). Taken together, these systemic manifestations caused by the chronic inflammatory state in RA patients result in an increased mortality. 2. Development of Rheumatoid Arthritis While the cause of RA is unknown, both genetic and environmental factors were shown to contribute to RA development [8] (Figure1). As it is hypothesized for other autoimmune diseases, it is likely that the initial establishment of RA requires two separate events: (1) genetic predisposition of the respective patient resulting in the generation of autoreactive T and B cells, and (2) a triggering event, such as viral and bacterial infections or tissue injury, providing the activated Antigen-presenting cells (APCs) to activate the previously generated autoreactive lymphocytes, resulting in disrupted tolerance and subsequent tissue/organ destruction. Therefore, RA likely develops in genetically predisposed individuals due to a combination of genetic variation, epigenetic modification, and environmental factors initiated by a stochastic event (e.g., injury or infection) [1]. Risk factors for the development of RA were reported to include smoking, obesity, exposition to UV-light, sex hormones, drugs, changes in microbiome of the gut, mouth, and lung, periodontal disease (periodontitis), and infections [1,2,5,7,9,10]. Among these factors, the link between periodontal diseases and RA development is especially interesting. While the association between periodontitis and RA development was recognized as early as the 19th century [11], recent studies have demonstrated that infections with the common periodontal bacterium Porphyromonas gingivalis can result in the induction of autoimmune responses via the citrullination of host peptides [2,9]. During this process, which is catalyzed by the enzyme protein arginine deiminase (PAD), positively charged arginine residues of “self” proteins are converted into neutral citrulline residues, resulting in a net loss of surface charge, an increased susceptibility of the citrullinated “self” proteins to protein degradation, and the generation of neoepitopes [2,9]. This breach of local tolerance by P. gingivalis expressing PADi4 (facilitating the conversion of arginine to citrulline) promotes autoimmune responses as well as the downstream generation of anti-citrullinated protein antibodies (ACPAs) [12]. In addition, other viral (Epstein–Barr virus) and bacterial infections (Proteus mirablis, Escherichia coli) were suggested to trigger the development of RA by mechanisms of molecular mimicry caused by similarities between amino acid sequences of “self” antigens and certain bacterial- or viral proteins [1,7,13–15]. Besides citrullination, carbamylation of lysine residues also contributes to the generation of neoepitopes from several “self” proteins (e.g., collagen, fibrinogen, or vimentin) and the subsequent breaking of immunological “self” tolerance [7,16]. Since both a family history of RA increases the risk to develop RA three to five times and concordance risk rates in identical twins are increased compared to both non-related control collectives and non-identical twins, we have to assume that genetic factors also contribute to RA development [1,17]. Genome wide association studies using single nucleotide polymorphisms (SNPs) have suggested more than 100 loci to be associated with RA development [1,18]. As expected, many of these loci are involved in the induction, regulation, and maintenance of immune responses and are shared with other chronic inflammatory diseases. Some of the RA risk factors are the presence of certain HLA alleles [19], alterations in co-stimulatory pathways (e.g., via changes in CD28 or CD40 expression) [20], as well as changes in innate immune cell activation [21], lymphocyte activation thresholds (e.g., PTPN22) [22], or cytokine signaling [1]. Among the genes contributing to RA development, HLA-DRB1 alleles (DRB1*01 and DRB1*04; DQ8) account for approximately 50% of the observed genetic susceptibility [2,23,24]. Studies have suggested that these HLA alleles, which share amino acid sequences within their peptide binding grooves, are able to preferentially present certain Cells 2020, 9, 880 3 of 43 Cells 2019, 8, x FOR PEER REVIEW 3 of 42 peptideHLA-DRB1 epitopes alleles derived are associated from relevant with RAmore autoantigens aggressive [ 1bone,25]. erosion In addition, and someincreased of these mortality HLA-DRB1 rates alleles[26]. are associated with more aggressive bone erosion and increased mortality rates [26]. TakenTaken together, together, these these findings findings suggest suggest a stronga strong T cell-dependent T cell-dependent component component in RA in andRA and indeed indeed Th1 andTh1 Th17and Th17 T cell T subsets cell subsets are the are predominant the predominant cell types cell types found found in the in inflamed the inflamed synovial synovial tissue tissue (see also(see belowalso below “pathomechanism “pathomechanism of RA”) of RA”) [2,27 ].[2,27]. FigureFigure 1.1.Factors Factors contributing contributing to rheumatoid to rheumato arthritisid arthritis (RA) development. (RA) development. Both environmental Both environmental (smoking, obesity,(smoking, as obesity, well as infectionsas well as infections with certain with pathogens certain pathogens such as Porphyromonas such as Porphyromonas gingivialis gingivialis) and genetic) and factorsgenetic (epigenetic factors (epigenetic modifications, modifi geneticcations, polymorphisms genetic polymorphisms influencing influencing antigen presentation antigen presentation (e.g., the HLA(e.g., genesthe HLA HLA-DRB1*01 genes HLA-DRB1*01/04),/04), T- and B cell T- function, and B ce cytokinell function, production,