Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

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: IL-6; TNF; autoimmunity; rheumatoid arthritis.

Figure 1

Factors contributing to rheumatoid arthritis (RA) development. Both environmental (smoking, obesity, as well as infections with certain pathogens such as Porphyromonas gingivialis) and genetic factors (epigenetic modifications, genetic polymorphisms influencing antigen presentation (e.g., the HLA genes HLA-DRB1*01/04), T- and B cell function, cytokine production, and signal transduction following immune cell activation) contribute to the development of RA. Moreover, also synovial injury and hyperplasia of synovial fibroblasts can contribute to the establishment of RA via the triggering of inflammatory conditions. Overall, these processes lead to the modification of autoantigens (mostly by citrullination) which generates neoepitopes by a loss of surface charge and an increased susceptibility to proteolytic degradation.

Figure 2

Pathomechanism of RA. Inflammation in RA is induced by autoreactive Th1- or Th17 T cells primed in the lymph nodes (LN) or locally by activated Antigen-presenting cells (APCs) that present autoantigen-derived peptides. In the affected joint, activated autoreactive T cells subsequently activate macrophages and fibroblasts via the secretion of the pro-inflammatory mediators TNF-α, IL-17, IFN-γ, and receptor activator of nuclear factor KB ligand (RANK-L). Activated macrophages in turn secrete large amounts of the strongly pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 which promote the establishment and maintenance of an inflammatory milieu in the synovium. Activated T cells also provide help to autoreactive B cells resulting in the production of anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) autoantibodies. These autoantibodies further drive inflammation by either direct macrophage activation of triggering the complement cascade. In addition, RANK-L produced by the activated fibroblasts promotes the differentiation of osteoclasts from macrophages. Together with fibroblast-derived matrix metalloproteases (MMPs), osteoclasts, and antibodies, activated neutrophils mediate inflammation-dependent cartilage destruction and bone erosion.

Figure 3

Clinical parameters frequently used in the diagnosis of RA and their quantification using the 2010 ACR-EULAR (American College of Rheumatology-European League against Rheumatism) classification criteria. Clinical diagnosis (left) of RA relies on joint examination (mainly via sonography, but also by magnetic resonance imaging (MRI)), and the serological determination of RA-specific autoantibodies (Rehmatoid factor (RF) and ACPAs) and detection of elevated levels of C-reactive protein (CRP) and an increased erythrocyte sedimentation rate (ESR). The 2010 ACR-EULAR RA classification criteria (right). Scoring parameters are number and size of the involved joints, the presence and concentration of RA-specific ACPAs and RF autoantibodies, presence of abnormal levels of CRP and increased ESR, and overall duration of disease symptoms. According to the 2010 ACR-EULAR RA classification criteria a RA diagnosis is made if the overall score is greater than six and other causes for synovitis (see above) can be excluded.

Figure 4

Overview over the available treatment strategies for RA patients. The possible treatments for RA are divided into four main strategies. Non-pharmacological treatments include a combination of physical therapy, patient counseling in lifestyle factors, and surgical procedures to remove and/or replace the affected joint and bone areas. Non-steroidal anti-inflammatory drugs (NSAIDs) are usually used only for symptomatic treatment and/or until the RA diagnosis is established since these drugs reduce pain and stiffness in the affected patients but have no influence on disease progression. In contrast to this, non-specific immune system suppression via the application of glucocorticoids has rapid disease-modifying effects but its long-term usage is limited due to severe side-effects. Finally, disease-modifying anti-rheumatic drugs (DMARDs) are used to target inflammation and prevent further joint damage and disease progression.

Figure 5

Overview over the currently available DMARDs. The different DMARDs are grouped into synthetic (further subdivided into conventional and targeted synthetic DMARDs) and biological DMARDs. Biological, antibody-based, DMARDs include anti-TNF-α and anti-TNF-R antibodies, anti-IL-6- and anti-IL-6R antibodies, B cell depleting anti-CD20 antibodies, as well as inhibitors of T cell co-stimulation. Abbreviations: JAK: Janus activated kinase, αTNF-α/αIL-6: anti-TNF-α/IL-6 antibody, sTNF-R: anti soluble TNF receptor antibody, αIL-6R: anti Il-6 receptor antibody, Fab: antibody fragment, inh.: inhibitor.

Figure 6

Molecular mode of action of Janus activated kinase (JAK) inhibitors. Binding of pro-inflammatory cytokines (e.g., IL-6, common γ-chain-containing cytokines (e.g., IL-2 or IL-15), type I and II interferons, or granulocyte-monocyte colony stimulating factor (GM-CSF)) to their respective receptors on the surface of immune cells triggers the recruitment of JAKs. JAKs subsequently phosphorylate the intracytoplasmic parts of the respective receptors, inducing the phosphorylation, auto-homodimerization, and nuclear translocation of different signal transducer and activator of transcription (STAT) molecules. In the respective cell’s nucleus STAT dimers promote the expression of many pro-inflammatory genes that initiate and sustain joint inflammation and tissue damage. The targeted DMARDs tofacitinib and baricitinib inhibit this activation of JAKs and thereby prevent immune cell activation and subsequent inflammatory responses.

Figure 7

Common side-effects of the available DMARDs. The side-effects are subdivided into the three DMARD classes conventional synthetic, targeted synthetic, and biological. Of note, in addition to common side-effects such as GIT problems, cytopenia, elevation of cholesterol, and liver damage, both targeted synthetic and biological DMARDs result in increased frequencies of infections, likely caused by the inhibition/neutralization of the respective inflammatory mediators and therefore the induction of protective immune responses. TB: tuberculosis.

Figure 8

Common treatment plan for the management of RA. Upon initial RA diagnosis (see above) non-pharmacological treatment is provided alongside the application of methotrexate and short-term application of glucocorticoids to reduce joint inflammation, resulting in remission/significantly lower disease activity rates in 30–50% of patients. In non-responsive patients triple therapy consisting of the addition of the conventional synthetic DMARDs hydrochloroquine and sulfadiazine to methotrexate treatment can achieve remission in an additional 10–27% of the patients. Subsequent application of either JAK inhibitors or biological DMARDs can achieve remission/reduced disease activity in an additional 30–40% of RA patients. For optimal treatment it is necessary to constantly reassess both the individual patient’s disease state and efficacy of treatment to make timely adjustments. Once the patient has reached stable remission over at least 6 months, sequential tapering or dose reduction of the administered drugs can be considered in order to reduce treatment-associated side-effects and costs.