The disease rheumatoid athritis (RA) is a manifestation of chronic inflammatory disorder. There are several drugs available in the market for RA, but they are incapable of eliminating the root cause of the chronic inflammation. They rather help to relieve the symptoms by acting on the pharmacological mediators and subdueing the inflammatory response. In this article a brief overview of RA and monoclonal antibody therapies against RA are discussed.
RA: RA is a common autoimmune disorders that affect approx. 0.5%–1% of adult population. It is characterised by inflammation of synovium accompanied by articular bone and cartilage damage. The synovium layer surrounds the joint and secretes the synovial fluid.
Sign and symptoms: The primary symptoms are joint pain, stiffness, swelling, redness and warmth. The joints of the hands and feet are the first to be affected and it typically develops symetrically on both side of the body. It can also cause other symptoms that do not directly corelate like fatigue, loss of apetite, inflammation to the lining around heart, heart muscle, lungs, damage to other parts of the body like skin, eyes, bones, kidneys, liver and other systemic disorders.
Cause: The precise cause of the disease remains elusive. A genetic bias has been oberseved associated with several loci like HLA-DRB1, PTPN22, PADI4, STAT4, TRAF1-C5 and TNFAIP3, that predisposes an individual to RA. Moreover, environmental factors like smoking and infection also ehances the risk of RA. These factors prime the immune system for an anticitrulline repsonse.
Citrulline: Citrulline is a post-translational modification (deimination) of arginine, catalysed by the enzyme peptidyl-arginine-deiminase (PAD). In RA the body looses tolerance for citrulline containing self proteins, resulting in anticitrulline antibody (ACA) response. These citrullinated proteins are present in the synovial membrane (eg. protein fibrin), that results in the manifestation of RA. In approx 67% cases of RA ACAs are present, which are also used to diagnose RA.
Pathogenesis/biology of RA:
(a) Adpative response: As the body mistakenly identifies self citrullinated proteins as foreign entities, it elicits an immune response against them. Peptides from citrullinated proteins are presented by the antigen presenting cells like dendritic cells (myeloid or plasmacytoid in synovium) to naive TH0 cells, which differentiates to CD4+ TH cell and induces production of antibodies by B cells. The antibodies produced are the anticitrulline antibody and anti-rheumatoid factor antibody (IgM and IgG). The anti-rheumatoid factor antibody work against the Fc portion of IgG antibodies. Moreover, several cytokines in the synovium like TGFβ, IL-1β, IL-6, IL-23, IL-21, which produced by macrophages and dendritic-cell, support the differentiation of T0 to TH17/TH1 cells but not to regulatory cells. This helps to sustain the inflammatory response.
(b) Immune complexes: The immune complexes of IgG, IgM and complement system are found to be depositied in the synovial fluid. These are immunogenic and are thought to be the cause of anti-rheumatoid factor antibodies produced by B-cells.
(c) Inflammatory response and cytokines: Macrophages take the center stage in the innate immune response at the synovium. Pattern-recognition receptors like Toll-like receptor 2, 3, 4 or 6 are known to activate the macrophages, which then induces inflammatory response either by cell contact or through cytokines. The key mediators of cell migration and inflammation are cytokines TNF-α, IL-6 and IL-1. But a complex network cytokines secreted by various other immune cells are also involved in pathogenesis of RA, some of them are:
- Macrophages produce TNF-α, IL-6, IL-1 cytokines. The major inflammtory response is brought about by the pro-inflmmatory cytokines TNF-α and IL-6, along with cytokines like IL-1, VEGF and IL-17.
- The TH17 cell and the macrophage activate each other by contact and by cytokines like IL-18, IL-15, IL-16 and TNFa
- Macrophages stimulates chrodocytes and osteoblasts with the help of cytokines IL-1, TNF, RANKL, M-CSF and IL-17.
- The antibody produced by B cell activate the macrophages.
- Cytokines VEGF, βFGF from macrophage stimulates angiogenesis, that is required to maintian an increased blood supply. VEGF is an endothelial cell mitogen and enhances vascular permeability.
- Cytokines IL-1, TNF, IL-6, TGFβ, IL-17, IL-32 released by the macrophage causes synovial hyperplasis
- The TH17 cells activate the osteoclast and chondrocytes by IL-17, RANKL and T-cell contact–mediated activation. This activation of osteoblast occurs indirectly via activation of synovial fibroblast by IL-17, which then secrete RANKL that acts on osteoblast precursor to differentiate into osteoclast. Bone erosion is caused by the osteoclasts. The activation of chondrocytes, is also via synovial fibroblast which release IL-1, IL-6 and TNFa for chondrocyte stimulation. The chrondocytes then release several proteases like matrix metalloproteinases (MMPs) that results in cartilage destruction.
- MMPs are also secreted by synovial fibroblast cells, leukocytes and macrophages that damages the articular cartilage.
- Mast cells and natural killer cells are found in the synovium, while neutrophils in the synovial fluid (migration from blood to tissue to inflammation site). Immune complexes and cytokines activate the neutrophils which then releases cytokines like TNF, IL-1, IL-18, IL-15 and IL-6, reactive oxygen or nitrogen species that enhaces the hypoxic conditions induced by inflammation. Mast cells also secrete pro-inflammtory cytokines and proteases. Several cytokines released by the macrophages activate the mast cells and neutrophils and vice versa.
mAb therapy for RA: Several biologic molecules called monoclonal antibodies are available for moderate to severe forms of RA. They are effective in relieving the symptoms of RA. Each of these mAbs have a different target, mode of action and safety profile. The decision to choose one therapy over other is based on pharmacology, clinical data, physician’s preference, patient information and specific RA.