There are several drugs available in the market for RA, but they are incapable of eliminating the root cause of chronic inflammation. They rather help to relieve the symptoms by acting on the pharmacological mediators and subduing the inflammatory response.
Rheumatoid arthritis (RA) market is currently dominated by large-cap pharmaceutical and biotech companies such as AbbVie, Amgen, Roche, and Johnson & Johnson. Sales of RA medications topped $22 billion worldwide in 2014. While the currently available therapies are effective at alleviating the symptoms of RA, almost all of them are associated with serious adverse side effects, thus representing an opportunity for safer therapies to enter the market, some of the new therapies are:
In late 2019, Gilead Sciences, Inc., submitted a new drug application to the FDA for the selective Janus Kinase 1 (JAK-1) inhibitor filgotinib (GLPG0634). The application seeks approval for the oral medication as a treatment for adults “who are living with moderate-to-severe” RA. The JAK-1 inhibitor works by hindering the activity of one or more of the Janus kinase enzymes, which are involved in cellular signalling pathways that causes the inflammation and immune responses observed in RA.
As the highly selective JAK-1 inhibitor targets a specific enzyme, researchers hypothesize that this narrower target could mean fewer side effects and higher potential doses.
Filgotinib has completed phase 3 clinical trials. In addition to the application submitted to the FDA, Gilead has also submitted a priority review application, which may speed up the approval process.
ART-I02 is being investigated by the biopharmaceutical company Athrogen. It’s a human interferon β (hIFN-β) gene therapy medication for the local treatment of RA.
Pre-clinical studies have found that one single injection of ART-I02 in animals is beneficial for managing the symptoms of RA and other types of arthritis, including osteoarthritis.
This drug used to be designated as CDD-450, but when Aclaris Therapeutics, Inc., acquired the company that was developing it, the designation changed to ATI-450. (Alpha-numeric designations are assigned before generic drug names)
It’s classified as a selective p38-alpha MAPK inhibitor, blocking cellular communications that can result in inflammation.
A 2018 study reported in the Journal of Experimental Medicine found that ATI-450 can reduce the damage associated with RA.
In early 2020, Aclaris announced positive results from its first Phase I human trial and an intent to move on to Phase II studies.
Size of Market
US Rheumatoid Arthritis Treatment Market Value was set to Reach $9.3 Billion. The US treatment market for Rheumatoid Arthritis (RA) is set to increase in value from $6.4 billion in 2013 to $9.3 billion by 2020, representing a Compound Annual Growth Rate (CAGR) of 5.5%, says business intelligence provider GBI Research
Signs and symptoms of RA: 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 symmetrically on both sides of the body. It can also cause other symptoms that do not directly correlate like fatigue, loss of appetite, inflammation of the lining around the heart, heart muscle, lungs, and damage to other parts of the body like skin, eyes, bones, kidneys, liver, and other systemic disorders.
Causes: The precise cause of the disease remains elusive. A genetic bias has been observed to be associated with several loci like HLA-DRB1, PTPN22, PADI4, STAT4, TRAF1-C5, and TNFAIP3, which predisposes an individual to RA. Moreover, environmental factors like smoking and infection also enhance the risk of RA. These factors prime the immune system for an anticitrullinated response.
Citrulline: Citrulline is a post-translational modification (deimination) of arginine, catalyzed by the enzyme peptidyl-arginine-deiminase (PAD). In RA the body loses tolerance for citrulline containing self-proteins, resulting in anti-citrulline antibody (ACA) response. These citrullinated proteins are present in the synovial membrane (eg. protein fibrin), which results in the manifestation of RA. In approx 67% of cases of RA ACAs are present, which are also used to diagnose RA.
Pathogenesis/biology of RA
(a) Adaptive 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 differentiate to CD4+ TH cell and induces the 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 are 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 systems are found to be deposited 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 receptors 2, 3, 4, or 6 are known to activate the macrophages, which then induce 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 complex network cytokines secreted by various other immune cells are also involved in the pathogenesis of RA, some of them are:
- Macrophages produce TNF-α, IL-6, IL-1 cytokines. The major inflammatory response is brought about by the pro-inflammatory 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 stimulate chondrocytes and osteoblasts with the help of cytokines IL-1, TNF, RANKL, M-CSF and IL-17.
- The antibody produced by B cell activates the macrophages.
- Cytokines VEGF, βFGF from macrophage stimulates angiogenesis, which is required to maintain 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 secretes RANKL that acts on osteoblast precursor to differentiate into osteoclast. Bone erosion is caused by osteoclasts. The activation of chondrocytes is also via synovial fibroblast which releases IL-1, IL-6 and TNFa for chondrocyte stimulation. The chondrocytes then release several proteases like matrix metalloproteinases (MMPs) that result in cartilage destruction.
- MMPs are also secreted by synovial fibroblast cells, leukocytes and macrophages that damage the articular cartilage.
- Mast cells and natural killer cells are found in the synovium, while neutrophils are in the synovial fluid (migration from blood to tissue to inflammation site). Immune complexes and cytokines activate the neutrophils which then release cytokines like TNF, IL-1, IL-18, IL-15 and IL-6, reactive oxygen or nitrogen species that enhance the hypoxic conditions induced by inflammation. Mast cells also secrete pro-inflammatory cytokines and proteases. Several cytokines released by the macrophages activate the mast cells and neutrophils and vice versa.
Monoclonal antibodies 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 has a different target, mode of action, and safety profile. The decision to choose one therapy over others is based on pharmacology, clinical data, physician’s preference, patient information, and specific RA.
1. Blocking the immune system in rheumatoid arthritis. The Pharmaceutical Journal (2016), doi:10.1211/PJ.2016.20201090.
2. C. Croia, R. Bursi, D. Sutera, F. Petrelli, A. Alunno, I. Puxeddu, One year in review 2019: pathogenesis of rheumatoid arthritis. Clin. Exp. Rheumatol. 37, 347–357 (2019).
3. I. B. McInnes, G. Schett, Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 7, 429–442 (2007).
4. I. B. McInnes, G. Schett, The Pathogenesis of Rheumatoid Arthritis. N Engl J Med. 365, 2205–2219 (2011).
5. Q. Guo, Y. Wang, D. Xu, J. Nossent, N. J. Pavlos, J. Xu, Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 6, 15 (2018).
6. Rheumatoid arthritis. nhs.uk (2018), (available at https://www.nhs.uk/conditions/rheumatoid-arthritis/).