World Arthritis Day | ACRO with You to Safeguard Joint Health

October 12 marks World Arthritis Day, established to raise global awareness of this highly disabling disease. Among its various forms, Rheumatoid Arthritis (RA) stands out as one of the most destructive, affecting the health and quality of life of approximately 23.7 million people worldwide. Beyond joint swelling, pain, and stiffness, RA is a systemic autoimmune disorder that can also involve the heart, lungs, vasculature, and other organs. Without timely and standardized treatment, up to 30% of patients may develop disability within five years of onset.

https://doi.org/10.1186/s13287-025-04495-z

General features of RA

Contrary to common belief, RA is not confined to the elderly. Its peak onset occurs between ages 35 and 50, primarily affecting young and middle-aged adults, with women facing nearly three times the risk compared to men. The disease is driven by aberrant immune activation, in which the immune system mistakenly attacks synovial tissue, leading to chronic inflammation and progressive joint destruction. While RA remains incurable, its hallmark clinical features include symmetric, recurrent inflammation of the small joints in the hands, wrists, and feet. These symptoms are often accompanied by systemic complications and can ultimately result in loss of joint function and disability.

Pathogenetic Mechanisms of RA: Why Does the Immune System Attack Its Own Joints?

The onset of RA begins with aberrant immune activation in the synovium. Under the combined influence of genetic predisposition (e.g., HLA-DRB1 alleles) and environmental triggers, the synovium progressively transforms into tertiary lymphoid–like structures populated by activated macrophage-like and fibroblast-like synoviocytes. These cells secrete high levels of proinflammatory cytokines such as IL-1, IL-6, and TNF-α, as well as matrix metalloproteinases (MMPs), fueling chronic inflammation and tissue destruction. Concurrently, CD4+ T cells become activated through antigen presentation and differentiate into pathogenic subsets such as Th17 cells, which produce cytokines including IL-17A, IL-17F, IL-22, and GM-CSF that further amplify the inflammatory cascade. Meanwhile, the function of regulatory T cells (Tregs)—normally critical for immune suppression—is impaired in the proinflammatory milieu. Together, these processes drive synovial hyperplasia, the formation of invasive pannus tissue, and the recruitment of additional immune cell infiltrates.

https://doi.org/10.3390/ijerph21060662

Pathogenetic mechanisms of RA

As the disease progresses, B cells intensify autoimmunity through multiple mechanisms. Activated B cells differentiate into plasma cells, producing rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPA). ACPAs not only activate the complement cascade and induce neutrophil extracellular trap (NET) formation, but also crosslink Fc receptors to stimulate macrophage release of TNF-α, creating a self-perpetuating inflammatory loop. The innate immune system also plays a central role in maintaining inflammation. Classically activated M1 macrophages secrete abundant proinflammatory mediators, while dendritic cells and innate lymphoid cells (ILCs) orchestrate immune amplification, with ILC3 cells producing IL-17 and IL-22. In contrast, ILC2 cells and regulatory B cells (Bregs), which normally contribute to immune tolerance, are markedly reduced during active disease, weakening immunoregulatory capacity. This interplay between innate and adaptive immunity establishes a vicious cycle that sustains synovial inflammation and ultimately drives irreversible joint damage.

Power Shift in RA Therapeutics: From TNF-α Dominance to a Landscape of Diverse Innovation

The RA drug market has evolved into a threefold landscape: TNF-α inhibitors as the traditional backbone, rapid expansion of emerging pathway therapies, and accelerated breakthroughs from innovative drugs.

As the first biologics to achieve large-scale adoption, TNF-α inhibitors long dominated the RA market. AbbVie’s adalimumab has generated more than $200 billion in cumulative sales over 20 years, holding the title of the world’s best-selling drug for a decade. Although it lost this position following patent expiration in 2023 and the entry of biosimilars, it remains a benchmark in the autoimmune therapeutics sector. Likewise, infliximab and etanercept have seen market share decline due to patent expirations, with 2024 global sales down 12.8% and 10% year-over-year, respectively.

Driven by rising clinical demands, therapies targeting upstream inflammatory pathways, particularly IL-17 and IL-23 inhibitors, are becoming mainstream. Novartis’s secukinumab surpassed $6.2 billion in 2024 sales, while Eli Lilly’s ixekizumab exceeded $3.6 billion, both sustaining double-digit growth on the strength of superior clinical response rates. Morphosys’s guselkumab, leveraging precise inhibition of the IL-23p19 subunit, reached $3.6 billion in 2024 global revenue—up 16.6% year-over-year—establishing itself as a dual growth driver in both RA and psoriasis.

Meanwhile, B cell–modulating therapies continue to play a vital role. Biogen’s rituximab (anti-CD20) and Rongchang Bio’s telitacicept (dual blockade of BAFF and APRIL to limit aberrant B-cell activation) reflect a diversified strategy and expanding market footprint.

https://doi.org/10.1038/s41413-018-0016-9

Cells and key receptors/pathways targeted by current RA therapy strategies

In recent years, the RA drug market has advanced along two parallel tracks: breakthrough innovation and expanded indications. In October 2023, Novartis’s secukinumab was approved for long-term maintenance therapy in RA, becoming the first IL-17 monoclonal antibody shown to slow structural joint damage. In March 2024, Eli Lilly’s ixekizumab received domestic approval for patients with inadequate response to tocilizumab, providing a targeted option for difficult-to-treat populations. Meanwhile, the uptake of biosimilars is accelerating, intensifying market competition and expanding affordable treatment options, particularly for patients transitioning from established biologics.

Approved originator biologics for RA (Source: Pharmacodia)

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