1. Introduction

Rheumatoid arthritis (RA) poses a significant challenge as an autoimmune disorder, affecting millions of individuals worldwide and presenting a substantial global health concern. To gain a deeper and more comprehensive understanding of this intricate disease and to pave the way for the development of more effective treatments, the scientific community has increasingly turned to the use of animal models. In this quest for insights and therapeutic breakthroughs, two prominent models have taken the forefront: Adjuvant-Induced Arthritis (AIA) and Pristane-Induced Arthritis (PIA). These models offer unique characteristics, distinct advantages, and, like any scientific tool, come with their limitations. In part two of this series, we will delve into the unique characteristics of AIA and PIA, exploring their advantages as research tools and discussing their limitations. By doing so, we aim to illuminate the pivotal role these animal models play in advancing our understanding of RA and in the ongoing quest to discover novel treatments and interventions that can significantly improve the lives of those affected by this devastating autoimmune disorder.

2. Adjuvant-Induced Arthritis (AIA): Unraveling the Pathways to Autoimmunity

AIA, initially induced by inoculating rats with a Freund-type water-in-oil emulsion, has evolved into a popular model for studying RA and related arthritic conditions. This monophasic, sub-chronic type of arthritis exhibits aggressiveness, often culminating in complete ankylosis and permanent joint deformities ^[1]. Clinically and serologically, AIA mimics many aspects of human RA, including elevated erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) levels ^[1]. Moreover, the histopathological, radiological, and immune changes in AIA closely resemble those seen in human RA, making it a valuable model for screening and testing anti-arthritic drugs ^[2][3].

One distinguishing feature of AIA is the well-defined joint-associated target autoantigen, allowing researchers to investigate how external triggers lead to self-recognition. To induce AIA in rats, a single injection of incomplete or complete Freund adjuvant with Mycobacterium tuberculosis (MTB) is administered into the tail base ^[4]. Notably, different rat strains exhibit varying genetic sensitivities to AIA. Lewis rats are often preferred for AIA studies due to their higher incidence of severe and consistent disease, while Sprague-Dawley (SD) rats are less genetically susceptible but offer a more cost-effective alternative ^[2]. The choice of rat strain and the variability in disease severity make AIA a versatile model for testing new anti-arthritis drugs ^[2].

However, the AIA model comes with its challenges. Even within inbred Lewis rats, the incidence and severity of arthritis can fluctuate significantly, limiting the predictability of the model. This variability necessitates careful consideration of disease intensity when evaluating different drug classes, highlighting the importance of optimizing experimental conditions.

3. Pristane-Induced Arthritis (PIA): A Unique Perspective on Chronic Inflammation

In contrast to AIA, PIA is induced by injecting the synthetic mineral oil pristane intraperitoneally (i.p.) in mice and rats ^[5][6]. PIA is characterized by a severe, chronic inflammatory arthritis, with variations in disease onset and incidence among susceptible strains ^[7]. Dark Agouti rats are highly sensitive to PIA, exhibiting a rapid onset of acute arthritis, leading to recurrent attacks, and eventually, chronic arthritis ^[7]. This model offers a remarkable 100% rate of osteoclast formation, inflammatory cell infiltration, bone erosion, and new bone formation ^[8].

The intriguing aspect of PIA is its induction by a non-infectious, non-antigenic oil, pristane ^[6]. Furthermore, there is a notable delay between exposure to pristane and the development of the disease ^[7]. The exact mechanisms underlying PIA are still under investigation, but it is believed that pristane promotes autoimmune responses through immune activation triggered by antigens found on microorganisms present in the environment ^[9]. This hypothesis is supported by the observation that maintaining mice in a specific pathogen-free (SPF) environment inhibits PIA development, and returning these mice to a normal environment reinstates susceptibility ^[10].

Histologically, PIA exhibits synovial hyperplasia, polymorphonuclear infiltration, periostitis, cartilage erosion, and progressive marginal erosion, closely resembling the pathological features of RA (32). Furthermore, serological markers such as rheumatoid factor (RF) and antibodies against heat shock proteins and type I and II collagen have been detected in PIA, mirroring the immune responses observed in human RA ^[6][10].

4. Comparative Analysis and Future Perspectives

Both AIA and PIA offer unique advantages and challenges for researchers studying RA. AIA, primarily conducted in rats, closely mimics human RA in terms of clinical, serological, and histopathological characteristics. Its well-defined joint-associated target autoantigen allows for in-depth investigations into the mechanisms underlying autoimmune responses. However, the variability in disease severity across rat strains necessitates careful experimental planning. PIA, on the other hand, stands out for its induction by a non-antigenic oil, shedding light on the complex interplay between environmental triggers and autoimmunity. Its chronic nature and resemblance to RA histopathologically and serologically make it a valuable model for long-term studies. However, the exact mechanisms driving PIA remain elusive.

In the future, researchers can capitalize on the strengths of both models. Combining insights from AIA and PIA could provide a more comprehensive understanding of the multifaceted nature of RA. Additionally, refining experimental techniques to control disease severity in AIA and elucidating the precise environmental triggers in PIA may enhance the translational relevance of these models.

5. Conclusion

In conclusion, AIA and PIA have significantly enriched our understanding of RA pathogenesis and have played pivotal roles in evaluating potential therapeutic interventions. These animal models, distinguished by their distinct characteristics, have provided invaluable insights into the intricate mechanisms that underlie autoimmune arthritis. AIA and PIA, by replicating key aspects of RA in controlled settings, have allowed researchers to dissect the complex interplay of genetic, environmental, and immunological factors contributing to the disease. They have served as reliable platforms for studying disease progression, immune responses, and the effects of novel treatments.

As the pursuit of effective treatments for RA continues, AIA and PIA remain indispensable tools. Their contributions extend beyond RA alone, as the knowledge gained from these models also informs our understanding of related arthritic conditions. In the ongoing battle against RA, these models stand as beacons of hope, guiding researchers toward innovative therapies that have the potential to alleviate the suffering of millions affected by this debilitating autoimmune disorder.