Rheumatoid Arthritis: How Much Progress Have We Made?

Rheumatoid arthritis (RA) is an autoimmune disease of the joints (i.e., inflammatory arthritis [IA]) that inflames the body (Deane & Holers, 2019). RA affects 1-2% of the world’s population and is two to three times greater in women than men (Ruffing & Bingham, 2019). RA can present itself at any age, yet statistics have shown it is more common during an individual’s third to sixth decades (Ruffing & Bingham, 2019). RA primarily attacks the joints in the hands, wrists, and knees, which causes inflammation along the joint lining and damages the joint tissue (Centers for Disease Control and Prevention, 2019). This chronic inflammatory disease can cause many significant burdens for a patient: a) muscle deficiency, b) decline in quality of life, c) comorbid risk, d) medical costs, and work disability (Smolen, Aletaha, & McInnes, 2016).

While it is true that modern advances in medical treatment have helped mitigate some symptoms and burdens, the specific cause of RA remains unknown. Due to the extensive amount of research methodologies, it is beyond the scope of this review to discuss all factors involved. Therefore, a summary of the research will address 1) the history of clinical descriptions for RA, 2) model of RA development, 3) potential for prevention, 4) current treatment therapies, and drug safety.

History of RA Clinical Descriptions

Evidence for the existence of RA dates back to ancient texts, various artwork, and even autopsies of skeletons (Entezami, Fox, Clapham, Chung, & Kevin, 2011). Due to the lack of scientific foundation across history, there is still controversy over the etiology of RA. The literature states the creation of three schools of thought from multiple periods throughout history: (a) ancient origin, (b) new origin, and (c) new world to old-world transfer concept (Entezami et al., 2011). In 1800, Augustin Jacob Landre-Beauvais hypothesized his patient was suffering from an unknown condition he called Goutte Asthenique Primitive, or primary asthenic gout (AJ, 2001). Later, others identified that Landre-Beauvais’s hypothesis was defective and not related to gout. However, his dissertation encouraged many others to continue studying these symptoms. Some researchers have pointed out ancient text descriptions from Hippocrates and other ancient physicians that appear to describe symptoms of RA (Copeman, 1964). Due to the inconsistency of definitions, it is suggested that Renaissance artwork can better explain if RA existed during the ancient era (Dequeker & Rico, 1992; Entezami et al., 2011). The most impressive piece of art was The Temptation of St. Anthony at the Flemish-Dutch School in 1992 (Dequeker & Rico, 1992).

During the mid-19th century, Alfred Garrod specified the different between gout and other arthritic conditions (Entezami et al., 2011). Specifically, he identified an overflow of uric acid in the blood of patients suffering from gout (Copeman, 1964; Garrod, 1859; Storey, 2001). He suggested that RA was not a disease of the modern era and has always been present since our ancestors’ time. This discovery laid the foundation for others to research the etiology of RA, and his son, Archibald Garrod, coined the term rheumatoid arthritis (Entezami et al., 2011). Unfortunately, others challenged Archibald’s claims due to the lack of supporting evidence.

In the twentieth century, Charles Short looked through Archibald’s Treatise and realized there were only claims about RA rather than evidence. Short decided to discredit the ancient origin hypothesis by proposing that RA was indeed a disease of the modern era. Others submitted similar claims, but it is Charles Short, who is credited for identifying the recent origin school of thought (Entezami et al., 2011; Short, 1974). Many researchers today continue to support the ancient texts and medical writings about RA. Nevertheless, the lack of scientific data has compelled others to dive into paleopathological studies and has created the third school of thought, new-world to old-world transfer concept (Entezami et al., 2011). During the past few decades, researchers have found suggestive signs of RA damage on skeletons and compiled into a large grouping of diagnostic criteria. Currently, Arcini’s 1992 prerequisite list is most favored. Furthermore, its measures have expanded as follows: subchondral cysts, erosions/sinuses in affected joints, rebuilding/presence of osteophytes, periarticular bone fragmentation, traces in cartilage-supporting bone tissues, osseous ankylosis of joint, eburnation, and bilaterally affected joints (Arcini, 1992; Entezami et al., 2011).

Overall Model of RA Development

Much of the research conducted on the development of RA has identified multiple genetic and environmental factors. Understanding how these factors influence the evolution of RA continues to advance with time; specifically, seropositive RA development. This development involves bacteria circling in the body and continues to grow. The circulation of bacteria can last several years before inflammatory arthritis (IA) presents itself (Deane & El-Gabalawy, 2014; Deane, Demoruelle, Kelmenson, Kuhn, Norris, & Holers, 2017). Although this recent finding is not universal, there are enough studies that can contribute scientific data to future studies in further understanding what factors are contributing to the development of RA (Deane et al., 2017). More importantly, the European League Against Rheumatism (EULAR) has been conducting multiple pharmacologic prevention trials to identify factors that can be used for prediction models (Gerlag et al., 2016). However, before this review discusses the preventions of RA, it is vital to examine the known genetic and environmental factors thoroughly.

Deane and colleagues (2017) have identified several factors from RA research that highly suggests that genetics constitute a significant influence on the development of RA. Frisell, Saevarsdottir, & Askling (2016), found an increased prevalence of RA within families, estimating 40-50% contribution of seropositive RA. Interestingly, other studies have suggested an increased incidence of RA amongst natives (Ferucci, Templin, & Lanier, 2005; Frisell et al., 2013; Hemminki, Li, Sundquist, & Sundquist, 2009). The most severe genetic risk factor is a group of genes within the immune system of major histocompatibility complex (MHC) (Deane et al., 2017; Gregersen, Silver, & Winchester, 1987; Raychaudhuri et al., 2012).

In 2017, Deane & Holers conducted a study that suggested there are underlying environmental factors that seem to increase the risk of cycling from an autoantibody-positive pre-RA state, to IA, and finally classified RA. A 2013 study had similar findings of environmental factors that included smoking, obesity, and alcohol consumption (De Hair, Maria J H, et al., 2013; Van de Stadt, Lotte Arwen, Witte, Bos, & Van Schaardenburg, 2013). One of the more recent controversies on the development of RA is whether smoking is associated with periodontal disease and lung disease. In 2017, Bruce Rothschild conducted a study to identify a correlation between periodontal disease with RA and ankylosing spondylitis (AS). His findings suggested that inflammatory arthritis does not seem to play a role. He implied that although dental disease is common amongst populations, it is not associated with arthritis, at least before modern rheumatologic medications (Rothschild, 2017).

Following this study, many researchers have discredited Rothschild by publishing their experiments or previous findings before 2017. Deane et al., (2017), referenced multiple studies within the past decade that focused on mucosal surfaces playing a role in the pathogenesis of RA (Barra et al., 2013; Deane & Holers, 2019; Holers et al., 2018; Kinslow et al., 2016). The general model underlying pre-clinical RA is as follows: interactions between microbes, environmental factors (e.g., tobacco smoke), and host factors begin at a mucosal surface (e.g., the oral cavity, lung, gut). The cycle leads to mucosal inflammation and initial breaks in RA-related immune tolerance (Deane et al., 2017; Demoruelle, M., Deane, & Holers, 2014; Demoruelle, M. Kristen, 2019).

 Potential for Prevention.

Based on the information discussed above, the European League Against Rheumatism (EULAR) developed a model outlining the phases of RA (Deane & Holers, 2019; Gerlag et al., 2012). It is essential to address that various aspects of RA development do exist and, therefore, the possibility to identify and target the prevention of future phases (Deane & Holers, 2019). During the pre-RA stage, genetic and environmental risk factors are presented individually or combined, possibly at a mucosal site. Next, autoimmunity and inflammation occur slowly over time, eventually becoming arthralgia, unclassified arthritis, and finally classified RA (Gerlag et al., 2012).

Not surprising to any reader, there are disagreements on which phases should be under the pre-RA stage. Deane & Holers (2017), address the constant discovery of autoantibodies that could change the course of what we currently know about autoimmunity in pre-RA. Similarily, EULAR (2012) proposes for future research to identify what specific testing should be used to see what phases are present in the individual. Research within the year of 2019 has been explicitly studying mucosa-based strategies of RA prevention. Dr. Demoruelle presented a strong association between mucosal sites and RA; therefore, hypothesizing mucosal-based approaches should be an add-on preventative intervention (Demoruelle, 2019). At this time, it unknown which strategies would be most effective, but considering what is already known in the research, smoking cessation, dental hygiene, and diet are good starting points (de Hair, Maria J H, et al., 2013; Deane et al., 2017; Deane & Holers, 2019).

As we know, predicting the exact risk someone may have for RA can be challenging. Therefore, it is essential to continue validating the current prediction models to improve an individual’s quality of life (Karlson, van Schaardenburg, & van der Helm-van Mil, Annette H, 2016). Van Boheeman and Van Schaardenburg (2019), suggested to include primary care by testing current prediction models with their patients. This inclusion would increase a positive interdisciplinary approach and fluent communication between all of the patient’s doctors. To help with prediction, the researchers in this same study suggested taking a closer look at genetic and environmental markers early on and then focus on imaging and autoantibodies.

Treatments

The guidelines for the treatment of RA (American College of Rheumatology; ACR, 2015), recommend treating to a target of the disease while also knowing when to increase treatment protocol pending activity (Singh et al., 2016). According to Dr. Wasserman (2011), “the goals of therapy should include minimizing joint pain and swelling, preventing deformity and radiographic damage, maintain an individual’s quality of life, control extra-articular manifestations.” Disease-modifying antirheumatic drugs (DMARDs) are the most preferred type of treatment for RA. However, other treatments suggested are dietary modifications, exercise, and physical therapy. Joint replacement becomes an option only if medical management cannot control symptoms, and joint damage will not heal (Wasserman, 2011). Looking back throughout the history of RA, we can see there has been improvement with the discovery of RA. Although researchers still find challenges with the prediction of pre-RA, it is crucial to continue medications and therapies that are evidence-based.

References

• AJ, L. B. (2001). The first description of rheumatoid arthritis. unabridged text of the doctoral dissertation presented in 1800. Joint Bone Spine, 68(2), 130-143. doi:10.1016/S1297-319X(00)00247-5
• Aletaha, D., Neogi, T., Silman, A. J., Funovits, J., Felson, D. T., Bingham, C. O., . . . Hawker, G. (2010). 2010 rheumatoid arthritis classification criteria: An american college of rheumatology/european league against rheumatism collaborative initiative. Annals of the Rheumatic Diseases, 69(9), 1580-1588. doi:10.1136/ard.2010.138461
• Al-Laith, M., Jasenecova, M., Abraham, S., Bosworth, A., Bruce, I. N., Buckley, C. D., . . . Cope, A. P. (2019). Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): A multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol. Trials, 20(1), 429. doi:10.1186/s13063-019-3403-7
• Arcini, C. (1992). Rheumatoid arthritis – rare findings from scanian skeletal remains from viking and medieval times. Sydsvenska Medicinhistoriska Sallskapets Arsskrift, 18, 11. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11639226
• Barra, L., Scinocca, M., Saunders, S., Bhayana, R., Rohekar, S., Racapé, M., . . . Bell, D. A. (2013). Anti–Citrullinated protein antibodies in unaffected First‐Degree relatives of rheumatoid arthritis patients. Arthritis & Rheumatism, 65(6), 1439-1447. doi:10.1002/art.37911
• Copeman, W. S. C. (1964). A short history of the gout and the rheumatic diseases. Berkeley (Los Angeles): University of California Press.
• de Hair, Maria J H, Landewé, R. B. M., van de Sande, Marleen G H, van Schaardenburg, D., van Baarsen, Lisa G M, Gerlag, D. M., & Tak, P. P. (2013). Smoking and overweight determine the likelihood of developing rheumatoid arthritis. Annals of the Rheumatic Diseases, 72(10), 1654-1658. doi:10.1136/annrheumdis-2012-202254
• Deane, K. D., Demoruelle, M. K., Kelmenson, L. B., Kuhn, K. A., Norris, J. M., & Holers, V. M. (2017). Genetic and environmental risk factors for rheumatoid arthritis. Best Practice & Research Clinical Rheumatology, 31(1), 3-18. doi:10.1016/j.berh.2017.08.003
• Deane, K. D., & El-Gabalawy, H. (2014). Pathogenesis and prevention of rheumatic disease: Focus on preclinical RA and SLE. Nature Reviews. Rheumatology, 10(4), 212-228. doi:10.1038/nrrheum.2014.6
• Deane, K. D., & Holers, V. M. (2019). The natural history of rheumatoid arthritis. Clinical Therapeutics, 41(7), 1256-1269. doi:10.1016/j.clinthera.2019.04.028
• Demoruelle, M. K. (2019). Mucosa biology and the development of rheumatoid arthritis: Potential for prevention by targeting mucosal processes. Clinical Therapeutics, 41(7), 1270-1278. doi:10.1016/j.clinthera.2019.04.012
• Demoruelle, M., Deane, K., & Holers, V. (2014). When and where does inflammation begin in rheumatoid arthritis? Current Opinion in Rheumatology, 26(1), 64-71. doi:10.1097/BOR.0000000000000017
• Dequeker, J., & Rico, H. (1992). Rheumatoid arthritis—like deformities in an early 16th-century painting of the flemish-dutch school. Jama, 268(2), 249-251. doi:10.1001/jama.1992.03490020097037
• Entezami, P., BS, Fox, D. A., MD, Clapham, P. J., BS, & Chung, Kevin C., MD, MS. (2011). Historical perspective on the etiology of rheumatoid arthritis. Hand Clinics, 27(1), 1-10. doi:10.1016/j.hcl.2010.09.006
• Ferucci, E. D., Templin, D. W., & Lanier, A. P. (2005). Rheumatoid arthritis in american indians and alaska natives: A review of the literature. Seminars in Arthritis and Rheumatism, 34(4), 662-667. doi:10.1016/j.semarthrit.2004.08.003
• Frisell, T., Holmqvist, M., Källberg, H., Klareskog, L., Alfredsson, L., & Askling, J. (2013). Familial risks and heritability of rheumatoid arthritis: Role of rheumatoid factor/Anti–Citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis & Rheumatism, 65(11), 2773-2782. doi:10.1002/art.38097
• Frisell, T., Saevarsdottir, S., & Askling, J. (2016). Family history of rheumatoid arthritis: An old concept with new developments. Nature Reviews. Rheumatology, 12(6), 335-343. doi:10.1038/nrrheum.2016.52
• Garrod, A. B. (1859). Treatise on nature of gout and rheumatic gout. London: Walton and Maberly. Retrieved from https://catalog.hathitrust.org/Record/006664329
• Gerlag, D. M., Raza, K., Baarsen, v., L.G.M, Brouwer, E., Buckley, C. D., Burmester, G. R., . . . Tak, P. P. (2012). EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: Report from the study group for risk factors for rheumatoid arthritis. Annals of the Rheumatic Diseases, 71(5), 638. Retrieved from https://www.narcis.nl/publication/RecordID/vu2:oai:dare.ubvu.vu.nl:1871%2F42645
• Gerlag, D., Safy, M., Maijer, K., de Hair, M., Tas, S., Starmans-Kool, M., . . . Tak, P. -. (2016). OP0182 Prevention of rheumatoid arthritis by B cell directed therapy in the earliest phase of the disease: The prairi study. Annals of the Rheumatic Diseases, 75(Suppl 2), 125-126. doi:10.1136/annrheumdis-2016-eular.6042
• Gregersen, P. K., Silver, J., & Winchester, R. J. (1987). The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis and Rheumatism, 30(11), 1205-1213. doi:10.1002/art.1780301102
• Hemminki, K., Li, X., Sundquist, J., & Sundquist, K. (2009). Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis and Rheumatism, 60(3), 661-668. doi:10.1002/art.24328
• Holers, V. M., Demoruelle, M. K., Kuhn, K. A., Buckner, J. H., Robinson, W. H., Okamoto, Y., . . . Deane, K. D. (2018). Rheumatoid arthritis and the mucosal origins hypothesis: Protection turns to destruction. Nature Reviews. Rheumatology, 14(9), 542-557. doi:10.1038/s41584-018-0070-0
• Hu, Y., Sparks, J. A., Malspeis, S., Costenbader, K. H., Hu, F. B., Karlson, E. W., & Lu, B. (2017). Long-term dietary quality and risk of developing rheumatoid arthritis in women. Annals of the Rheumatic Diseases, 76(8), 1357-1364. doi:10.1136/annrheumdis-2016-210431
• Karlson, E. W., van Schaardenburg, D., & van der Helm-van Mil, Annette H. (2016). Strategies to predict rheumatoid arthritis development in at-risk populations. Rheumatology (Oxford, England), 55(1), 6-15. doi:10.1093/rheumatology/keu287
• Kinslow, J. D., Blum, L. K., Deane, K. D., Demoruelle, M. K., Okamoto, Y., Parish, M. C., . . . Holers, V. M. (2016). Elevated IgA plasmablast levels in subjects at risk of developing rheumatoid arthritis. Arthritis & Rheumatology, 68(10), 2372-2383. doi:10.1002/art.39771
• Raychaudhuri, S., Sandor, C., Stahl, E. A., Freudenberg, J., Lee, H., Jia, X., . . . de Bakker, Paul I W. (2012). Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature Genetics, 44(3), 291-296. doi:10.1038/ng.1076
• Rothschild, B. (2017). Correlation of periodontal disease with inflammatory arthritis in the time before modern medical intervention. Journal of Periodontology, 88(3), 266-272. doi:10.1902/jop.2016.160422
• Short, C. L. (1974). The antiquity of rheumatoid arthritis. Arthritis and Rheumatism, 17(3), 193-205. doi:10.1002/art.1780170302
• Singh, J. A., Saag, K. G., Bridges, S. L., Akl, E. A., Bannuru, R. R., Sullivan, M. C., . . . McAlindon, T. (2016). 2015 american college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care & Research, 68(1), 1-25. doi:10.1002/acr.22783
• Smolen, J. S., Prof, Aletaha, D., MD, & McInnes, I. B., Prof. (2016). Rheumatoid arthritis. Lancet, The, 388(10055), 2023-2038. doi:10.1016/S0140-6736(16)30173-8
• Sparks, J. A., Iversen, M. D., Yu, Z., Triedman, N. A., Prado, M. G., Miller Kroouze, R., . . . Karlson, E. W. (2018). Disclosure of personalized rheumatoid arthritis risk using genetics, biomarkers, and lifestyle factors to motivate health behavior improvements: A randomized controlled trial. Arthritis Care & Research, 70(6), 823-833. doi:10.1002/acr.23411
• Storey, G. D. (2001). Alfred baring garrod (1819–1907). Rheumatology (Oxford, England), 40(10), 1189-1190. doi:10.1093/rheumatology/40.10.1189
• van Boheemen, L., & van Schaardenburg, D. (2019). Predicting rheumatoid arthritis in at-risk individuals. Clinical Therapeutics, 41(7), 1286-1298. doi:10.1016/j.clinthera.2019.04.017
• van de Stadt, Lotte Arwen, Witte, B. I., Bos, W. H., & van Schaardenburg, D. (2013). A prediction rule for the development of arthritis in seropositive arthralgia patients. Annals of the Rheumatic Diseases, 72(12), 1920-1926. doi:10.1136/annrheumdis-2012-202127
• Victoria Ruffing, & Clifton Bingham. (2019). Rheumatoid arthritis signs and symptoms. Retrieved from https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms
• Wasserman, A. M., MD. (2011). Diagnosis and management of rheumatoid arthritis. American Family Physician, 84(11), 1245-1252. Retrieved from https://www.clinicalkey.es/playcontent/1-s2.0-S0002838X11604140