Rheumatoid Arthritis

Rheumatoid Arthritis Overview and Management

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disorder where the immune system mistakenly attacks healthy cells, leading to painful inflammation in various parts of the body. Affecting over 18 million people worldwide, RA is predominantly seen in women, who make up 70% of the patient population. This disease primarily targets the joints, often causing pain in multiple areas simultaneously, such as the hands, wrists, and knees. The resulting joint swelling can damage tissues, leading to chronic pain, instability, cartilage and bone damage, and visible deformities. Effective RA management hinges on early diagnosis, a comprehensive medication regimen, and proper symptom management.

Diagnosing Rheumatoid Arthritis

Diagnosing RA involves reviewing patient symptoms, conducting a physical examination, and possibly performing lab tests or x-rays. Symptoms to look for include joint pain and stiffness, tenderness and swelling, weight loss, fever, fatigue, and weakness. Once symptoms are identified, assessing risk factors such as age, gender, genetics, obesity, and smoking is crucial. RA risk increases with age, particularly for those over 55. Women are nearly three times more likely to develop RA than men. Genetics also play a role; individuals with HLA class II genotypes are at higher risk. Obesity heightens RA risk, and smoking can both increase the likelihood of developing RA and worsen its symptoms.

Timely diagnosis is critical. Recognizing and noting when symptoms first appeared is essential, as early and accurate diagnosis—within six months of symptom onset—helps distinguish RA from other types of arthritis and autoimmune diseases, allowing for appropriate treatment and prevention of long-term complications. Early intervention can significantly mitigate the disease's progression and its associated long-term effects.

RA Medication Regimen

Managing RA involves various medications, including NSAIDs (nonsteroidal anti-inflammatory drugs), glucocorticoids (GCs), and DMARDs (disease-modifying anti-rheumatic drugs).

NSAIDs: Drugs like naproxen, celecoxib, and ibuprofen reduce joint swelling and pain by inhibiting cyclooxygenase (COX), specifically COX-2, which is elevated during inflammation. COX-2 specific NSAIDs, such as celecoxib, valdecoxib, and rofecoxib, offer targeted action with fewer side effects compared to non-selective NSAIDs. Potential side effects include gastrointestinal issues, renal failure, heart failure, rashes, dizziness, confusion, and seizures.

Glucocorticoids: Potent anti-inflammatory drugs like prednisone, dexamethasone, prednisolone, and hydrocortisone are effective in managing RA but come with a higher side effect profile than NSAIDs. These include immunosuppressive effects and long-term issues like weight gain, water retention, muscle weakness, diabetes, and bone thinning. Due to these risks, GCs are recommended for short-term use and require careful tapering to prevent complications.

DMARDs: These drugs, such as methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, are essential in RA treatment for their ability to suppress autoimmune activity and delay joint degeneration. Initiating DMARD therapy early, upon diagnosis, leads to better outcomes. Despite their efficacy, DMARDs can cause side effects like diarrhea, nausea, liver damage, thrombocytopenia, leukopenia, pulmonary fibrosis, and pneumonitis.

Overall, effective RA management involves a balanced approach to medication, early and precise diagnosis, and ongoing symptom management to improve patient outcomes and quality of life.

Smolen, Josef. “Rheumatoid Arthritis.” Shibboleth Authentication Request, pubmed-ncbi-nlm-nih-gov.jerome.stjohns.edu/27156434/. Accessed 18 Jun. 2024. 

“Rheumatoid Arthritis (RA).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 27 July 2020, www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. 

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that causes damage to the joints in the hands, wrists, and knees. The damage from RA can result in long-lasting (chronic) pain, swelling, balance issues, and deformed joints. Signs and symptoms of RA include pain, aching, or stiffness in more than one joint, tenderness, redness, warmth and swelling in joints, weight loss, fever, fatigue, and weakness.

Although the specific cause of RA is unknown, the disease stems from a combination of genetic susceptibility and nongenetic factors combined with a triggering event. Genetic polymorphisms play a huge role according to epidemiologic studies. Additionally, there is a hypothesis indicating that multiple genes are involved, specifically those of the human leukocyte antigen (HLA) system. The function of our immune system is to detect foreign matter, initiate a response, and control the threat. In RA, the immune system is unable to differentiate between self and nonself. This eventually results in cell proliferation, inflammation, and destruction of tissues and fluids throughout the body. In the pathogenesis of this inflammatory response, antigen-presenting cells process and present antigens to T cells, which may stimulate B cells to produce antibodies and osteoclasts to destroy and remove bone. Macrophages stimulated by the immune response can stimulate T cells and osteoclasts to cause further inflammation. Furthermore, they can also stimulate fibroblasts, which create matrix metalloproteinases to degrade the bone matrix and produce proinflammatory cytokines. Lastly, activated T cells and macrophages release factors that promote tissue destruction, increase blood flow, and result in cellular invasion of synovial tissue and joint fluid. 

Treatment Overview:

Current available pharmacologic therapies used to treat RA as well slow the progression of the disease include conventional and biologic disease-modifying antirheumatic drugs (DMARDs) and small-molecule agents such as tofacitinib, baricitinib, and upadacitinib. Drugs that fall into the category of conventional DMARDs include methotrexate, leflunomide, sulfasalazine, hydroxychloroquine. Moreover, biologic DMARDs fall into two categories: tissue necrosis factor (TNF) inhibitor biologics such as (adalimumab, etanercept, certolizumab, golimumab, and infliximab) and non-TNF biologics (abatacept, tocilizumab, rituximab, anakinra, and sarilumab).

Nonpharmacological approaches for the treatment of RA include occupational and physical therapy, social work, and reviewing pain coping skills. Both mental and physical health are crucial for patients with RA, since central neuroendocrine and dopaminergic pathways may be involved in both RA disease activity. Patient education should include education regarding disease state as well as medication education related to potential adverse effects and how to administer injectable agents appropriately. Physical therapy has shown benefits for reducing pain and inflammation while preserving joint function, exercise and physical activity including aerobic activity and muscle-strengthening exercises, have also proven to improve RA-related disease outcomes. Assistive devices and orthoses such as braces and supports are helpful to improve pain and function. Occupational therapy may be helpful and provide benefits such as exercises, appropriate footwear, and splinting. Weight loss can also help decrease stress on joints and surgical options including joint replacements, are reserved for patients with more accelerated disease where they may have significant cartilage loss. 

Rheumatoid arthritis, an autoimmune condition affecting about 1% of the population, is a progressive disease that can result in disability and reduced quality of life. Treatment options vary and include both nonpharmacologic and pharmacologic approaches. It is crucial to start a patient on a thorough treatment plan, aiming for disease remission or low disease activity. Tailoring pharmacologic treatment to the individual’s disease activity, previous medication responses, comorbidities, and preferences is essential. Ongoing research continues to seek a deeper understanding of the etiology of rheumatoid arthritis to develop more targeted therapies and expand the use of biosimilars, offering hope for improved management of the condition.

Resources:

1. Gruber, S., Hyland, S., & Harris, B. (n.d.). Shibboleth authentication request. https://accesspharmacy-mhmedical-com.jerome.stjohns.edu/content.aspx?sectionid=268014360&bookid=3097&Resultclick=2#1201558814

2. professional, C. C. medical. (n.d.). Rheumatoid arthritis (RA): Causes, symptoms & treatment faqs. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/4924-rheumatoid-arthritis

3. Ra Pathophysiology • Johns Hopkins Arthritis Center. Johns Hopkins Arthritis Center. (2019, March 27). https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/

   
   

Summary of Rheumatoid Arthritis: 

Rheumatoid Arthritis (RA) is an autoimmune disorder whereby the immune system mistakenly attacks healthy cells in the body which subsequently causes painful swelling and inflammation in different areas of the body. The primary site commonly affected by RA are the joints and can inflame multiple joints at once, therefore leading to painful hands, wrists and knees. In addition to affecting joints and causing pain/inflammation in these areas, rheumatoid arthritis can also extend and cause complications in areas such as the lungs, heart and eyes. 

While the search to identify a single trigger for RA is still ongoing, there have been a number of epidemiological and genetic studies that have been conducted, yielding valuable insights into possible pathophysiological reasons for why one develops RA. One of the most common theories regarding the pathogenesis of RA originated in the early 1980s, when a correlation between rheumatoid arthritis and class II MHC antigens was identified. Specifically, the epitope present in HLA-DR4, was found to engage with T-cell receptors and showed a hypervariable region with highly conserved characteristics in sequence and charge, which is now thought to account for about 30% of RA’s genetic risk. 

How is RA Diagnosed: 

When it comes to diagnosing RA, healthcare providers often refer to the 2010 American College of Rheumatology/European League Against Rheumatology (ACR/EULAR) classification criteria as a guide for diagnosis. However, not all RA patients will meet these criteria during the initial stages of their disease but could still be suitable candidates for treatment. Based on the criteria found in the ACR/EULAR, a diagnosis of “definite RA” relies on the presence of synovitis in at least one joint, the absence of another explanation/diagnosis that better explains the synovitis, and a cumulative score of 6 (out of a potential 10) from the individual scores across four domains. The highest score found in each domain is the number that is used in this calculation. The domains considered in this calculation include the number and site of involved joints, any serological abnormalities (RF or ACPA), symptom duration of at least six weeks and an elevated acute phase response, indicated by ESP or CRP levels above the upper limit of normal. 

Pre-treatment screenings for RA: 

Before beginning treatment for RA, rheumatologists usually conduct a pre-treatment evaluation to identify any contraindications to non biologics, targeted synthetic small molecules or DMARDs. The following are some of the evaluations that are conducted prior to initiation of RA treatment: 

General testing - Baseline bloodwork consisting of a CBC, Scr, ESR and CRP levels are usually collected. For patients who will possibly be receiving IL-6 or JAK inhibitors, baseline lipid levels are also collected. 

Hepatitis virus screening - This is done in all patients without a known history of hepatitis infection. Presence of Hepatitis B or C is screened prior to treatment with DMARDs or JAK inhibitors 

Ophthalmologic screening for hydroxychloroquine use: A comprehensive baseline ophthalmologic screening is conducted prior to treatment with hydroxychloroquine to monitor for any ocular toxicity that may occur due to treatment. This screening includes a thorough examination of the retina with pupil dilation and automated visual field testing. 

Treatment Options: 

There are a number of different treatment options available for RA, therefore individual patient factors must be considered before initiating treatment. Factors such as the level of disease activity, presence of any comorbidities and patient preferences must be considered before prescribing a treatment to a RA patient. 

The first-line treatment for RA often consists of a DMARD (disease-modifying antirheumatic drug), usually Methotrexate (MTX). MTX is administered as a once-weekly dose, typically administered orally. Usual dosing begins at 7.5 mg to 15 mg once weekly, however the dose may be escalated as needed to appropriately manage the patient’s symptoms and disease control. However, unfortunately, MTX does have a number of contraindications for use such as women who may become pregnant, women who are pregnant, patients with liver disease or excessive alcohol intake and patients with severe renal impairment (eGFR < 30 mL/min). For patients with these contraindications, there are alternatives to MTX available such as Leflunomide, Sulfasalazine and Hydroxychloroquine. 

For symptomatic breakthrough treatment of RA, NSAIDs or glucocorticoid medications are usually recommended to quickly treat inflammation without providing long-term control. Common examples of NSAIDs that are used to treat breakthrough RA include Ibuprofen 2400 to 3200 mg/day, Naproxen 1000 mg/day or Meloxicam 15 mg/day. It is recommended that NSAIDs are administered at their full anti-inflammatory doses as the first-line treatment for patients with breakthrough RA symptoms, unless contraindicated due to GI, renal or CV conditions. Another option, as aforementioned, are glucocorticoids. Although glucocorticoids are usually given in addition to NSAIDs, they can be used alone to treat active symptoms. Prednisone is the most common glucocorticoid prescribed and is usually dosed between 5 to 20 mg/day, depending upon the severity of the symptoms. 

Resources: 

Rheumatoid Arthritis. Centers for Disease Control and Prevention. April 7, 2022. Accessed April 13, 2024. https://www.cdc.gov/arthritis/types/rheumatoid-arthritis.html. 

RA Pathophysiology. Johns Hopkins Arthritis Center. March 27, 2019. Accessed April 13, 2024. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/. 

Baker J. Diagnosis and differential diagnosis of rheumatoid arthritis. UpToDate. March 21, 2024. Accessed April 13, 2024. https://www-uptodate-com.jerome.stjohns.edu/contents/diagnosis-and-differential-diagnosis-of-rheumatoid-arthritis?search=rheumatoid+arthritis&topicRef=7516&source=see_link#H2293005574. 

2010 RA Classification Tree Format . American College of Rheumatology. Accessed April 13, 2024. https://rheumatology.org/api/asset/bltc4dbe994c49eac11. 

Cohen S. Initial treatment of rheumatoid arthritis in adults. UpToDate. January 5, 2024. Accessed April 13, 2024. https://www-uptodate-com.jerome.stjohns.edu/contents/initial-treatment-of-rheumatoid-arthritis-in-adults?search=rheumatoid+arthritis&topicRef=7516&source=see_link#H919605925. 

Rheumatoid Arthritis. Mayo Clinic. January 25, 2023. Accessed April 13, 2024. https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/diagnosis-treatment/drc-20353653. 

This discussion post will delve into a recently published journal article about the long term efficacy of daily baricitinib for Rheumatoid Arthritis. The article also mentions the significance of low discontinuation rates due to adverse events.  I chose this article because it was published recently in January 2024, making it one of the most current articles for this medication in the treatment of RA.

Rheumatoid arthritis is a chronic inflammatory condition that targets the joints, leading to pain, swelling, and stiffness and also has systemic effects, impacting various organs. There is no cure for rheumatoid arthritis, thus high quality treatments are crucial for patients. The burden of disease over time only increases. While the variety of treatments offered today is good for the majority of patients, many do not respond to current therapies. Thus, this journal reviews the long term efficacy of daily barcitinib in patients who have had inadequate response to first line treatments: Methotrexate, csDMARDS, and bDMARDS. 

Rheumatoid arthritis is treated with disease-modifying antirheumatic drugs known as DMARDs. These medications aim to alleviate symptoms, slow disease progression, and improve overall quality of life. In addition to DMARDS, NSAIDs are also used to manage pain and inflammation. Biologic DMARDs, such as etanercept and adalimumab, target specific components of the immune system to further suppress inflammation. Janus kinase (JAK) inhibitors, such as tofacitinib, represent another class of medications that work by interfering with signals involved in the inflammatory process. Barcitinib, the medication mentioned in the article, is an oral selective Janus kinase inhibitor. It is a targeted synthetic DMARD. 

The goals of treatment tracked in the study were low disease activity, clinical remission, and physical function. The article reviews the percentage of LDA and remission that occurred in patients taking barcitinib. “At week 340 or 336, LDA was achieved in 37%/83% of MTX-IR, 35%/83% of csDMARD-IR and 23%/73% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively (1).” In addition, “Remission was achieved in 20%/40% of MTX-IR, 13%/32% of csDMARD-IR and 9%/30% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively (1).” These results demonstrate maintained efficacy through 6.5 years. The article recognizes the importance of long term efficacy demonstrated by barcitinib, as RA is a chronic disease that affects the patient’s livelihood for as long as they live. Barcitinib was also well tolerated, “as the larger proportion of patients who discontinued from the study was due to sponsor decision, with fewer than one-fifth of patient discontinuing due to adverse events, death of lack of efficacy (1).” The sponsor decision discontinuations were due to specific study objectives found in the protocol. 

In conclusion, the findings of this study demonstrate the enduring effectiveness of both 4 mg and 2 mg doses of baricitinib in treating rheumatoid arthritis (RA) patients over 6.5 years. The consistently low rates of discontinuation attributed to adverse events, mortality, and insufficient efficacy suggest that the 4 mg dosage of baricitinib not only proves to be efficacious but is also well-tolerated over an extended treatment duration.

References:

1. Roberto Caporali, Peter C Taylor, Daniel Aletaha, Raimon Sanmartí, Tsutomu Takeuchi, Daojun Mo, Ewa Haladyj, Natalia Bello, Liliana Zaremba-Pechmann, Ying Fang, Maxime Dougados, Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis up to 6.5 years of treatment: results of a long-term study, Rheumatology, 2024;, keae012, https://doi.org/10.1093/rheumatology/keae012

   
   

2. Smolen, J. S., Aletaha, D., & McInnes, I. B. (2016). Rheumatoid arthritis. Lancet (London, England), 388(10055), 2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8

Rheumatoid arthritis is an chronic disorder that causes inflammation and pain primarily at the joints. It is an autoimmune condition, meaning that the immune system mistakenly attacks the body's own connective tissues, especially the synovium, which is the lining of the membranes that surround the joints. Leukocytes invade the cartilage and the bone surface, leading to erosion of bones and cartilages within the joints and narrowing of the joint space. This leads to inflammation in the affected joints, causing pain, swelling, stiffness, and eventually joint damage. Rheumatoid arthritis commonly affects the small joints in the hands and feet, but it can also involve larger joints and other organs such as the eyes, heart, circulatory system, and lungs. Rheumatoid arthritis is the most common systemic autoimmune inflammatory arthritis. In the United States, about 1.3 million American adults have RA, according to the American College of Rheumatology (ACR). Mortality hazards are 60%–70% higher in patients with RA compared with the general population.

The mechanism of action of rheumatoid arthritis involves chronic inflammation of the synovial tissue lining the joint capsule results in the proliferation of this tissue, forming the pannus, which is characteristic of RA. The complement system is activated by immunoglobulins which stimulates the production of T and B cells. CD4+ and T cells in the synovial membrane recognize antigens in the joint and communicate with plasma cells, mast cells, macrophages, and synovial fibroblasts to produce inflammatory mediators, including pro-inflammatory cytokines, which include the tumor necrosis factor (TNF) and interleukin 1 (IL-1). These interactions result in an upregulation of TNF and IL and matrix-degrading activities, especially in patients with obesity. About 40% higher risk in obese patients than general population.

The symptoms of rheumatoid arthritis can vary in severity, and the disease may have periods of flare-ups and remission. While the exact cause of rheumatoid arthritis is not fully understood, a combination of genetic and environmental factors is believed to contribute to its development. A family history of human leukocyte antigen, serotype DR4 (HLA-DR4) plays a role and some environmental triggers include smoking, pulmonary disease, infectious disease (viral or bacterial; for example, Epstein-Barr virus or Escherichia coli), and pesticides. Women are two to three times more likely to get rheumatoid arthritis than men and it usually develops in middle age. It mostly affects individuals between the ages of 15 and 45 years old.

Early diagnosis and appropriate treatment are crucial to managing the symptoms and preventing joint damage in people with rheumatoid arthritis. Treatment typically involves medications, such as disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as lifestyle modifications and, in some cases, surgery. Treatment goals include reducing joint pain and swelling, controlling the inflammation process and achieve disease remission and low disease activity, slowing the irreversible, destructive joint changes, prevent radiologic damage and visible deformity, maintaining personal activities of daily living, continuing working (if applicable), and improve quality of life. It's important for individuals with RA to work closely with healthcare professionals to develop a personalized treatment plan based on their specific needs and circumstances.

References:

https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648

https://www.cdc.gov/arthritis/types/rheumatoid-arthritis.html#:~:text=Rheumatoid%20arthritis%2C%20or%20RA%2C%20is,usually%20many%20joints%20at%20once.

https://www.arthritis.org/diseases/rheumatoid-arthritis

https://doi-org.jerome.stjohns.edu/10.21019/pharmacotherapyfirst.ra_overview

Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease affecting joints. The immune system attacks the body's tissue. The damage is mainly symmetrical, with the joints on the same side of the body being affected. Continuous erosion of the cartilage and bone will decrease one's physical capabilities. RA, untreated, can lead to cardiovascular disease, osteoporosis, and/or lymphoma. It can also increase the risk of lung infections and cancer. Early diagnosis is key, treating the disease before its progression into joint destruction. Distinct signs of Rheumatoid Arthritis include joint erosion and rheumatoid nodules. Other symptoms include morning stiffness, unintentional weight loss, fatigue, and joint pain and swelling.

         RA cannot be cured, however, there are treatments to help with progression, increase quality of life, and prevent joint damage. Disease-modifying anti-rheumatic drugs (DMARDs) are used in the early stages to treat inflammation and decrease structural damage. DMARDs are divided into two classes, synthetic (sDMARDs) and biological (bDMARDs). bDMARDs examples include etanercept, adalimumab, abatacept, and tocilizumab. Synthetic DMARDs are further divided into conventional synthetic (csDMARDs) and targeted synthetic (tsDMARDs). Conventional synthetic DMARDs are methotrexate (MTX), sulphasalazine, leflunomide, gold salts, and hydroxychloroquine. Targeted synthetic DMARDs are used to target the inflammation caused by RA. Examples include Janus Kinase (JAK) inhibitors, such as tofacitinib. NSAIDs can help treat pain and inflammation, however, this will only be a temporary benefit. Steroids can be used to treat disease flares and severe RA. Steroids treat symptoms such as pain and stiffness and decrease joint swelling and tenderness. The type of drug chosen depends on the patient's RA severity, response to medications, and drug availability. First-line treatments are usually DMARD. if the DMARD is ineffective, it can be substituted or used in addition to another DMARD.

        Nonpharmacological treatments can help control Rheumatoid Arthritis and its damage. Exercise is key to maintaining muscle strength and joint motion. This may be hard for patients with joint pain and stiffness, but it can increase the strength of the joint and endurance. It also reduces fatigue, inflammation, and pain. Examples of exercise can include walking, swimming, and cycling. Physical therapists can be used to consult patients and create individualized care plans. Mediterranean diets can reduce inflammation and pain. The diet consists of vegetables, fruits, and whole grains. if a patient is taking methotrexate, folic acid supplements are key. Other supplements that help arthritis pain and swelling are omega-3 fatty acids and Vitamin d. Losing weight will reduce the weight on the joints. Quitting smoking and drinking alcohol is also important. Improving Quality of life and decreasing the effects of Rheumatoid Arthritis on the body is the key treatment plan. The doctor and the patient must work together to combat this disease and create a happier and healthier outcome. 

Radu AF, Bungau SG. Management of Rheumatoid Arthritis: An Overview. Cells. 2021 Oct 23;10(11):2857. doi: 10.3390/cells10112857. PMID: 34831081; PMCID: PMC8616326.

Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016 Oct 22;388(10055):2023-2038. doi: 10.1016/S0140-6736(16)30173-8. Epub 2016 May 3. Erratum in: Lancet. 2016 Oct 22;388(10055):1984. PMID: 27156434.

Rheumatoid Arthritis

Rheumatoid arthritis is “an autoimmune and inflammatory disease, which means that your immune system attacks healthy cells in your body by mistake, causing inflammation (painful swelling) in the affected parts of the body.” This autoimmune disorder affects over 18 million individuals, with 70% of these patients being women. This disease will mainly affect the individual’s joints and will typically cause pain in multiple joints at once. There is a swelling of the joints, which can occur in the patient’s hands, wrists and knees causing damage to any tissues that are being affected. This type of damage can have severe effects such as long-lasting or chronic pain, unsteadiness, cartilage/bone damage, and visual deformities. The key to adequately treating patients with RA (rheumatoid arthritis) is early diagnosis, a thorough medication regimen and proper symptom management. 

In order to correctly diagnose a patient’s RA, there needs to be a review of the patient’s symptoms, a physical examination of the patient and labs or x-rays may be needed. The symptoms need to be recognized and taken note of. These symptoms can include: paining/aching joints, stiffness in the joints, tenderness and swelling of the joints, weight loss, fever, fatigue and/or weakness. Once these symptoms are presented, risk factors then need to be assessed, along with other tests, in order for the patient to fully be diagnosed with RA. There are an abundance of risk factors when it comes to RA, but a few of them include: age, gender, genetics, obesity, and smoking. The risk of developing RA increases with age, making those 55 years and older higher risk patients than those younger than 55 years old. In the case of gender, rheumatoid arthritis is almost three times more prevalent in the female population than in the male population. Genetics can help determine whether or not you are a candidate for developing RA. If an individual has HLA class II genotypes, they are at risk for developing or worsening their rheumatoid arthritis. Obesity is a risk factor because according to studies, the more overweight a person is the greater their risk for developing rheumatoid arthritis becomes. Smoking has been shown to increase the risk of developing RA, as well as worsening the symptoms of a patient who has already been diagnosed with it. Time is very essential and being thorough is key, especially when asking the patient to be specific about when the symptoms first began to occur. According to studies, “Early and accurate diagnosis of RA is highly important in order to differentiate between types of arthritis and types of autoimmune disease and to promptly establish the correct treatment and prevent long-term complications.” Early diagnosis is considered within six months of the symptom onset, therefore urging the patient to really think about when the symptoms first occurred is essential. Stopping or slowing the progression of this disease at an early stage would be extremely beneficial in terms of preventing the long term effects associated with rheumatoid arthritis. 

For an RA medication regimen, there are a few drugs that are listed in the guidelines to help manage rheumatoid arthritis. There are NSAIDs (nonsteroidal anti-inflammatory drugs), GCs (glucocorticoids), and DMARDs (disease modifying anti-rheumatic drugs). Some examples of NSAIDs that are typically used in RA would be naproxen, celecoxib and ibuprofen. These drugs all aid in the reduction of the joint swelling, which in turn eases the pain that comes from the swelling. These medications work by inhibiting COX (cyclooxygenase), specifically COX-2 because it is usually elevated when inflammation is present. There is great benefit for using COX-2 specific NSAIDs for this reason, along with the lowered risk of side effects associated with the COX-2 specific drugs. Some examples include celecoxib, valdecoxib and rofecoxib. Not only do these COX-2 selective drugs have a more stringent mechanism of action, they are also better tolerated than the nonselective NSAIDs.  Some side effects that can occur include “bleeding, gastrointestinal ulceration, renal failure, heart failure, rashes, dizziness, confusion, and seizures” due to the inhibition of prostaglandins that are also part of the NSAIDs mechanism of action. Glucocorticoids have proven to be more potent and efficacious compared to NSAIDs. Some examples include prednisone, dexamethasone, prednisolone and hydrocortisone. These are extremely effective in rheumatoid arthritis due to their anti-inflammatory properties. Although these glucocorticoids are more effective than NSAIDs, NSAIDs prove to have less side effects and the severity of the side effect profile is also lower when compared to GCs. Glucocorticoids are typically known for their immunosuppressive properties, which is the biggest side effect that patients are cautioned of when their treatment is first initiated, however the long term side effects are worth mentioning because they will have an effect on the patient’s everyday life. Some long term effects include “weight gain, water retention, muscle weakness, diabetes and bone thinning.” Because of these effects, glucocorticoids have only been approved for short term use. Tapering these drugs are also very important and should be done properly to ensure safety of the patient, entailing that glucocorticoids cannot be abruptly discontinued. These drugs can be used as a bridging therapy for DMARDs until those effects have taken action or as an adjunctive therapy for active RA that continues even with the use of DMARDs. DMARDs act by promoting “remission by suppressing autoimmune activity and by delaying or preventing joint degeneration.” Because of this mechanism of action, it is critical to initiate this drug therapy as soon as a diagnosis is confirmed because the earlier the implementation of the drug the better the results. There are different DMARDs that are available for use including: methotrexate, hydroxychloroquine, sulfasalazine and leflunomide. DMARDs are considered first line for the treatment of rheumatoid arthritis and have yielded impressive outcomes, proving to be efficacious. Like all drug therapies, there are side effects to expect including: diarrhea, nausea, liver damage with a lower incidence of cirrhosis, thrombocytopenia, leukopenia, pulmonary fibrosis, and pneumonitis.” 

Resources

Kalyuzhny, Alexander. “Management of Rheumatoid Arthritis: An Overview.” Shibboleth Authentication Request, www-ncbi-nlm-nih-gov.jerome.stjohns.edu/pmc/articles/PMC8616326/. Accessed 22 Aug. 2023. 

Smolen, Josef. “Rheumatoid Arthritis.” Shibboleth Authentication Request, pubmed-ncbi-nlm-nih-gov.jerome.stjohns.edu/27156434/. Accessed 22 Aug. 2023. 

“Rheumatoid Arthritis (RA).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 27 July 2020, www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. 

      Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction. As joints deteriorate, patients suffer from pain and loss of function, often accompanied by decreasing quality of life and increasing mortality. Depending on the severity of the disease at onset, the risk of disability may be up to 30%, and mortality can be increased by up to 52%, frequently as a result of infection or circulatory disease.

RA treatment aims to minimize disease activity, thereby preventing or controlling joint damage and reducing the risk of other serious comorbidities, such as heart disease or stroke. Early intervention is vital in patients with confirmed RA to preserve joint function.

      Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are used to control pain and the inflammatory process. Following the diagnosis of RA, patients receive disease-modifying antirheumatic drugs (DMARDs), which reduce the signs and symptoms of the disease, and potentially inhibit radiographic progression. While a number of RA patients respond to DMARDs, a large proportion of RA remains active despite such treatments. The approach of targeting cytokines has considerably improved the success in the treatment of RA. In the clinical application, five tumor necrosis factor (TNF)-α inhibitors are available: infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GOLI) and certolizumab pegol (CZP).

TNF-α is a significant cytokine that mediates inflammation in RA. Elevation of TNF-α levels have been observed in synovial fluid and the synovium of patients with RA. TNF-α plays an extremely central role in driving inflammation and bone degradation. Introduction of TNF-α inhibitors has revolutionized RA treatment options resulting in the development of further biologic DMARDs.

      IFX is a recombinant IgG1 monoclonal antibody specific for TNF-α that hinders the cytokine from triggering the cellular TNF receptor complex. IFX needs to be administered by intravenous infusion and has a terminal half-life of 8–10 days. Thus, it is administered every 4–8 weeks and the dosage varies from 3 to 6 (to 10) mg/kg. The efficacy of IFX with MTX was previously demonstrated in several trials. Patients receiving combination therapy exhibited evidently higher median improvements compared to patients in the MTX plus placebo group

The most common adverse events found in clinical trials of IFX are infusion reactions and infection. The therapy of IFX might increase the risk of malignancies and cardiovascular conditions. The incidence of serious infections, acute infusion reactions and death was similar in patients treated with IFX plus MTX and those who received MTX only. Among the serious infections, pneumonia and tuberculosis occurred more frequently in the IFX-treated patients compared to those treated with MTX alone

      ETN is a genetically engineered protein comprising two molecules of the extracellular domain of TNF receptor II (p75) and the Fc portion of IgG1. Due to its half-life of 3–5.5 days, ETN is administered subcutaneously, either on a weekly basis (50 mg) or twice a week (25 mg). The superiority of the combination therapy of ETN plus MTX over ETN or MTX monotherapy in patients with RA has been demonstrated. The 2-year data from the TEMPO study confirmed that a larger proportion of patients treated with combination therapy exhibited clinical response compared to those receiving either ETN or MTX monotherapy. Therefore, treatment with a combination of ETN and MTX stopped joint damage and patients exhibited disease remission.

Biological agents render the treatment of RA a new era, especially for patients with an insufficient response to DMARDs. Biological agents can quickly relieve clinical symptoms and delay bone destruction. When the TNF-α inhibitors are applied in clinical practice, the combination with DMARDs are conductive to ease the symptoms and prevent bone structural damage and elevate physical function. Moreover, the conversion between various agents may have the same function. Certain drugs, such as ETN, in combination with MTX are better compared to monotherapy regarding long-term efficacy. Most adverse events of agents are infection-site reactions. Although severe side-effects may be treated appropriately, they still prevent clinical remedy. Physicians should prescribe various treatment regimens according to the patient’s symptoms as well as constantly explore the immune mechanism of RA, and develop novel biological agents. In the future, immunotherapy is likely to bring fundamental changes for patients with RA.

References: 

1. Ma, X., & Xu, S. (2013). TNF inhibitor therapy for rheumatoid arthritis. Biomedical reports, 1(2), 177–184. https://doi.org/10.3892/br.2012.42

2. Mikuls TR, Saag KG, Criswell LA, et al: Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women: results from the Iowa Women’s Health Study. Ann Rheum Dis. 61:994–999. 2002.PubMed/NCBI

3. St. Clair EW, van der Heijde DM, Smolen JS, et al: Active-controlled study of patients receiving infliximab for the treatment of rheumatoid arthritis of early onset study group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 50:3432–3443. 2004.

4. Maini RN, Breedveld FC, Kalden JR, et al: Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 50:1051–1065. 2004.

5. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al: TEMPO Study Investigators. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 54:1063–1074. 2006.

6. Genovese MC, Bathon JM, Fleischmann RM, et al: Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 32:1232–1242. 2005.PubMed/NCBI

             Rheumatoid arthritis (RA) is a chronic disorder for which there is no known cure. In patients whose condition is resistant to an initial course of treatment with a nonbiologic (also termed conventional synthetic [cs] or traditional) disease-modifying antirheumatic drug (csDMARD), such as methotrexate (MTX), timely adjustments in the treatment regimen are required to achieve effective disease control and prevent damage to the joints.

             In patients resistant to initial DMARD therapy, add additional DMARDs or switch the patient to a different DMARD or DMARD combination, while also treating the active inflammation with antiinflammatory drug therapy. DMARD "triple therapy" with MTX plus SSZ and HCQ or the use of the combination of continued MTX plus a TNF inhibitor, rather than monotherapy with another conventional synthetic (cs) nonbiologic or biologic DMARD is preferred. The specific approach is influenced by the treatments the patient has already received and the level of disease activity:

             Tumor necrosis factor alpha (TNF) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in large quantities in the rheumatoid joint and is produced locally in the joint by synovial macrophages and lymphocytes infiltrating the joint synovium. TNF is one of the critical cytokines that mediate joint damage and destruction due to its activities on many cells in the joint as well as effects on other organs and body systems. TNF-alpha inhibitors are often preferred in patients with moderate to high disease activity, particularly when nonbiologic alternatives such as LEF are contraindicated.

There are currently five TNF inhibitors FDA approved for the treatment of RA (listed in order of their approval for RA); etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), and golimumab (Simponi®). Etanercept is a soluble TNF receptor-Fc immunoglobulin fusion construct; infliximab, adalimumab, and golimumab are monoclonal antibodies; and certolizumab pegol is an anti-TNF antigen binding domain-polyethylene glycol construct.  While differing in structure, the efficacy and safety of the drugs is similar across the class in reducing the signs and symptoms of RA, as well as in slowing or halting radiographic damage, when used either as monotherapy or in combination with methotrexate.

             DMARD triple therapy has shown equal long-term efficacy to the combination of MTX plus anti-TNF therapy. Concerning safety data on tsDMARDs (Janus kinase inhibitor class) have led to guidance that they be used only after an inadequate response to a TNF inhibitor. 

Fortunately in the last few years, a shift in strategy toward the earlier institution of disease modifying drugs and the availability of new classes of medications have greatly improved the outcomes that can be expected by most patients. The goal of RA treatment now aims toward achieving the lowest possible level of arthritis disease activity and remission if possible, minimizing joint damage, and enhancing physical function and quality of life. 

References: 

1. Cohen, S., & Mikuls, T. R. (2022, February 23). Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults. UpToDate. Retrieved from uptodate.com/contents/alternatives-to-methotrexate-for-the-initial-treatment-of-rheumatoid-arthritis-in-adults?search=rheumatoid%20arthritis&topicRef=7516&source=see_link#H3703799241

2. Smolen JS, Burmester GR, Combe B, et al. Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study. Lancet 2016; 388:2763.

3. Singh JA, Christensen R, Wells GA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 2009; 181:787.

             The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint damage, which begins early in the course of disease and may ultimately result in disability. Patients are less likely to respond well to therapy the longer active disease persists, and it is widely accepted that patients with active RA should be treated with disease-modifying antirheumatic drugs (DMARDs) at the earliest stage of disease, ideally within less than three months of symptom onset. 

The most commonly used DMARD for the initial treatment of RA is methotrexate (MTX).              Alternatives to MTX are sometimes used for the initial treatment of RA either because of comorbidities that present an absolute or relative contraindication to MTX, or because of patient or clinician preferences. The choice of the alternative agent to MTX is largely based upon the following: disease severity; comorbidities; patient preferences regarding relative risks and benefits and route of administration; and regulatory, insurance, and cost limitations. It is further shaped by evidence from indirect comparisons and limited head-to-head comparisons.

             Most patients unable to take MTX can be treated initially with another nonbiologic conventional synthetic DMARD (csDMARD), such as leflunomide (LEF). LEF is suggested rather than another csDMARD or a biologic DMARD. LEF is preferred over sulfasalazine (SSZ) because it may have greater efficacy, especially for the treatment of moderate to severely active RA. The advantages of LEF over TNF inhibitors are that it is taken orally and has a lower risk of serious adverse effects, including infection. Alternative nonbiologic DMARDs, depending upon comorbidities, prognostic features, and other factors, include SSZ, hydroxychloroquine (HCQ), and other much less frequently used agents. The use of HCQ monotherapy is typically limited to patients with very mild or limited disease. 

             In patients unable to use MTX because of liver disease, LEF should also be avoided and an alternative such as SSZ (1 to 1.5 g twice daily) or a TNF inhibitor (eg, etanercept 50 mg subcutaneously once weekly or adalimumab 40 mg subcutaneously every two weeks) should be used. Patients with high disease activity and significant functional impairment can use TNF inhibitors (eg, etanercept or adalimumab) as alternatives for initial therapy in patients with moderate to high disease activity or significant functional impairment who are not restricted by regulatory or cost constraints.

In patients who have low disease activity, HCQ is recommended as the initial alternative DMARD to MTX, rather than a more potent csDMARD or biologic DMARD. LEF and SSZ are other reasonable alternatives for this population. Reasonable options for women planning pregnancy include SSZ, HCQ in patients with mild disease, or a TNF inhibitor, while LEF should be avoided. 

             In patients unable to use these medications, a biologic agent such as a tumor necrosis factor (TNF) inhibitor is typically preferred, but several other biologic agents can be used for initial monotherapy. Other potential treatment options include kinase inhibitors, which have been classified as targeted synthetic DMARDs (tsDMARDs).

During the initial treatment of patients with active RA, the patient should be reevaluated every four to eight weeks to assess the effectiveness of therapy and to monitor for possible drug toxicity. Periodic reevaluation of disease activity using a quantitative composite measure at each assessment is suggested. In patients who fail to achieve remission or low disease activity within three months of initiating therapy or who require more than 5 to 7.5 mg/day of prednisone or equivalent glucocorticoid to maintain a state of remission or low disease activity, a more potent DMARD or combination of DMARDs is recommended rather than continuing the same treatment for a greater duration. 

             In patients with RA, affected areas may be irreversibly damaged or destroyed if inflammation persists. Thus, prompt diagnosis, early recognition of active disease, and measures to quickly achieve and maintain control of inflammation and the underlying disease process, with the goal of remission or low disease activity, are central to modifying disease outcome. The application of these principles in the management of patients with RA, together with the development and use of newer and more potent drugs, has resulted in significant improvement in the outcomes of treatment.

References: 

1. Cohen, S., & Mikuls, T. R. (2022, February 23). Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults. UpToDate. Retrieved from uptodate.com/contents/alternatives-to-methotrexate-for-the-initial-treatment-of-rheumatoid-arthritis-in-adults?search=rheumatoid%20arthritis&topicRef=7516&source=see_link#H3703799241

2. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76:960.

3. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2021; 73:924.

4. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:723.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation of the joints, leading to pain, swelling, and joint damage. Since the late 1990s, methotrexate (MTX) has been the anchor disease-modifying anti-rheumatic drug (DMARD) for RA. While MTX was an undoubted breakthrough in treatment options, not all patients achieve the desired response with approximately 30% discontinuing treatment within the 1st year due to a lack of efficacy or side effects. Among the latest breakthroughs in RA management are Janus kinase (Jak) inhibitors. JAK inhibitors are small, orally active drugs that are categorized as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) and have generally similar risks as the biologic DMARDs (bDMARDs) in treating immune-mediated inflammatory disease.

Jak inhibitors work by targeting the Janus kinase signaling pathway, which plays a pivotal role in the inflammatory response involved in RA. When cytokines, such as interleukins, bind to receptors on immune cells, Jak proteins are activated. This activation triggers a cascade of intracellular signaling events that lead to the production of inflammatory molecules. Jak inhibitors block the action of Jak proteins, thereby inhibiting the signaling process and reducing inflammation in the joints.

Jak inhibitors have demonstrated significant efficacy in the treatment of rheumatoid arthritis. Clinical trials have shown that these drugs can effectively reduce the signs and symptoms of RA, improve physical function, and slow down joint damage progression. They have been particularly beneficial in individuals who have not responded adequately to other DMARDs or who have experienced intolerable side effects with traditional therapies.

Compared to other DMARDs, Jak inhibitors offer certain advantages. First, they are orally administered, which is more convenient for patients compared to intravenous or injectable therapies. Second, they have a rapid onset of action, providing relief from RA symptoms sooner than some other medications. Additionally, Jak inhibitors have shown efficacy as monotherapy, reducing the need for concurrent use of multiple medications. This can simplify treatment regimens and potentially minimize side effects associated with polypharmacy.

There are currently three Jak inhibitors approved for the treatment of rheumatoid arthritis: tofacitinib, baricitinib, and upadacitinib. Tofacitinib was the first Jak inhibitor approved for RA and has been widely studied. Baricitinib and upadacitinib have also demonstrated efficacy and safety in clinical trials. Each of these medications has a unique profile, and their specific use may depend on factors such as disease severity, patient characteristics, and prior treatment history.

While Jak inhibitors have shown promise in RA management, it is important to consider potential side effects associated with their use. Common side effects include increased risk of infections, such as upper respiratory tract infections and urinary tract infections. Rare but serious adverse events, such as blood clots, liver abnormalities, and malignancies, have been reported. Regular monitoring of patients receiving Jak inhibitors is essential to identify and manage any potential complications. Safety data have led the US Food and Drug administration (FDA) to recommend tsDMARD use only after intolerance or an inadequate response to at least one TNF inhibitor. The FDA has also advised consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer.

Jak inhibitors have emerged as a promising class of medications for the treatment of rheumatoid arthritis. By selectively targeting the Janus kinase pathway, they effectively reduce inflammation and improve disease outcomes. With ongoing research and continued advancements, Jak inhibitors are expected to play a significant role in reshaping the management of rheumatoid arthritis and improving the quality of life for individuals living with this chronic autoimmune disorder. This ongoing research aims to further optimize the use of Jak inhibitors and explore their potential in managing other autoimmune and inflammatory conditions.

References:

1. Harrington, R., Al Nokhatha, S. A., & Conway, R. (2020). JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical Data. Journal of inflammation research, 13, 519–531. https://doi.org/10.2147/JIR.S219586

2. FDA Drug Safety Communication: FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. https://www.fda.gov/media/151936/download (Accessed on January 17, 2022).

3. Cohen, S., & Reddy, V. (2023, May 23). Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders. UpToDate. Retrieved from uptodate.com/contents/overview-of-the-janus-kinase-inhibitors-for-rheumatologic-and-other-inflammatory-disorders?search=rheumatoid%20arthritis&topicRef=7490&source=see_link#H2599056974

4. Cohen, S., & Cannella, A. (2023, April 28). Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy. UpToDate. Retrieved from uptodate.com/contents/treatment-of-rheumatoid-arthritis-in-adults-resistant-to-initial-conventional-synthetic-nonbiologic-dmard-therapy?search=rheumatoid%20arthritis&topicRef=7516&source=see_link#H4122541541

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic systemic autoimmune inflammatory disease associated with severe damage of the cartilage, bone, and joints. The disease progresses in a symmetrical manner. One of the most common clinical presentations of rheumatoid arthritis include polyarthritis of small joints of the hands, such as the proximal interphalangeal and metacarpophalangeal joints. Other affected areas may include the wrist, elbows, shoulders, hips, knees, angles, and metatarsophalangeal joints. Thus, rheumatoid arthritis is a painful disease, and both pharmacological and non-pharmacological treatments are significant in improving the quality of life of the patient. The goals of treatment include reduction of joint inflammation and pain, improve joint function, and prevent destruction of joints and deformations.

Rheumatoid arthritis begins with a complex interplay of environmental, genetic, and immunologic triggers that causes immune system dysregulation, leading to inflammation. However, its exact mechanism is poorly understood. T-cells, B-cells, and macrophages are immune cells that infiltrate the synovium, also known as the synovial membrane. The synovial membrane is the connective soft tissue membrane lining the inner surface of synovial joint capsules and houses blood vessels and lymphatics. It is an important tissue component that forms the joint. Infiltration of immune cells in the synovium contributes to the inflammatory nature of this disease. Destruction of the bone and cartilage of the joints and weakening of tendons and ligaments are expected thereafter. Further, B-cells produce auto-antibodies and secrete cytokines (IL-1, IL-6, IL-8, TNF) which further activate other antigen presenting immune cells. Secretion of chemokines induce chemotaxis whereas secretion of matrix metalloproteinases (MMPs), collagenase, and hydrolase leads to cartilage degradation. Essentially, the body is attacking the synovial lining of the joints. Overtime, the inflammation causes destruction of tissues, edema, and the development of pannus on the joint, which is extra tissue growth that is spongy. Development of pannus can cause pain and damage to the joints and surrounding cartilage, thereby decreasing mobility and affecting joint function.

One of the first-line therapies for the treatment of rheumatoid arthritis is the use of a disease-modifying antirheumatic drug, DMARD. DMARD reduces inflammation, reduces joint damage, and preserves joint function. Conventional DMARDs include methotrexate, hydroxychloroquine, and sulfasalazine. Biologic DMARDs include etanercept, adalimumab, abatacept, and tocilizumab, and are provided as an injection or intravenous infusion. New DMARDs on the market include tofacitinib, and are considered “targeted synthetic DMARDs.” Methotrexate, a conventional DMARD, reduces inflammation and slows down the individual’s overactive immune system. It is considered the gold standard or first-line treatment in individuals with moderate to high disease who have not taken a DMARD before. Methotrexate is a folic acid analog that competitively inhibits the enzyme, dihydrofolate reductase. As a result, the substrate, dihydrofolic acid, cannot bind to the enzyme. This inhibits the conversion of dihydrofolic acid to folinic acid, which is required for purine and pyrimidine metabolism, thereby inhibiting DNA and RNA synthesis. It also inhibits pro-inflammatory properties of T-cells, macrophages, endothelial cells, and fibroblast-like synoviocytes, which are all responsible for inflammation.

Monotherapy with methotrexate is preferred over combination treatments and other types of DMARDs due to lower incidence of side effects and flexibility in dosing. However, it is an immunosuppressive drug that requires regular blood tests, and can pose risk of hepatic impairment, cirrhosis, and bone marrow deterioration.

On the other hand, hydroxychloroquine (conventional DMARD) is reserved for those with mild symptoms. Hydroxychloroquine is an antimalarial drug that works by decreasing the secretion of monocyte-derived proinflammatory cytokines. Expected side effects include stomach pain and skin rashes. Individuals on this medication must consult with the ophthalmologist regularly as it can cause ocular toxicity, which decreases or blurs vision. Another conventional DMARD is sulfasalazine. Its mechanism of action is unclear. One reason is that the reduced form of sulfasalazine, sulfapyridine, reduces IL-8 and monocyte chemoattractant protein (MCP). Given that it is a sulfa and salicylate containing medication, it must be avoided in patients with sulfa allergies. Expected side effects include stomach pain and rash.

Moreover, corticosteroids or NSAIDs, such as aspirin, naproxen, ibuprofen, and etodolac, may be prescribed in addition to a DMARD to help relieve pain and inflammation. At high doses, aspirin inhibits prostaglandins, thereby reducing inflammation. NSAIDs inhibit cyclo-oxygenase, which prevents prostaglandin, prostacyclin, and thromboxane synthesis. It is important to note that NSAIDs do not reduce long-term, rheumatoid arthritis-induced damages of the joints, and it is imperative that a DMARD be prescribed for symptom management. Corticosteroids may also be prescribed due to its anti-inflammatory properties. It is more potent than NSAIDs, but has additional side effects. Thus, it is recommended for short-term use and at low doses during a flare-up or exacerbation of rheumatoid arthritis. Corticosteroids prevent the release of phospholipids and decrease eosinophil action, which decreases inflammation. Side effects of corticosteroid use include bone-thinning, weight gain, diabetes, and immunosuppression. To reduce side effects, it is recommended to gradually taper the dose upon improvement of symptoms. Abrupt discontinuation of injected or oral corticosteroid can initiate a rheumatoid arthritic flare-up or can lead to suppression of the hypothalamic-pituitary-adrenal axis, which may manifest as fatigue, immune system suppression, depression, and anxiety.

Non-pharmacological treatment includes regular physical activity. Although rheumatoid arthritis may impair joint mobility, inactivity can further weaken muscle strength and lead to loss of joint function. It is important that the individual performs regular physical activity, such as walking, swimming, cycling, or tai chi, as it can preserve and restore movement of joints and increase strength as well as endurance. Working alongside a physical therapist may also help improve joint mobility and function. Specific types of therapy may include balance training for the prevention of falls, and orthotics, which are foot device/shoe wear recommendations to reduce foot pain and improve walking.

In conclusion, to improve the quality of life of the individual and manage rheumatoid arthritis symptoms, both pharmacological and non-pharmacological therapy are used in an effort to reduce pain and inflammation, preserve joint function, and improve mobility.

References

Bullock, Jacqueline, et al. “Rheumatoid Arthritis: A Brief Overview of the Treatment.” Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre, 2 Sept. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6422329/.

Chauhan, Krati, et al. “Rheumatoid Arthritis: A Brief Overview of the Treatment.” Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre, pubmed.ncbi.nlm.nih.gov/30173215/. Accessed 6 June 2023.

Cronstein, Bruce N., and Thomas M. Aune. “Methotrexate and Its Mechanisms of Action in Inflammatory Arthritis.” Nature News, 17 Feb. 2020, www.nature.com/articles/s41584-020-0373-9.

“Hand Rheumatoid Arthritis.” Physiopedia, www.physio-pedia.com/Hand_Rheumatoid_Arthritis. Accessed 6 June 2023.

“Patient Education: Rheumatoid Arthritis Treatment (Beyond the Basics).” UpToDate, www.uptodate.com/contents/rheumatoid-arthritis-treatment-beyond-the-basics#H402960751. Accessed 6 June 2023.

“Rheumatoid Arthritis Treatment Guidelines.” Rheumatoid Arthritis Treatment Guidelines, www.arthritis.org/diseases/more-about/rheumatoid-arthritis-treatment-guidelines. Accessed 6 June 2023.

Rheumatoid Arthritis is a chronic inflammatory disorder that can have a major impact on quality of life. In some people, this condition can damage many different body systems such as skin, eyes, lungs, heart, and blood vessels. The cause of this condition is when a person’s immune system mistakenly attacks the body’s own tissues. Rheumatoid arthritis is progressive and affects the lining of the synovial joints which causes painful swelling that can lead to bone erosion and joint deformity. If untreated, this can lead to significant pain, deformity, loss of manual function and deterioration in overall quality of life. The inflammation caused by rheumatoid arthritis can cause physical disabilities even with new types of medications having improved treatment options. Many of the treatment options for rheumatoid arthritis are NSAIDs, corticosteroids, methotrexate, tumor necrosis factor inhibitors, interleukin 1 inhibitors, rituximab, abatacept, and more. There has recently been data supporting the use of Janus Kinase Inhibitors in the treatment of rheumatoid arthritis. Some janus kinase inhibitors are upadacitinib, baricitinib, and tofacitinib. This is probably the most recent new drug class being tested for the use of this condition.

There are many trials on the use of janus kinase inhibitors. The ORAL scan trial was 24 month trial undertaken to evaluate the efficacy and safety of tofacitinib in patients with active rheumatoid arthritis that have an inadequate response to methotrexate. In this trial, there were seven hundred seventy-nine patients randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo switching to tofacitinib 5 mg twice daily with stable background methotrexate or placebo switching to 10 mg twice daily with stable background methotrexate. Patients receiving placebo switched to tofacitinib at month 3 or month 6 based on if they were not responding to treatment. In this trial, they evaluated clinical efficacy, structural progression, and treatment-emergent adverse events. Out of the 797 patients that were treated, 539 completed 24 months of treatment which was about 67.6 percent. The proportion of patients in whom remission or low disease activity was achieved according to the 4-variable disease activity score in 28 joins using erythrocyte sedimentation rate, clinical disease activity index, or simplified disease activity index, Boolean remission, and health assessment questionnaire disability index scores were maintained from month 12 to month 24 and were similar between the tofacitinib dosages. The safety events were also similar in type and frequency and were consistent with previous reported data. In this study, they found that the treatment of rheumatoid arthritis using janus kinase inhibitors like tofacitinib in combination with methotrexate would best sustain the effects of clinical and radiographic treatment. There was limited structural damage observed at months 12 and 24. The safety profile in this study was consistent with previous tofacitinib studies. This was a study that was conducted soon after tofacitinib has been approved for the use in the treatment of patients with moderate to severe rheumatoid arthritis. I believe studies like the ORAL scan study can help contribute to progressing treatment options for rheumatoid arthritis in the future.

References:

1. van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R; ORAL Scan Investigators. Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study. Arthritis Rheumatol. 2019 Jun;71(6):878-891. doi: 10.1002/art.40803. Epub 2019 Apr 24. PMID: 30666826; PMCID: PMC6593705.

2. “Rheumatoid Arthritis.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 18 May 2021, https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648.