Rheumatoid Arthritis, A Laconic Review to understand their Basic Concept and Management Process

 

Sweta1*, Archana Chaudhary2, Vinay Pandit3, M. S. Ashawat4, Tarun Kumar5

1Research Scholar, Laureate Institute of Pharmacy, Kathog, Jawalamukhi, Himachal Pradesh, 176031, India.

2Assistant Professor, Department of Pharmaceutics, Laureate Institute of Pharmacy,

Kathog, Jawalamukhi, Himachal Pradesh, 176031, India.

3Head of Department, Department of Pharmaceutics, Laureate Institute of Pharmacy,

Kathog, Jawalamukhi, Himachal Pradesh, 176031, India.

4Director cum Principal, Laureate Institute of Pharmacy, Kathog, Jawalamukhi, Himachal Pradesh 176031.

5Assistant Professor, Laureate Institute of Pharmacy, Jawalmukhi - 176031, Himachal Pradesh, India.

*Corresponding Author E-mail: sweta24021999@gmail.com

 

ABSTRACT:

Rheumatoid arthritis is a chronic inflammatory illness characterized by joint stiffness, bone and cartilage destruction, and swelling above the joints. The condition is linked to chemicals found within the major histocompatibility complex, also as T-cells that are hooked in to them. The condition is more severe in women than in men, also as within the elderly population. The effects of gender on the clinical course of the disease are studied, but the results are mixed. The factor like genetic, environmental, smoking, and age of a person were trigger’s the rheumatoid arthritis. The other clinical complications were observed in patients with rheumatoid arthritis which includes depression, infection, malignancy, cardiovascular disorder, pulmonary disease etc. According to research, RA risk might be impacted by a genetic predisposition, environmental factors, or a combination of both. Immune cells such as lymphocytes, neutrophils, and macrophages have long been thought to have a role in the development of RA involved in pathological mechanism. Rheumatoid arthritis have been diagnosed by imaging with colour doppler sonography or gadolinium-enhanced magnetic resonance imaging can detect the presence of osynovitis, and serologic testing for auto-antibodies and APRs was required to diagnose rheumatoid arthritis. To cure and prevent the patients form rheumatoid arthritis it is very necessary to take suitable treatment. So, in present work we also highlighted the available drugs used for the treatment of RA. The first line therapy agents include Non-steroidalantiinflammatory drugs, and corticosteroids. The second line agents used in RA are Disease modifying Antirheumatic drugs (DMARDs). The patients having age more than 60 years also need surgery to cure rheumatoid arthritis. To decrease the side effects from some potent agents include methotrexate the vitamin D, folic acid, and dietary supplements were used with treatment. So, this review article helps the researcher’s to understand the basic overview of rheumatoid arthritis, causes, other disease development, and management process with regards to available FDA approved therapeutics, and published patents.

 

KEYWORDS: Rheumatoid arthritis, Etiology, Pathophysiology, Diagnosis, Treatment.

 

 


 

INTRODUCTION:

Rheumatoid arthritis is a chronic inflammatory illness characterized by joint stiffness, bone and cartilage destruction, and swelling above the joints. The condition is linked to chemicals found in the major histocompatibility complex, as well as T-cells that are dependent on them. The condition is more severe in women than in men, as well as in the elderly population 1. The condition results in systemic inflammation of the joints, persistent synovitis, tissue destruction due to the release of cytokines, and inflammation due to an autoimmune cell imbalance. The tissues will be damaged by the autoimmune antibodies2.

 

In the adult population, rheumatoid arthritis affects 1% of the population. The major cytology of comprehensive frailty ranks this disease 42nd. The fatality rate from rheumatoid arthritis-related heart illnesses and pulmonary problems is 10-20% and 60-80%, respectively3. Patients with rheumatoid arthritis currently have parallel occurrences linked to an elevated risk of cancer during or after treatment4. In the 1970s, rheumatoid arthritis was diagnosed by examining the synovial fluid of patients and identifying high levels of prostaglandins.

 

 

Figure 1: (A) Systematic Representation of Normal Joint (B) Systematic Representation of Joint Affected by Rheumatoid Arthritis.

 

RA affects 0.5-1 percent of the population, with a woman-to-man ratio of 3:12. It is 4–5 times higher in women under the age of 50, but after 60 years, the ratio drops to about 2 to 13. The frequency of this condition is high in Latin America, with a ratio of 5.2 women per male in Colombia4,5.2 to 1 in Argentina5, and 5.5 to 1 in Cuba 6.

 

 

Figure 2: Different Stages of Rheumatoid Arthritis.

 

The effects of gender on the clinical course of the disease have been studied, but the results have been mixed. Some studies indicate that men are in a worse position than women7, while others assert the contrary8–11. Women exhibit more functional disability, disease activity, and pain than men, according to Lesuis et al.12, Sokka et al.13, and Hallert et al.14. Being a guy has also been found to be a predictor of remission8,9, and women have more job disability in terms of lost work days and productivity15. In this review article we discuss about the basic fundamentals related with rheumatoid arthritis with respect to pathological mechanism involved in the production of rheumatoid arthritis, and the risk of other disease complications were studied. Also, we identify the diagnosis and available medications which includes non-steroidal anti-inflammatory drugs NSAIDs, corticosteroids, Disease modifying Antirheumatic drugs DMARDs, and biological DMARDs.  Also, with this the published patents for the disease management, and FDA approved products were highlighted in Table 1.

 

ETIOLOGY:

Rheumatoid arthritis has yet to be identified as a cause. It could be due to a shift in a genetically sensitive host's reaction to an infectious pathogen. Mycoplasma, CMV, Epstein Barr virus, rubella virus, and parvovirus are some of the possible causal agents. It is uncertain how an infectious agent that causes chronic inflammatory arthritis spreads in a specific way.

 

Rheumatoid arthritis is influenced by the following factors:

a)    Genetic and environmental factors

b)   Smoking

c)    The microbiota of humans

 

 

Figure 3: Causes of Rheumatoid Arthritis.

 

a)   Genetic and environmental factors:

According to several genetic researches the hereditary impact for rheumatoid arthritis is between 30% and 60%. The “shared epitope” found in the DRB1 allele is the most important genetic component linked to rheumatoid arthritis. The presence of a common epitope is linked to a threefold increase in the occurrence of rheumatoid arthritis.

 

b)   Smoking:

Smoking is a major contributor to the development of a variety of chronic diseases. According to several studies, ACPA-positive people who drink coffee have a higher risk of developing rheumatoid arthritis. People who drink more than four cups of coffee had a relative risk factor2.According to a Swedish study, men's exposure to mineral oil at work is a risk factor. Rheumatoid arthritis was shown to be more common in the Swedish population who worked in mineral oil resources, with a 57 percent rise in cases. Individuals who are APCA positive will develop rheumatoid arthritis if they are exposed to silica at work. Other factors that have been linked to an increased risk of rheumatoid arthritis include a lower intake of vitamin D and antioxidants, as well as a higher diet of sugar, sodium, red meats, proteins, and iron.

 

c)    Human microbiome:

The transition from a symbiotic to a dysbiotic microbiome, which is characterised by high microbe growth and a lack of bacteria/organisms, is a contributing risk factor for the development of rheumatoid arthritis. Deviations in innate and adaptive immunity may result as a result of this9.

 

Risk Factors Associated with Rheumatoid Arthritis:

Hormone exposure, drinking decaffeinated coffee more than three times a day, tobacco use, and smoking are all examples of environmental influences.

 

·      Hormone exposure:

Estrogens have pro-inflammatory properties in women, while androgens have anti-inflammatory properties. Oestrogens have varied effects on different immune cells (activation and inhibition) depending on serum concentration, reproductive stage or ageing phase of the ovary, oestrogen receptor expression, or intracellular metabolism. Exposure to oestrogen (HRT, Ocs), polycystic ovary syndrome, and postpartum 10.

 

·      Coffee consumption:

Coffee consumption is a risk factor for the release of rheumatoid factor. Age, serum LDL cholesterol, and smoking are not dependently associated with coffee consumption. The amount of cups of coffee consumed can predict positive rheumatoid arthritis. Rheumatoid arthritis is more common in people who smoke and drink coffee11.

 

·      Tobacco usage:

Tobacco smoking produces an increase in oxidative stress in the human body, which leads to the development of rheumatoid arthritis. The expression of matrix metalloproteinase-12 (MMP-12) has increased as a result of cigarette smoking (produced by macrophages and dendritic cells). MMP-12 overexpression results in the development of the pannus, opaque synovium, macrophage infiltration, and obvious cartilage damage in the articules in later stages 12.

 

·      Gender (female):

Family history, advanced age, and HLA genotype are all genetic factors.

Vitamin D, tea, oral contraceptives, and breastfeeding can all help to minimize the incidence of rheumatoid arthritis.

 

Signs and Symptoms:

Rheumatoid arthritis affects about 1% of the world's population, though there is significant regional variation. Native Americans, such as the Chippewa Indians, have a high rate of this disease (6%), while Japanese, Chinese, and Saharan blacks have a lower rate. Rheumatoid arthritis affects the wrists, fingers, feet, elbows, ankles, and knees, as well as other body areas such as the shoulders, hips, and cervical spine. Passive movement pain, swelling, heat sensation, and morning hardness lasting more than an hour are all symptoms of the condition. Fingers with a spindle form are common. All of the symptoms listed above will last for more than 6 weeks, and you will be diagnosed with rheumatoid arthritis.

 

Rheumatoid arthritis is frequently accompanied by rheumatoid nodules, which are non-vascular manifestations. The central necrotic core of white cells and a radiating palisade of connective tissue on the stretching surfaces of fingers and elbows are located in the hypodermis. Other regions of the body with nodules include the scalp, back, feet, hands, buttocks, and knees, as well as the heart valves, pericardium, lung parenchyma, and spleen.

 

Due to thrombosis of blood vessels in the periphery, myocardial infarction, stroke, Reynaud's syndrome, and very infrequently skin ulcers, vascular insufficiency in the region of the periphery arises. Lethargy, melancholy, thinness, lymphitis, clinical depression, abnormal enlargement of the spleen, muscle weakness, white nails, quicker heartbeat, and fever are all systemic symptoms of rheumatoid arthritis (origin is unknown). Sclerotitis, anterior sclerotitis (bluish hue and painful) and posterior sclerotitis (Grave's disease or hyperthyroidism, choroid leaking, and vision loss) are ocular diagnoses13.

 

Clinical Complications:

·      Depression:

40% of the population is influenced by the usage of corticosteroids. Socioeconomic factors (pay, education, job, race, neighbourhood circumstances), patient factors (sex, age, ethnicity, comorbidities, social support), and rheumatoid arthritis disease factors (injury, disease activity, pain, frailty, clinical reduction) are all linked to depression14.

 

·      Infection:

Infection can be caused by rheumatoid arthritis or the use of immunosuppressive drugs. The use of biologics, in combination with the usage of steroids and DMARDs, can result in severe infections15.

 

·      Malignancy:

Lymphoma (risk is twice in rheumatoid arthritis patients), Lung cancer (causes-smoking, interstitial lung disease), Skin cancer (risk synergizes with immunosuppressant usage). Cardiovascular illness -Heart failure, ischemic heart disease, myocardial infarction, and coronary revascularization are all risks connected with rheumatoid arthritis in terms of cardiovascular disease16.

 

·      Pulmonary Manifestations:

Pleural disease, parenchymal disease, pulmonary nodules, airway disease, and vasculitis were first reported in association with RA in 1948, and since then, various lung involvements such as pleural disease, parenchymal disease, pulmonary nodules, airway disease, and vasculitis have been reported 17,18. Pulmonary involvement accounts for a large proportion of systemic symptoms, ranging from 60% to 80%, which is exacerbated by opportunistic infections linked to immunosuppressive drug use or direct pulmonary toxicity from methotrexate and anti-tumor necrosis factor drugs17.

 

·      Cardiovascular Manifestations:

Cardiovascular disease (CVD), heart failure, arrhythmia, valve disease, pericarditis, and myocarditis are some of the cardiac and vascular signs of RA. CVD is the primary cause of death in RA; with mortality rate 1.5 to 3.0 times that of the general population18. Traditional atherosclerotic risk factors like smoking, high blood pressure, and hyperlipidemia are essential, but they don't explain the whole range of CVD risk.Genetic variables, oxidative stress, and treatment medications such as Nonsteroidal anti-inflammatory medicines (NSAIDs) or GCs have all been identified as independent risk factors for endothelial dysfunction and vascular injury.

 

·      Neurological Manifestations:

The peripheral (PNS) or central (CNS) nervous systems are affected by neurological abnormalities in RA, with symptoms ranging from sudden death to moderate paresthesia. The majority of problems result from articular inflammation compressing or invading the neighboring spinal cord, peripheral nerve, or neural structures. Cervical myelopathy, vasculitis, rheumatoid meningitis, CNS rheumatoid nodules, and progressive multifocal leukoencephalopathy are all CNS disorders. Cervical myelopathy is the most common sign of CNS, with up to 50% of RA patients experiencing it19.

 

·      Musculoskeletal Involvement:

Many alterations in bone health are caused by RA-related systemic and local inflammation. Periarticular osteopenia and juxta-articular bone erosions occur near inflamed and swollen joints early in the disease. Joint ankylosis can develop as a result of high disease activity and protracted disease duration. It is commonly accepted that lowering disease activity early on with conventional or biologic DMARDs can slow or stop the course of bone erosions.

 

Pathogenesis of Rheumatoid Arthritis:

Rheumatoid arthritis is an autoimmune disease in which the synovial lining becomes inflamed. The number of synoviocytes and immune cells increases as a result of inflammation. As a result, the synovial membrane becomes hyperplastic, causing cartilage and bone loss in the long run20. Figure 4 depicts the pathophysiology of rheumatoid arthritis.

 

RA risk may be influenced by a genetic predisposition, environmental variables, or a combination of both, according to research. Immune cells like lymphocytes, neutrophils, and macrophages are well known to play a role in the pathogenesis of RA21. Macrophages and T cells in the synovium of RA patients release cytokines that increase inflammation and cell migration. Macrophage-produced cytokines tumour necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) and CD4+ T cell-produced cytokines interleukin-17 (IL-17) are all involved in the inflammatory response and subsequent cartilage breakdown.

 

Figure 4: Pathological Mechanism of Rheumatoid Arthritis.

These cytokines drive synoviocytes to proliferate and produce proteases in the synovial fluid, resulting in cartilage disintegration and hypertrophied synovial tissue, a condition known as pannus22. Angiogenesis can aggravate pannus even more. Immune cells infiltrate the joints as a result of the increased blood supply to invading cartilage and bone, increasing synovial hyperplasia23. Cytokines also stimulate osteoclast activity, which leads to bone erosion, when they combine with the receptor activator of nuclear factor kappa-ligand (RANKL). T cells influence RANKL expression as well24.

 

Synovial dendritic cells boost the immune system by recruiting T lymphocytes and activating antigen-specific T cells, which then activate B cells. Activated B cells boost CD4+ T cells, causing them to produce additional cytokines in a positive feedback loop25,26. Plasma cells, which create autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), are formed when B cells proliferate27. These auto-antibodies infiltrate the joint through newly formed blood vessels and are now utilized to diagnose and prognostic RA28.

 

Diagnosis of rheumatoid arthritis:

Early on in the disease, RA may only affect one or a few joints. Tendon inflammation (tenosynovitis) develops at the same time or even sooner. Imaging with colour Doppler sonography or gadolinium-enhanced magnetic resonance imaging can detect the presence of osynovitis, such as at the flex or carpiulnarist end on, and subclinical synovial inflammation, which show expansion of intra-articular soft tissue or hypervascularization of the synovial membrane.

 

There are no diagnostic criteria for RA. The 2010 classification criteria, on the other hand, may aid physicians in establishing a diagnosis, while being designed primarily for the identification of homogeneous patient populations in clinical investigations of RA28,29. A recent report highlighted the disparities between classification and diagnosis. Up to 5 points are awarded for joint involvement based on physical examination or imaging by ultrasound or magnetic resonance imaging; increased levels of RF, ACPAs, or both earn an extra 2 points).

 

Because early diagnosis and treatment prevent joint damage progression in 90% of patients with early RA30. It is critical to identify RA patients as soon as possible. Arthritic pain and swelling in the metacarpophalangeal joints, metacarpophalangeal joints, or both, morning stiffness of finger joints lasting 30 minutes or longer, and autoantibody positivity are all symptoms that could indicate RA31.

 

An initial evaluation of the joints, as well as serologic testing for auto-antibodies and APRs, is required. Joint assessment, review of APRs, and evaluation of patient-reported outcomes such as patient global assessment of disease activity and physical function are critical for follow-up. In practice (and in trials), composite measures that include joint counts, i.e., the number of sore and swollen joints, are the best way to assess RA disease activity since they include the most significant disease characteristics in a single score. The clinical disease activity index (CDAI), the disease activity score utilizing 28 joint counts (DAS28), and the simplified disease activity index (SDAI) are all scores that correlate with damage progression and functional destruction32,33.


 

Table 1: List of Available Drugs for the Treatment and Management of Rheumatoid Arthritis.

S. No.

Types of Treatment

Name of Drug

Common Side Effects

 

 

1.

 

Disease modifying Antirheumatic drugs (DMARDs)

Hydroxychloroquine Sulfate (Plaquenil)

Leflunomide (Arava)

Methotrexate (Traxall)

Sulfasalazine(Azulfidine)

Upset stomach

Rashes

Hair loss

Mouth sores

Skin reactions

 

 

 

2.

 

 

 

Biologics DMARDs

Abatacept (Orencia)

Adalimumab (Humira)

Certolizumab pegol (Cimzia)

Etanercept (Enbrel)

Golimumab (simponi)

Infliximab (Remicade)

Rituximab (Rituxan)

Tocilizumab (Actemra)

 

 

Liver damage

Nausea

Pain and swelling

Risk of cancer

Lung infection

 

 

 

 

 

 

 

3.

 

 

 

 

 

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

Celecoxib (Celebrex)

Ibuprofen (Prescription strength)

Nabumetone (Relafen)

Naproxen (Naprosyn)

Naproxen sodium(Anaprox)

Piroxicam (Feldene)

Diclofenac (Voltaren)

Diflunisal

Indomethacin (Indocin)

Ketoprofen (Actron)

Etodolac (Lodine)

Fenprofen (Nalfon)

Flurbiprofen

Ketorolac (Toradol)

Meloxicam (Mobic)

 

 

 

Black or bloody stool

Severe pain

Hives

Skin rash

Irritation

Redness

Dizziness

Blurred vision

Allergic reaction

 

 

 

 

4.

 

 

 

 

Corticosteroids

Betamethasone

Cortisone

Dexamethasone (Hexadrol)

Hydrocortisone (A-hydrocort)

Prednisolone

Methylprednisolone (Predacorten)

Prednisone (Deltasone)

High blood pressure

Weight gain

Mood changes

Rashes on skin

Irritation

Stomach pain

Nausea

Weak bones

 


 

These indices can be used to quantify disease activity, and disease activity states based on certain cut points have been created to aid treatment. Remission, defined as no disease activity, and low disease activity, corresponding to mild residual activity with low risk of damage progression, are two treatment goals; these two states contrast with moderate and high disease activity states, which indicate uncontrolled disease with time progression. The CDAI is the most straightforward of all the indicators. On a 10-cm visual analogue scale, it is a simple numerical total of four variables: swollen and tender joints (using 28 joint counts), patient global assessment, and evaluator global assessment. The CDAI is a scale that spans from 0 to 76. (higher scores worse) 34.

 

To track therapy using the "treat-to-target" strategy, assessment instruments, especially the CDAI, should be employed. This technique entails treating patients and adjusting therapy as needed to achieve a 50% improvement in disease activity by 3 months and hence a greater than 50% chance of reaching low disease activity or remission at 6 months. Clinical remission (particularly in early RA) or minimal disease activity are the treatment goals (in established RA if remission is not achievable). Clinical remission, as measured by the CDAI or SDAI, is a state in which physical function is at its best and joint damage development is halted.  The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recently created remission criteria using a Boolean approach or indices, such as the SDAI and CDAI35.

 

Treatment For Rheumatoid Arthritis:

Treatment for RA aims to minimize joint inflammation and pain while also maximizing joint function and preventing joint degeneration and deformity. Combinations of medicines, weight-bearing exercise, disease education, and rest are used in treatment regimens36. Treatments are usually tailored to a patient's specific needs and are determined by their overall health. This includes things like illness progression, affected joints, age, overall health, occupation, compliance, and disease education37.  This article quickly summarises the traditional and contemporary therapy options for RA symptoms and consequences. Smolen et al. 37 recently published an in-depth review. The available drugs which are used in RA were enlisted in Table No. 138.

 

·      First-Line Treatment: NSAIDS and Corticosteroids:

The general goal of first-line treatment is to reduce inflammation and relieve pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylate (Aspirin), naproxen (Naprosyn), ibuprofen (Advil and Motrin), and etodolac, are fast-acting medications (Lodine). Because it inhibits prostaglandins, aspirin is an effective anti-inflammatory for RA when taken in large dosages. It's one of the oldest Nonsteroidal anti-inflammatory drugs (NSAIDs) for joint discomfort. Tinnitus, hearing loss, and gastrointestinal intolerance are all side effects of taking too much aspirin. There are newer NSAIDs on the market that are just as effective as aspirin. Furthermore, these medications require fewer daily doses. NSAIDs prevent the formation of prostaglandins, prostacyclin, and thromboxanes by inhibiting cyclooxygenase. Nausea, abdominal pain, ulcers, and gastrointestinal (GI) bleeding are all common adverse effects. If used with meals, antacids, proton pump inhibitors, or misoprostol, these symptoms can be lessened (Cytotec), Celecoxib (Celebrex), a more recent NSAID, is a selective Cox-2 inhibitor with fewer GI side effects 37.

 

Corticosteroids are more effective anti-inflammatory drugs than NSAIDs, but they have higher negative effects. As a result, they are only prescribed at low doses for a brief period of time during RA exacerbations or flares. Corticosteroid injections into the articular cartilage can be used to treat local inflammatory symptoms38. They reduce inflammation by limiting the release of phospholipids and lowering the actions of eosinophils. Bone thinning, weight gain, diabetes, and immunosuppressant are all possible side effects. It is possible to avoid bone weakening by advising the patient to take calcium and vitamin D supplements. It is critical not to stop using injectable or oral corticosteroids suddenly, since this might cause suppression of the hypothalamic-pituitary-adrenal axis (HPA) and RA flares39.

 

·      Second-Line Treatment: Disease-Modifying Antirheumatic Drugs (DMARDs):

The overall goal of second-line treatment is to induce remission by reducing or stopping joint degeneration and deformity from progressing. Slow-acting medications are defined as those that take weeks to months to take effect. DMARDs (disease-modifying Antirheumatic drugs) can also reduce the risk of lymphoma, which is linked to RA40.

 

The initial second-line medication is Methotrexate (MTX) (also considered an anchor drug). It's a folic acid analogue that competes with dihydrofolic acid (FH2) for binding to the enzyme responsible for converting FH2 to folinic acid (FH4). Purine and pyrimidine metabolism is hampered without FH4, and amino acid and polyamine production is impeded. Due to its side effects, such as liver issues, cirrhosis, and bone marrow degradation, MTX is an immunosuppressive medicine that requires regular blood tests. Supplementing with folic acid can help to lower the chance of negative effects. It is an effective DMARD with less adverse effects than other DMARDs and dosage flexibility, which allows for dose adjustments as needed41. Until date, there hasn't been enough evidence to support the use of standard synthetic DMARDs in combination with MTX monotherapy. Biological and synthetic DMARDs used together, on the other hand, are said to be better than MTX, but with more side effects and higher costs42,43.

 

Plaquenil (Hydroxychloroquine) is an antimalarial medicine that can be used to treat RA for a long time. The release of monocyte-derived proinflammatory cytokines is reduced by this medication. Problems with the gastrointestinal tract, skin, and central nervous system are all common side effects. When this medicine is taken in excessive amounts, it can have an adverse effect on the eyes in particular. Patients taking this medication should see an ophthalmologist on a regular basis44.

 

Sulfasalazine (Azulfidine) is a DMARD that is commonly used to treat irritable bowel syndrome. This DMARD can be used to treat RA when used with anti-inflammatory medicines. This drug's mechanism of action in the treatment of RA has yet to be discovered. Sulphapyridine, a decreased version of the medicine after delivery, is hypothesized to inhibit interleukin (IL)-8 and monocyte chemoattractant protein secretions (MCP). This medication has gastrointestinal (GI) and central nervous system (CNS) symptoms, as well as a rash. It is generally well accepted by patients, but because it includes sulfa and salicylate components, it should be avoided in people with sulfa allergy45. Aurothioglucose (Solganal), auranofin (Ridaura), gold sodium thiomalate (Myochrysine), and D-penicillamine (Depen and Cuprimine) are examples of gold salts that have been used to treat RA. Due to damage to the bone marrow and kidneys, many DMARDs necessitate periodic blood and urine testing. They haven't been used in a long time because more effective medications, particularly MTX, have replaced them. Other immunosuppressive drugs, such as azathioprine (Imuran), cyclophsphamide (Cytoxan), chlorambucil (Leukeran), and cyclosporine (Sandimmune), can be used, but they're usually reserved for individuals with highly active RA or problems46,47.

 

·      Biological DMARD’s:

Biologics, also known as biological DMARDs, are highly successful at slowing down the course of RA-related joint deterioration. They are thought to offer a more "direct, defined, and targeted" therapy strategy48. Despite this, biologics have substantial adverse effects, such as an increased risk of infection. Neurologic illnesses such as multiple sclerosis and lymphoma are also common adverse effects49-51.

 

·      Surgery:

In the 1990s, joint surgery for RA patients was at an all-time high. However, a 2010 study found that RA patients aged 40 to 59 had lower rates of joint surgery. Patients above the age of 60, on the other hand, had a higher rate of surgery41.  Surgery is only used as a last resort to treat RA. Intractable joint discomfort or functional deterioration owing to joint damage after all nonsurgical options have failed are examples of indications. The sickness is considered “end-stage” at this time. The goal of surgical management is to reduce the patient's pain and restore joint function.

 

·      Other Therapies:

Contrary to popular belief, people with RA do not need to avoid any specific foods. Dietary “aggravation” of symptoms is no longer a widely held belief 53. Although they are not as effective as DMARDs, home treatments have been shown to be beneficial for patients with RA. Short-term RA symptoms can be helped with fish oils and omega-3 fatty acid supplementation. In people with this condition, cumin has been proven to have anti-inflammatory properties. Preventing osteoporosis can be as simple as taking calcium and vitamin D supplements. Finally, folic acid may aid in the prevention of MTX adverse effects54.

 

Physical and occupational therapy are also beneficial to RA patients. They should exercise on a regular basis to maintain joint mobility and strengthen the muscles that surround the joints. Swimming, yoga, and taichi are examples of movement workouts that are less stressful to joints while yet improving muscle strength. Pre- and post-exercise use of heat and cold packs reduces uncomfortable symptoms. Different forms of connective tissue collagen are being studied in order to better understand and reduce RA disease activity. Finally, as science progresses and our understanding of molecular pathways improve, newer and better therapeutic alternatives should become available in the near       future 55-60.


 

Table 2: List of Published Patents for the Treatment and Management of Rheumatoid Arthritis.

S. No.

Patent No.

Invention

Assignee

Year of Publication

Reference

1.

WO1998005357A1

Anti-tnf antibodies and methotrexate in the treatment of autoimmune disease

 

Feldmann M, Maini R

 

1998

 

[61]

2.

CN107385034B

Methods for treating, diagnosing and monitoring rheumatoid arthritis

Dennis G, Martin F, Townsend MJ

 

2017

 

[62]

3.

JP5675829B2

Biomarkers and methods for measuring and monitoring inflammatory disease activity

Cavet GL, Shen Y, Knowlton N, Centola M

 

2015

 

[63]

4.

US4732757A

Methods for treating, diagnosing and monitoring rheumatoid arthritis

Stolle RJ, Beck LR

1988

[64]

5.

US20040006038A1

Method for therapy of rheumatoid arthritis

Nithyashree RS, Deveswaran R

2009

[65]

6.

US20090252692A1

Esterified fatty acid composition

Spencer WP, Millsap PS

2009

[66]

7.

US20100190755A1

Tetracycline compounds for the treatment of rheumatoid arthritis and related methods of treatment

Abato Paul, Bowser

2010

[67]

8.

US9067992B2

Use of TNF-α inhibitor for treatment of psoriatic arthritis

Hoffman RS, Weinberg M

2015

[68]

10.

US20170350884A1

Rheumatoid arthritis related biomarker

 

2017

[70]

11.

US8703718B2

Methods for treating juvenile rheumatoid arthritis by administering a soluble CTLA4 molecule

Cohen R, Belder-Carr S, Hagerty D, Peach RJ, Becker JC

2014

[71]

12.

JP2021019594A

Methods for treating, diagnosing and monitoring rheumatoid arthritis

Dennis G, Martin F, Townsend MJ

2009

[72]

13.

US8519096B2

Citrullinated peptides for diagnosing and prognosing rheumatoid arthritis

Ling NC, Wang SL, Wang D, Singh S

2013

[73]

14.

US8728469B2

Method of treating rheumatoid arthritis using anti-IL-20 antibodies

Thompson P, Blumberg H, Chandrasekher YA, Novak JE

2014

[74]

15.

US5399347A

Method of treating rheumatoid arthritis with type II collagen

Trentham DE, Weiner HL, Hafler DA

1995

[75]

16.

US5741488A

Treatment of rheumatoid arthritis with anti-CD4 antibodies in conjunction with anti-TNF antibodies

Feldman M, Maini RN, Williams RO

1998

[76]

17.

AU2013279597B2

Aminotriazolopyridine for use in the treatment of inflammation, and pharmaceutical compositions

van'tKlooster GA, Namour FS, Brys RC, Van Rompaey LJ

2016

[77]

18.

EP2279196B1

Compounds including an anti-inflammatory pharmacore and methods of use

O'brien PM, Anderson E, Bolton GL, Ferguson DA, Jiang X, KralJr RM, Visnick M

2015

[78]

19.

US9987272B2

Compound useful for the treatement of degenerative and inflammatory diseases

Menet CJ, Hodges AJ, Vater HD

2014

[79]

20.

US20160280776A

Uses and Compositions for Treatment of Juvenile Rheumatoid Arthritis

Medich JR, Ruperto N, Martini A, Lovell DJ, Giannini EH

2016

[80]

21.

JP2017137338A

Compositions for the treatment of rheumatoid arthritis and methods of using same

Huang X, Jasson M, Marks V, Radin A, Fan C, Van Hoogstraten H, Fiore S, Van Adelsberg J, Genovese M

2016

[81]

22.

US20160022692A1

Treatment of rheumatoid arthritis and asthma using pi3 kinase inhibitors

Palombella VJ, Kutok JL

2014

[82]

23.

US9737521B2

Pharmaceutical compositions containing a PDE4 inhibitor and a PI3 delta or dual PI3 delta-gamma kinase inhibitor

Vakkalanka SK, Viswanadha S

2017

[83]

24.

US7732587B2

Nucleic acids encoding truncated soluble tumor necrosis factor

Fisher E, Edwards III C, Kieft G

2010

[84]

25.

US9987272B2

Compound useful for the treatement of degenerative and inflammatory diseases

Menet CJ, Hodges AJ, Vater HD

2014

[85]

26.

US20180291112A1

Methods for Treating Disseminated Intravascular Coagulation by Inhibiting MASP-2 Dependent Complement Activation

Schwaeble HW, Dudler T, Tedford CE, Parent JB, Demopulos GA

2014

[86]

Table 3: List of FDA Approved Therapeutics for the Management of Rheumatoid Arthritis 87.

S. No.

Category

Drug

Brand Name

Adult Dose

Company

Approval of FDA

 

 

 

 

 

1.

 

 

 

 

 

NSAIDs

Celecoxib

Celebrex

Tablet 100 to 200 mg orally twice daily.

G.D. Searle

FDA 1998

Nabumetone

Relafen

1000 mg daily

Teva

FDA 2000

Piroxicam

Feldene

20-4 mg daily

Pfizer

FDA 1982

Naproxen

Anaprox

Neprelan

500- 1000 mg daily 375mg, 500 mg daily

Atnahs Pharma

FDA 1980

Ibuprofen/Famotidine

Duexis

800 mg/26.6 mg

Horizone Pharma

FDA 2011

Etodolac

Lodine

100- 200 mg not more than 1000mg/d ay

Teva

FDA 2000

Rofecoxib

Vioxx

25 mg Daily

Merck

FDA 2002

 

 

 

 

2.

 

 

 

 

Glucocorticoid’s

Hydrocortisone

Cortef

10-320 mg/day

Hospira

FDA 2006

Prednisone

Deltasone

5- 60 mg/day in divided doses

Pharmacia and UP John

FDA 1955

Methyl Prednisone

Predacorten

2-60 mg/day

_

_

Dexametha sone

Hexadrol

0.75 – 9 mg/day

Merck

FDA 1958

 

 

3.

 

 

Nonbiologic DMARD

Leflunomide

Arava

Initial dose 100 mg orally once a day for 3 days

Sanofi Aventis US

FDA 1998

Methotrexate

Trexall

Maximum weekly dose: 20 mg.

Silvergate Pharms

FDA 2001

FDA 2017

Sulfasalazine

Azulfidine

0.5-2 mg/day

Pharmacia & Upjohn

FDA 1996

4.

Biologic DMARDs

Golimumab

Simponi

Dose 50mg

Centocor ortho Biotech

FDA 2009

Tocilizumab

Actemera

Dose 4 mg/kg followed by an increase to 8 mg/kg

Genentech

FDA 2017

 


 

CONCLUSION:

Rheumatoid arthritis is a chronic autoimmune illness characterised by loss of the synovium, cartilage, and joints. Environmental, smoking and genetic variables play a significant impact in the progression of rheumatoid arthritis, as well as the pathological events that occur. Much advancementhas been made in the treatment and diagnosis of the condition. Figure 4 illustrated the pathological mechanism to understand the production rheumatoid arthritis. The inflammation-causing substance is removed through surgery. The Table 1 includes a list of available drugs as well as their classes. The available treatment trends for the condition were briefly discussed which include Non steroidal anti-inflammatory drugs (NSAIDs), Disease modifying Antirheumatic drugs, and corticosteroids. Also a nutritious diet, combined with exercise, and some other supplements like vitamin D, folic acid should be followed to avoid or manage arthritis and to prevent by other adverse effects of drugs. Also, the available marketed formulations approved by FDA and published patents with regards to the treatment methods, and diagnoses of RA were enlisted in Table 2 and Table 3. All these, illustration’s were obliging to understand the management process or rheumatoid arthritis.

 

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Received on 16.01.2022       Modified on 07.03.2022

Accepted on 26.05.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2022; 12(4):312-322.

DOI: 10.52711/2231-5691.2022.00051