Alternative Approaches for Rheumatoid Arthritis Management: Future Perspective, Herbal, Dietary, Lifestyle, Psychological, Nutritional Intervention and Healthcare

Rheumatoid arthritis is an inflammatory disease autoimmune disorder that develops when our immune system attacks the tissues near joints due to the release of chemicals and enzymes. Although the exact pathogenesis of the disease has yet to be determined, studies indicate that cellular proliferation of synoviocytes results in pannus formation, which damages cartilages and bones. Recent research also supports the role of free radicals in the disease's pathogenesis. For rheumatoid arthritis treatment, a variety of anti-inflammatory and other types of drugs are available. However, long-term use of such types of pharmacological drugs is associated with serious side effects. As a result, herbal remedies, lifestyle, nutritional, probiotics, dietary and psychological interventions provide a rich source of anti-arthritic agents along with management of rheumatoid arthritis. This review focused on pathogenesis, treatments approaches for RA, mechanism of action, patents of marketed products. Tailored made approaches for arthritis management helps the scientists and researchers for finding newer leads, promotes growth and development of herbal industries, significantly improving health. Review Article Gupta et al.; JPRI, 33(54A): 342-363, 2021; Article no.JPRI.78265 343


INTRODUCTION
Arthritis is a widespread health problem that affects millions of people in the United States. It is a condition characterized by chronic joint pain and inflammation. There are about 200 rheumatic diseases or serious ailments related to tissues, joints, and other connective tissues. Rheumatoid Arthritis (RA) develops when immune system targets the tissues near our joints, resulting in the release of specific chemicals and enzymes that begin to eat away at the cartilage and bone [1,2]. Although the etiology of RA is uncertain and thought to be caused by a dysfunctional immune system [3]. The fundamental aspect of arthritis is a continuous discomfort that gets localized in the damaged joint. The pain worsens with daily wear and tear on the joints, muscle tension from vigorous motions against stiff, painful joints, and exhaustion [4][5][6].
Patients with arthritis have significant joint pain and approximately half of all people with arthritis experience chronic pain [7]. There are over 100 different forms of arthritis. Osteoarthritis and rheumatoid arthritis are two of the most frequent forms [8]. Rheumatoid arthritis (RA) is an inflammatory illness that mostly disturbs the body's junctions coated with synovium (specific tissue responsible for sustaining the nutrition and lubrication of the joint). The distribution of afflicted joints (synovial joints) is typical [9]. According to the WHO, Rheumatoid arthritis affects 0.3-1 % of the global residents, with females three times more than males [10]. RA is a systemic autoimmune disease that results in chronic inflammation. The foremost symptoms of RA include pain, swelling, cartilage, and bone degeneration, resulting in permanent disability [11]. Although the actual cause is unknown, various studies suggest, that is caused by a combination of hereditary tendencies and exposure to environmental factors such as viruses [12]. Inflammation of the joints causes pain, edema, and joint deterioration, as well as deformity. Other internal organs, such as the eyes, lungs, heart, and nerves, can be affected on rare occasions. The symptoms fluctuate significantly from individual to individual. In various situations, RA begins by infecting a few joints and then spreads to other joints all over the body over the development of a few weethks or months. RA, on the other hand, can proceed exceedingly quickly; non-specific indications of RA include weariness, discomfort in and around the joints, fever, and weight loss/poor appetite. RA can expand to more and more joints on both sides of the body over time, generally in a symmetrical pattern [13].
The goal of rheumatoid arthritis treatment is to alleviate indications, halt disease development, and improve value of life. Before beginning RA treatment, consider the conditions such as analgesia relief, inflammation reduction, articular structure protection, function maintenance, and systemic involvement control [14].

Rheumatoid Arthritis Versus Osteoarthritis
The development of osteoarthritis and rheumatoid arthritis and the differences between them are shown in Figs. 1-3 and Table 1.

PATHOPHYSIOLOGY OF RHEUMATO-ID ARTHRITIS
Immune complexes and the complement system initiate RA, supported by cytokines, and rely on metalloproteinases Antigen-activated CD4 + T cells stimulate monocytes, macrophages, and synovial fibroblasts to produce the cytokines interleukin 1 (IL-1), interleukin 6 (IL-1), and Tumor Necrosis Factor (TNF), as well as matrix metalloproteinases, via cell surface signaling. In the early stages of RA, the synovial fluid contains a high concentration of neutrophils. Protrusions in the joint capsule form as a result of chronic hypertrophy and hyperplasia. Immunoglobulin G (IgG)/antigen-anti-IgG antibody complexes found in synovial fluid. In RA, cartilage dissolved results in erosion caused by osteoclasts and proteolytic enzymes. Immunoglobulins M and A (IgM and IgA) are significant pathogenic markers in RA [16,17]. Molecular mechanism involved in rheumatoid arthritis, is shown in Fig. 4.

PROCESS OF TARGETING STAGE TO FULMINANT DISEASE
Many cells and their cytokines play vital roles in the development of RA. Leukocytes infiltrate the synovial section and the synovial fluid flood with pro-inflammatory mediators. It starts an inflammatory cascade that involves fibroblasts like synoviocytes interacting with innate immune system cells like monocytes, macrophages, mast cells, dendritic cells, and adaptive immune system cells (T and B cells). Endothelial cells play an essential role in angiogenesis. The hyperplastic synovial membrane, cartilage damage, bone erosion, and systemic consequences are all in the fulminant stage. Bone resorption causes bone erosion, usually found where the synovial membrane is introduced into the periosteum and referred to as an area bare by certain anatomical features. Degeneration of articular cartilage can occur due to the destruction of subchondral bone, reduction in osteoblasts and an increase in osteoclasts and synovial cells. TNF, matrix metalloproteinase (MMP), transforming growth factor (TGF), platelet growth factor (PGF), interferon (IFN), granulocyte-macrophage colony-stimulating factor (GMCSF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are involved in fulminant disease [9,18].

STAGES/ CAUSES OF RHEUMATOID ARTHRITIS
RA happens when the immune system attacks the synovial membrane, the lining of the membranes, surrounding the joints; the resulting tenderness thickens the synovial membrane, ultimately abolishing the cartilage and bone inside the joint. The tendons and ligaments holding the joint together, deteriorate and stretch. Gradually, the joint loses the figure and arrangement [19].

SYMPTOMS
Symptoms include joint swelling, discomfort, morning joint stiffness, lack of sleep, exhaustion, weight loss, and the sensation of having flu symptoms. Rheumatoid factors, antibodies (IgG) found in the blood are used to diagnose rheumatoid arthritis. These bind to the antigen and create an antigen-antibody complex, causing discomfort and inflammation of the synovial membrane. The American College of Rheumatology requires at least four out of the seven criteria listed below to confirm the diagnosis [20].
 Morning joint stiffness lasts at least one hour.  Three or more joints have been arthritic for at least six weeks.  Hand joints have been arthritic for at least six weeks.  At least six weeks of arthritis on both sides of the body.  Under-the-skin rheumatoid nodules.  Rheumatoid factor detected in blood tests.  X-rays show evidence of RA [21].

DIAGNOSIS
Rheumatoid arthritis is problematic to diagnose in its early phases because the symptoms are parallel to those of other diseases. There are no results from blood tests or physical checkups to back up the analysis. During the physical examination, look for swelling, redness, and hotness in the joints. You can also put your responses and strength to the test [22].

Blood Tests
People with RA have a higher rate of red blood cell sedimentation. Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), signifying an inflammatory process in the body. Other standard blood tests look for rheumatoid factor antibody levels and anti-circulating citrulline peptides (anti-CCP).

Visual Examination
X-rays can aid in tracking the development of rheumatoid joint arthritis over time. In addition, MRI and ultrasound scans help assess the severity of the disease.

Treatment
Treatment aims to reduce the inflammatory state with some relief, minimize joint damage, and ultimately improve physical condition and quality of life. If you change your lifestyle, medications may be prescribed. There are medications available to treat rheumatoid arthritis [22]. Based on the severity of symptoms and the length of time, various drugs are used in the treatment of RA.

Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications that are used to treat pain and inflammation. Over-the-counter NSAIDs include ibuprofen (Advil, Motrin IB, and others) and naproxen sodium (Aleve). Possible side effects include stomach upset, heart problems, and kidney damage [23].

Steroids
Prednisone and other corticosteroid drugs relieve inflammation and pain while also reducing joint deterioration. Bone deterioration, weight gain, and diabetes are all possible side effects. Doctors frequently prescribe corticosteroids to relieve symptoms quickly and gradually wean patients off the medication [20].

Traditional Disease-modifying antirheumatic medications (DMARDs)
These drugs may reduce the development of rheumatoid arthritis and avoid permanent damage to joints and other tissues. Methotrexate (Trexall, Otrexup, etc.), leflunomide (Arava), hydroxychloroquine (Plaquenil), and sulfasalazine are examples of common DMARDs (Azulfidine). Side effects can range from mild to severe but can include liver damage and severe lung infections [5,16].

Surgery for rheumatoid arthritis
Some people require joint replacement surgery if joint pain and inflammation become unbearable or significantly injured joints. The hips and knees and the shoulders, on occasion, are the most commonly replaced joints. The pain and mobility are significantly improved with surgery. Most people wait until they are over 50 since prosthetic joints wear out after 15 to 20 years [5,25].

Limitations of Rheumatoid Arthritis Treatment
The management of pain, avoiding long-term joint damage, and reducing inflammation are critical issues when treating RA. DMARDs and non-steroidal anti-inflammatory medicines (NSAIDs) have been the primary treatments utilized to treat the disease's symptoms and after-effects. [26] Corticosteroids, an antiinflammatory hormone generated by the adrenal glands, are another steroidal medication used to treat RA inflammation [27]. An optimal steroid should meet the requirements at a low dose while avoiding adverse effects. Both steroidal and non-steroidal medications reduce symptoms but cannot cure or prevent disease in the long run [28].
Aside from that, patients may experience severe side effects, such as impacts on the kidney, liver, and heart, resulting from long-term usage of such medications. Short-term adverse effects include shortness of breath, nausea, infections, and allergic reactions, result in fundamental constraints and issues, dealing with steroidal medicines for the treatment of rheumatoid arthritis [29].

Herbal Intervention for Rheumatoid Arthritis
Traditional treatments have been used successfully to treat inflammatory and arthritic disorders. Chronic inflammatory illnesses, such as rheumatoid arthritis, remain one of the world's major health concerns. Although various medications are used to treat it, long-term use results in unfavorable severe side effects, the most prevalent being gastrointestinal bleeding and peptic ulcers. As a result, new antiinflammatory medicines with negligible side effects. It is worth noting that most of today's analgesic medicines have an extensive variety of adverse properties [30].
Most ethnic people still rely on native medicinal plants to heal various diseases, employing knowledge of herbal treatment passed down from their forefathers as summarized in Table 2. However, due to the accessibility of recent medical facilities and other socioeconomic circumstances, this ethno-therapeutic knowledge and medicinal plants are decreasing at a distressing rate. On the other hand, the command is helpful in the quest for novel medicines to improve human health. Herbal medicines have gained popularity in recent years, both at home and abroad, because of less hazardous than synthetic medicines [30,31]. The Inflammation pathway in RA and mechanism of action of herbs are depicted in Fig. 8.

Lifestyle Intervention for RA Management
Rheumatoid arthritis is a chronic disease and may be exacerbated in patients due to unhealthy lifestyle, nutrition and exercise. There are certain evidences and facts that are proven beneficial for management of arthritic pain. Regular exercise, along with healthy eating habits reduces stiffness in joint and helps in weight management, thus reduces stress on the hips and knees and lower back. The consumption of omega 3 fatty acids, nuts, vegetables and fruits further helps in weight management, reduces inflammation and promotes well-being [80][81][82][83].
Regular exercise reduces pain and swelling of joint and improves endurance capacity and muscle strengthening around joints. Walking and swimming are non-impacted exercises found beneficial for management of arthritic patients. Exercising 30 minutes at moderate intensity for 5 times a week are recommended for arthritic patients [84][85].
Other lifestyle interventions for arthritic pain are education, dietary management, smoking cessation, massaging and psychological intervention. The exercise goals for RA patients are explained in Table 3 [81-85].

Nutritional intervention
Nutrition helps in improvement of arthritic condition where modern medicine fails to provide permanent cure. Dieticians play important role in educating patients about safety and effectiveness of healthy eating. This further controls comorbidities like hypertension, diabetes and obesity. Dietary intervention like grains, omega 3 fatty acids, fruits and leafy vegetables are successful medium for management of arthritic patient through weight control. Healthy nutrition helps in improving joint pain and increases endurance capacity. Nutritional interventions are discussed in Table 4

Psychological Intervention
Psychological stress is very common in arthritic patient due to pain discomfort. The chronic pain disturbs the mental psychology and affects patients' behaviour. This results in treatment withdrawal symptoms and avoidance from therapy by patients and causes feeling of fear, anger and stress. Medical intervention for improving mental well-being plays significant role in improving psychological stress through selfregulation and regular follow ups [81][82]85].

Educational Intervention
Education programmes of right information in appropriate manner should be shared and delivered for management of chronic patients. The following points for educating the patients are discussed below [82][83][84][85].
 Understanding disease pharmacology and patient mind-set.  Make patient aware about of movements of joints.  Focuses on lifestyle intervention.
 Educating patients how to cope with disease with pain.  Involvement of family members, positive impact on patient.  Other intervention are low-laser therapy and electro therapy.

FUTURE PERSPECTIVE
Alternative medications are way forward for management of arthritis pain. The drug therapy is complicated and troublesome due to risk of adverse effects, patient withdrawal and cost of medication. The various herbs such as Devil's claw, Boswellia, Rosehip used for management of RA results in side effects like insomnia, stomach upset and some interact with prescribed medicines but are not so significant [86]. Natural remedies patents for management of RA are discussed in Table 5.

HERBAL MARKETED PRODUCTS FOR ARTHRITIS
The various marketed herbal products used in the management of arthritis shown in the ( Table  6).

Pet-ether Chloroform extract
Decrease the latency time to explore [56].

Plant name Family
Part used Chemical constituents Extract Mechanism of action Staph. Ficus bengalensis Linn.

Ginkgo biloba Linn.
Ginkgoaceae Leaf Protocatechuic acid Methanolic Inhibition of NO production from the macrophages that infiltrated to the inflamed site [59]. Glycosmis pentaphylla Linn.

Hydroalcoholic extract
Low levels of C-reactive proteins and ESR [76].

Commiphora wightii Oroxylum indicum
Chronic pain in disorders such as rheumatoid arthritis.

CONCLUSION
In today's scenario arthritis affect a large population of the world. The main problem of arthritis is our lifestyle. RA is a chronic inflammatory disease affecting humans and there are many drugs and therapies available in the market for its management. These medications are expensive and have adverse effects, so alternative therapy can be considered as a primitive stone for the management. Nature has bestowed us with very rich botanical treasure.
There are many shreds of evidence that tell the use of herbs in various diseases. Appropriate treatment with herbal remedies, life style, dietary and nutritional intervention is the need of hour, help in improving medication response of patients. Tailor made approaches of omega fatty acids, physical activity programme, reduction of sedentary lifestyle, and breathing exercise together improve mental well-being and reduce co-morbidities in cardiovascular, diabetic and obese patients. Therefore, further findings are necessary for improving the safety and efficacy of herbal approach. This helps in disease management and building confidence among patients.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.