INTRODUCTION:

Despite breakthroughs in medical and pharmacological research, treating arthritis, specifically osteoarthritis (OA) and rheumatoid arthritis (RA), remains difficult¹. Symptoms of both diseases include cartilage matrix degradation and inflammation. There are no known preventative strategies to stop the onset of the disorders, but management of the disease is dependent on early detection. Many medicinal treatments have been investigated to minimize inflammation and repair joint injury. The medications are delivered orally, parenterally, or intra-articularly. When medications are taken orally or parenterally, they are transported from the systemic circulation to the intra-articular location.

Drugs, such as recombinant proteins, may be degraded over time. Since the synovial cartilage has a restricted blood supply, drugs with high bioactive drug concentrations may have trouble reaching the target region. Intra-articular administration can be utilized to administer low bioavailability medications such as recombinant proteins, therapeutic genes, and compounds such as TNF-α, matrix metalloproteinases, or p38 mitogen-activated protein kinase inhibitors^2-6.

Intra-articularadministration is therefore an effective tool for treating arthritis, including rheumatoid arthritis and osteoarthritis. The procedure of directly injecting the medicine into the synovial cavity is known as intra-articular drug delivery. It is a drug delivery system (DDS) that causes a large portion of the medication to be delivered near the target location. Depending on the chemical nature of the active ingredients, rapid clearance from the joint may occur, necessitating multiple injections, which may result in bacterial infections (septic arthritis), and joint impairment⁷. Knee or joint aspiration is commonly utilized for diagnostic and therapeutic purposes. When corticosteroids are administered intra-articularly, they can produce crystal-induced arthritis, which has been reported in 10% of patients and has been shown to resolve within 10-12 days⁸. As a result, the intra-articular route of drug delivery looks promising because large drug concentrations may be administered directly to the synovial joint, avoiding systemic adverse effects as compared to the oral and parenteral drug delivery systems^9,10. This review article examines both older and contemporary medication delivery techniques for treating RA.

The Synovial Joints:

Synovial joints are extremely specialized anatomical components of joints. They are made up of two articulating capsules, one with an outer fibrous layer and one with an inner synovial membrane surrounded by a fluid-filled synovial cavity. These joints, known as diarthroses, move freely.

Types of Synovial Joints:

· Ball- and-Socket Joint

· Hinge Joint

· Condyloid Joint

· Saddle Joint

· Pivot Joint

· Plane Joint

The surrounding fibrous capsule, a robust structure with an abundance of connective tissues, maintains the structural integrity of the joint. The capsule is made up of thick bands of parallel collagen fibers known as ligaments and nerve terminals¹¹.The knee proprioceptive sense and deep pain perception are controlled by nerve endings, tendons, and ligaments. The connective tissue that assists in joint motion is not smooth but rather features irregular depressions and undulations¹². Scanning electron microscopy¹³and atomic force microscopy¹⁴ investigations have shown these structures.

Cartilage:

A smooth hyaline cartilage layer surrounds a healthy synovial joint. The cartilage acts as a shock absorber. Chondrocytes are cartilage cells that are found in healthy cartilage. They keep the cartilage matrix, which is made up of collagen and proteoglycans, in good condition. Chondrocytes continuously repair and renew their extracellular matrix. The interaction of negatively charged proteoglycans with type II collagen fibers is responsible for the tissue's high tensile strength¹⁵.

The synovium/synovial membrane:

The capsule or wrap that covers the synovial joint is known as the synovium. The synovium is a highly vascular tissue. A synovial membrane lines the layer's interior surface. Type B synoviocytes are implanted, and their major job is to exude high-molar-mass hyaluronans into the synovial fluid continually.

Synovial Fluid:

The synovial fluid is viscous and non-newtonian. Synovial fluids make up 2ml of a healthy adult joint. Pathological circumstances can cause synovial fluid to grow by several hundred milliliters. The following synovial fluid alterations are caused by inflammation.

· An increase in the concentration of plasma-derived macromolecules due to increased leakiness of synovial capillaries.

· A decrease in the viscosity of synovial fluid due to enzyme-mediated cleavage of hyaluronan chains^16-17.

The synovium serves asa biochemical pool through which nutrients and regulating cytokines pass. In a healthy joint, synovial fluid acts as a biological lubricant, allowing the joints to move freely. Proteoglycan and the substance hyaluronic acid molecules aid in joint mobility and lubrication. These chemicals also help in the reduction of friction and wear-tear on the synovial membrane^18-19.

The synovial membrane performs ultrafiltration of blood plasma, resulting in the development of a biochemical store known as synovial fluid. The synovium is a thin coating made up of tissue macrophages and B cells that look like fibroblasts. A loose layer of connective tissue covers the synovium in the subsynovium. The lymphatic system in the subsynovium aids in the removal of the transported molecules²⁰. The synovium cells create a discontinuous layer with intercellular voids that is made up of collagen I, III, and V as well as hyaluonan. The extracellular matrix is designed to facilitate the transit of tiny molecules while also providing adequate barrier to the flow of bigger molecules of synovial fluid with the joint cavity²¹. Hyaluronic acid is a disaccharide made up of D-glucoronic acid and N-acetyl-D-glucosamine²². It is essential for the preservation of articular cartilage as well as the delivery of nutrients. It has been shown that in individuals with rheumatoid arthritis, hyaluronic acid functions as an anti-inflammatory agent, either by limiting immune complex adhesion to neutrophils or by preventing synovium membrane attachment to inflammatory mediators²³.

In rheumatoid arthritis, the synovial joint has a form of prolonged inflammatory response. Inflammatory cells such as T cells, dendritic cells, fibroblasts, macrophages, mast cells, neutrophils, and B cells are present^24,25. These inflammatory cells activate and increase the production of interferon-c, tumor necrosis factor- (TNF-α), and interleukins such as IL-1, IL-6, IL-15, and IL-18. The production of pannus tissue is a feature of rheumatoid arthritis. A pannus tissue is a fibrovascular layer that is aberrant^26-29. The synovial lining initially hypertrophys, followed by angiogenesis, and lastly pannus development, as seen in Fig 1³⁰.

Fig. 1: Normal Joint and Joint with Pannus Formation³⁰

Rheumatoid Arthritis:

Rheumatoid Arthritis is a synovial joint inflammatory condition that is persistent. It has an asymmetric effect on the synovial joints. Clinically, it is distinguished by persistent synovial joint inflammation, bone cartilage degradation, and a rise in the levels of an autoantibody known as the Rheumatoid Factor (RF Factor)^31,32. Rheumatoid arthritis is classified into two types: "seropositive" and "seronegative" illness. Seropositivity is defined as the presence of autoantibodies rheumatoid factor (RF), also known as antibodies to citrullinated protein/peptide antigens (ACPAs), in the blood. The absence of the rheumatoid factor is termed as seronegative disease³³.

Etiology of Rheumatoid Arthritis:

The etiology of the disease is not totally understood, although there are certain reasons that claim to help in the disease's formation. Because it is an autoimmune illness, it is usually discovered to be hereditary. According to research, the condition manifests itself through an increase in circulating autoantibodies, which can endure for many years before the first indications of inflammation appear. This is referred to as "Preclinical RA"³⁴. Smoking has been identified as a major non-genetic cause of seropositive rheumatoid arthritis. According to research, heavy chain smokers are three times more likely to develop rheumatoid arthritis³⁵. Vitamin D insufficiency is also quite frequent in rheumatoid arthritis sufferers. It has been shown that an active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), interacts with bone metabolism via controlling calcium and phosphate channels³⁶. According to research, rheumatoid arthritis is more frequent in women than in males. Rheumatoid arthritis in women has been linked to menopause when there is a considerable drop in ovarian sex hormones. Men, on the other hand, have a relative reduction in testosterone around the age of 60-70³⁷.

The Pathogenesis of Rheumatoid Arthritis:

The condition occurs in two stages. Phase 1: Damage to the microvasculature and synovial growth, as well as plasma component inflow. Phase 2: Macrophages, lymphocytes, and neutrophils accumulate at the joint. This contact with neutrophils triggers phagocytic reactions, which result in the production of reactive oxygen species, proteolytic enzymes, and inflammatory mediators. This causes synoviocyte proliferation, which is followed by cartilage degeneration and, lastly, pannus formation^38-40.

Fig. 2: Pathogenesis of RA⁴¹

Conventional Therapeutic Approaches:

There is no permanent treatment for RA, but therapy techniques try to relieve the patient's pain and suffering, therefore minimizing inflammation and joint degeneration and allowing the patient to live a healthy life.

First–Line Management (NSAIDS and Corticosteroids):

The major purpose of the treatment regimen is to reduce inflammation. As a result, medicines such as NSAIDS, which assist relieve pain and inflammation, are employed. Aspirin, ibuprofen, and naproxen are a few examples. NSAIDs suppress the formation of prostaglandins, prostacyclin, and thromboxanes by inhibiting cyclo-oxygenase (COX-1 and COX-2). Nausea, stomach discomfort, ulcers, and gastrointestinal (GI) bleeding are all common adverse effects. These effects can be alleviated by taking the medication with meals, antacids, or proton pump inhibitors. Corticosteroids are powerful anti-inflammatory medicines that work by blocking the production of phospholipids and inhibiting the activity of eosinophils, ultimately reducing inflammation. Because corticosteroids have several negative effects, they are only used in tiny dosages for a limited period of time. Corticosteroids have been linked to bone thinning, weight gain, diabetes, and immunosuppression⁴⁰.

Second-Line Management (DMARDS):

Second-line medications' primary purpose is to halt the progression of joint deformity and joint deterioration. After the usage of NSAIDS, Disease Modifying Anti Rheumatoid Drugs (DMARDS) are discovered to be the predominant therapy protocol. They aid in the improvement of symptoms, the reduction of joint damage, and the enhancement of overall functional skills, resulting in a delay in the advancement of joint deformity⁴². Methotrexate (MTX) is the first-line gold standard medication for the treatment of rheumatoid arthritis. It is similar to folic acid. It works by preventing dihydrofolic acid (FH2) from attaching to the enzyme responsible for converting FH2 to folinic acid (FH4). FH4 deficiency impairs purine and pyrimidine metabolism and inhibits amino acid and polyamine production. Because MTX might promote immunosuppression in patients, liver and renal function must be monitored^43,44. According to a recent study on 400 patients with rheumatoid arthritis, methotrexate is the most widely used (52.7%) DMARD to treat RA⁴⁵.

Aurofin, gold sodium thiomlate, and D- pencillamine are all gold salts that are commonly used to treat RA. However, the administration of these gold salts must be closely managed since they may induce bone marrow and renal damage^46,47. Sulfasalazine, another DMARD, scavenges the hazardous oxygen metabolites generated by neutrophils, blocking the transcription of different chemokines⁴⁸. Azathioprine works by suppressing cell and antibody-mediated immune responses by limiting clonal proliferation in the early stages of the immune response. Following methotrexate, leflunomide has shown encouraging outcomes in the treatment of RA. It works by directly blocking T cells, preventing inflammatory cells from adhering and migrating⁴⁹. With the introduction of less toxic and more dependable drugs, the usage of gold salts in the treatment of RA has practically vanished.

Biological Agents:

These biological agents, also known as the "newer class of DMARDs," suppress the overproduction of pro-inflammatory cytokines at the site of inflammation. Tumour necrosis factor - (TNF-α) is a protein that increases joint inflammation. TNF-α inhibitors suppress the activation of this protein, resulting in immediate symptom alleviation from inflammation. Etanercept, infliximab, adalimumab, and certolizumab are a few examples⁴⁹. Anakinra is a biological DMARD given as a subcutaneous injection. It inhibits the inflammatory response by binding to interleukin -I^50,51. Tocilizumab inhibits interleukin-6, lowering inflammation. It is given either as an IV infusion once a month or as a weekly subcutaneous injection. It is useful in individuals who have not responded to second-line DMARDs⁵².

Targeted DMARDs:

JAKs are cytoplasmic protein tyrosine kinases thatare required for signal transduction to the nucleus from the plasma membrane receptors for interleukin (IL)-2, -4, -7,-9, -15, and -21⁵³. JAK are receptor-associated intracellular proteins that contain a tyrosine-kinase component. They have critical roles as downstream mediators of various pro-inflammatory cytokines, includinginterferons and interleukin 6. When a ligand interacts with its receptor, the intracellular kinase is phosphorylated, which causes the signal transducer and activator of transcription (STAT)-pathway to be phosphorylated and activated. Thus, control of inflammatory reactions can be done by inhibiting these enzymes using a specific molecule⁵⁴.

CONCLUSION:

As a complicated condition, RA may cause a great deal of discomfort and anguish in people. Early identification of RA can be a godsend to patients in the modern period, with the emergence of novel changes in medication delivery methods and breakthroughs in medicine. Despite the fact that the condition is still incurable, patients now have much better quality of life. Epidemiological parameters can be greatly improved by disease prevention techniques, RA risk screening programmes, and providing the public with thorough information on the disease monograph.The treat-to-target (T2T) approachbegins with the rheumatologist outlining the goals and then applying the procedures to accomplish and evaluate them.Furthermore, given that certain genetic abnormalities have a strong correlation with the traits and magnitude of the immune response, it is reasonable to consider the potential preclinical use of these data as screening tools to anticipate the onset of disease.As a result, early identification of RA and the use of medical breakthroughs have the potential to significantly enhance RA care⁵⁵.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

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Received on 02.09.2023 Modified on 12.01.2024

Research J. Pharm. and Tech 2024; 17(7):3467-3472.

DOI: 10.52711/0974-360X.2024.00542