Nanomedicines Used in The Treatment of the Rheumatoid Arthritis

Abstract

Rheumatoid arthritis(RA) is an autoimmune disorder that affects the joints. Various medications successfully alleviate the symptoms of RA in clinical. Still, few therapy strategies can cure RA, especially when joint destruction begins, and there is currently no effective bone-protective treatment to reverse the articular damage. Furthermore, the RA medications now used in clinical practice accompany various adverse side effects. Nanotechnology can improve the pharmacokinetics of traditional anti-RA drugs and therapeutic precision through targeting modification. Although the clinical application of nanomedicines for RA is in its infancy, preclinical research is rising. Current anti-RA nano-drug studies mainly focus on the following: drug delivery systems, nanomedicines with anti-inflammatory and anti-arthritic properties, biomimetic design with better biocompatibility and therapeutic features, and nanoparticle-dominated energy conversion therapies. These therapies have shown promising therapeutic benefits in animal models, indicating that nanomedicines are a potential solution to the current bottleneck in RA treatment. This review will summarize the present state of anti-RA nano-drug research.

Keywords

Introduction

Nanoparticles for the management of RA

First-Line Management: NSAIDS and Corticosteroids

The overall goal of first-line treatment is to relieve pain and decrease inflammation. Medications, considered to be fast-acting, are nonsteroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylate (Aspirin), naproxen (Naprosyn), ibuprofen (Advil and Motrin), and etodolac (Lodine). Aspirin is an effective anti-inflammatory for RA when used at high doses, due to the inhibition of prostaglandins. It is one of the oldest NSAIDs used for joint pain. Side effects of aspirin at high doses include tinnitus, hearing loss, and gastric intolerance. There are other NSAIDs that are newer on the market than aspirin and just as effective. In addition, these drugs require fewer doses per day. NSAIDs work by inhibiting cyclo-oxygenase to prevent the synthesis of prostaglandins, prostacyclin, and thromboxanes. Common side effects are nausea, abdominal pain, ulcers, and gastrointestinal (GI) bleeding. These symptoms can be reduced if taken with food, antacids, proton pump inhibitors, or misoprostol (Cytotec), An even newer NSAID called celecoxib (Celebrex) is a selective Cox-2 inhibitor that has less risk of GI side effects [12]. Corticosteroids are a more potent anti-inflammatory medication than NSAIDs, but they come with greater side effects. For this reason, they are only indicated for a short period of time at low doses, during exacerbations or flares of RA. Intra-articular injections of corticosteroids can be used for the local symptoms of inflammation [13]. They work by preventing the release of phospholipids and decreasing the actions of eosinophils, thereby decreasing inflammation. Their side effects include bone-thinning, weight gain, diabetes, and immunosuppression. Advising the patient to take calcium and vitamin D supplementation can prevent thinning of the bone. Side effects can be reduced by gradually tapering doses as a patient's condition improves. It is important to not abruptly discontinue injected or oral corticosteroids as this can lead to suppression of the hypothalamic-pituitary-adrenal axis (HPA) or flares of RA [14].

Opioid Analgesics

Whittle et al.  addressed the question of the use of opioid analgesics for patients with pain due to RA. From their conclusions, weak opioids such as codeine, dextropropoxyphene, and tramadol may play an effective role in the short-term management of pain caused by RA, but the adverse effects outweigh the benefits. They recommend that other analgesics be considered first [16].

Second-Line Management: Disease-Modifying Antirheumatic Drugs

The overall goal of second-line treatment is to promote remission by slowing or stopping the progression of joint destruction and deformity. Medications are considered to be slow-acting because they take from weeks to months to be effective. Disease-modifying antirheumatic drugs (DMARDs) can also reduce the risk of developing lymphoma that can be associated with RA [17]. Methotrexate (MTX) is the initial second-line drug (also considered an anchor drug). It is an analog to folic acid that competitively inhibits the binding of dihydrofolic acid (FH2) to the enzyme that is responsible for converting FH2 to folinic acid (FH4). Without FH4, the metabolism of purine and pyrimidine is impaired, and the synthesis of amino acids and polyamine is inhibited. MTX is an immunosuppressive drug that requires regular blood tests due to its side effects, i.e., liver problems, cirrhosis, and bone marrow deterioration. Folic acid supplementation can reduce the risk of side effects. It is an effective DMARD, has a lower incidence of side effects than other DMARDs, and has dosage flexibility, meaning that doses can be adjusted as needed [18]. Until now, there is convincing data showing the benefits of combinations of conventional synthetic DMARDs over MTX monotherapy. However, biological and synthetic DMARDs in combination are reported to be better than MTX but with more side effects and greater costs [11, 14, 19]. Hydroxychloroqyine (Plaquenil) is an antimalarial drug and can be used for long-term treatment of RA. This drug decreases the secretion of monocyte-derived proinflammatory cytokines. Common side effects include problems in the GI tract, skin, and central nervous system. The eyes, in particular, can be affected when this drug is taken at high doses. Patients on this medication require routine consultation with an ophthalmologist [20]. Sulfasalazine (Azulfidine) is a DMARD typically used in the treatment of irritable bowel disease. Combined with anti-inflammatory medications, this DMARD can be used to treat RA. The mechanism of action of this drug in the treatment of RA has not been identified. It is thought that sulfapyridine, a reduced form of the medication after administration, may reduce secretions of interleukin (IL)-8 and monocyte chemoattractant protein (MCP). This drug has side effects of GI and central nervous system symptoms as well as rash. It is usually well-tolerated among patients, but should be avoided in patients with sulfa allergies since it contains sulfa and salicylate compounds [21]. Gold salts, such as aurothioglucose (Solganal), auranofin (Ridaura), gold sodium thiomalate (Myochrysine), and D-penicillamine (Depen and Cuprimine) have been used frequently in the treatment of RA. These DMARDs require frequent blood and urine tests due to damage to the bone marrow and kidneys. They have not been used recently due to the more effective treatments, particularly MTX. Other immunosuppressive medications like azathioprine (Imuran), cyclophsphamide (Cytoxan), chlorambucil (Leukeran), and cyclosporine (Sandimmune) can be employed but are typically reserved for patients with very aggressive RA or complications of the disease [22, 23].

CONCLUSION

There is increasing understanding of the pre-RA stage of disease development, which has already driven the completion or development of multiple clinical prevention trials. Importantly, growing interest in this area and the huge potential for improvements in the public health impact of this disease is driving even more studies in understanding the biology of disease development and developing effective preventive interventions; efforts are also underway in other rheumatic autoimmune diseases such as systemic lupus erythematosus and psoriatic arthritis. Further, there is now an approved preventive intervention in type 1 diabetes, which is a disease that has a model of development similar to RA. It is exciting to see the field moving forward to a point where rheumatologists can include in clinical care the discussions around prediction of the clinical onset of RA, and potentially of other rheumatic diseases, as well as the use of potentially soon-to-be-approved preventive interventions. -Nanomaterials have great promise as theranostic agents for RA. Drugs may be delivered to inflamed joints using nanomaterials, which can also provide imaging data at the same time. The use of nanomaterials for RA theranostics has a number of benefits. The effectiveness of medicine delivery can be increased by using nanomaterials since they can be made to target certain cells or tissues. They can also be used to image the illness, which can be useful for tracking RA development and evaluating how well a medication is working. The accuracy of using nanomaterials for diagnosing RA is highly dependent on selecting biomarkers. However, currently developed biomarkers have lower diagnostic accuracy than imaging assays such as X-rays. Biomarkers frequently indicate conditions other than RA. This limitation of specific markers is one of the barriers in developing nanomaterials for the early detection of RA. On the other hand, if detection depends on using tools such as X-rays, it often creates a high time gap between disease occurrence and detection time, increasing the risk of disease. In addition, the lack of reliable biomarkers for accurately diagnosing RA constrains the effectiveness of nanomaterial-based biosensors, which are primarily advantageous in predicting joint pain. In clinical practice, a physical examination of the joints is still necessary to confirm the presence of inflammatory synovitis, leading to duplicated efforts. Thus, this limitation emphasizes the significance of developing specific biomarkers tailored and designed for the diagnosis of RA in the future. Lastly, implementing automation for RA theranostics is definitely a possibility, although there are not many RA theranostic situations in the real world at the moment. As research advances, we can expect further automation and integration of nanomaterials for precise and successful RA therapy.

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