ANTI-INFLAMMATORY EFFECT OF DISEASE-MODIFYING ANTI-RHEUMATIC DRUG, LEFLUNOMIDE: A REVIEW

ANTI-INFLAMMATORY EFFECT OF DISEASE-MODIFYING ANTI-RHEUMATIC DRUG, LEFLUNOMIDE: A REVIEW

Vivek Verma * and T. S. Easwari

IIMT College of Medical Sciences, IIMT University Ganga Nagar Mawana Road, Meerut, Uttar Pradesh, India.

ABSTRACT: The epidemiology, pathophysiology, clinical capabilities, diagnosis and scientific route of rheumatoid arthritis (RA) and the function of disorder-editing anti-rheumatic tablets (DMARDs) in its remedy are reviewed. RA, a giant disorder affecting humans of all races and sexes around the sector, has an unknown and perhaps multifactorial etiology. Conflicting proof supports RA's immune-complex, infectious, metabolic, or genetic foundation. The sickness impacts arthrodial joints and starts as an immune reaction to unknown antigenic stimuli. A proliferative process ensues, leading to the formation of a vascular lesion referred to as a pannus, which then infiltrates into cartilage, subchondral bone, and tendon. This detrimental segment ends in traditional RA signs of pain, the predicament of motion, swelling, warmth, and redness of the affected joint. Symptoms and laboratory checks form the basis for prognosis. For maximum RA sufferers, a conservative remedy presents a significant advantage. More competitive intervention is vital to prevent everlasting incapacity in those sufferers who suffer from unrelenting and regularly negative sickness. The DMARDs are reserved for treatment of this institution of sufferers. Leflunomide, a brand as DMARD & for anti-inflammatory residence, has been delivered to the armamentarium towards RA after more than 10 years of using established DMARDs. It has proven equivalent efficacy, protection, and tolerability, compared with the prevailing first-line DMARDs - SSZ and MTX- in controlled medical trials.

Keywords: Rheumatoid arthritis, Leflunomide, Anti-inflammatory Activity, DMRD, Methotrexate

INTRODUCTION: Rheumatoid arthritis is a complex autoimmune disease that affects about 0.5-1 percent of the global population and causes persistent inflammatory pain and swelling in joints, elbows, shoulders, ankles, and other body organs ¹.

It is caused by a complex interplay of environmental, physiological, and genetic factors, making it challenging to investigate its pathophysiology and find an effective treatment. The body's immune system impacts the body's tissues and joints in rheumatoid arthritis ².

The condition can also affect the body's internal organs in extreme cases ³. Rheumatoid arthritis affects the linings of joints, resulting in severe swelling. Rheumatoid arthritis causes long-term inflammation, leading to bone degradation and joint deformity.

The treatment of rheumatoid arthritis focuses on reducing pain, preventing infection and minimizing joint damage ^{4, 5}. There are several unique drug delivery methods for treating rheumatoid arthritis, including enteral channels such as oral, buccal, sublingual and parenteral routes such as intramuscular, intravascular, subcutaneous and intra-articular, or topical approaches ⁶. The drug is placed onto the body's floor by integrating it into a composition that can be absorbed in the topical drug shipping system. Topical distribution has several advantages over oral delivery for treating illnesses, including the ability to provide medicine quickly and continuously and the reduction of drug plasma concentration (Cmax) ^{7, 8, 9}.

The amount of medication delivered by dermal software is greatly reduced because of the inability of multiple pills to pass through the skin at a healing rate due to the outside stratum corneum membrane barrier. It's been speculated that a device that uses nanoparticles to deliver drug could also provide a novel method for influencing drug permeability, and it's also possible that a topical transport machine using nanoparticles could provide an alternative to their use in the treatment of rheumatoid arthritis. The topical administration systems of medicine use a variety of dosage bureaucracies, including liquids, sprays, semisolids, and solids. Lotions, ointments and gels are semisolid dosage forms that are most commonly employed for topical delivery systems. When the gel comes into touch with fluids, it swells up into a community of pass-connected polymer. The interaction between the stable-state polymer and the aspect of the liquid media is completely dependent on the kind of gel. Topical gels are a good shipping method for Drugs, because they have a low degree of greasiness and are easily removed from the skin. Compared to creams and ointments, gel training provides superior balance and awareness ^{8, 9}.

Nanoemulsions are heterogeneous colloidal structures on the submicronic scale. In contrast, colloidal particulate structures are isotropous dispersions that are thermodynamically and kinetically solid, consisting of two incompatible components, namely water, and oil, stabilized by an accomplice surface layer containing an appropriate co-surfactant and surface energetic agent to form a single-degree emulsion ⁹. The nanoemulsions are now classified into three types: oil-in-water (oil dispersed in water phase), water-in-oil (aqueous phase dispersed in oil phase), and bi-non-stop (aqueous phase dispersed in oil phase) (micro-domains of aqueous section and oil segment are interconnected within the tool). Lipophilic and hydrophilic floor-energetic compounds are utilized in tandem to stabilize these emulsions ¹⁰. The nano-emulgel is a Nano-emulsion-based hydrogel created by incorporating Nano-emulsion into a hydrogel matrix ^{11, 12, 13}. Nanoemulgel offers several advantageous properties, including being readily spreadable, clean to apply, considerably less oily, causing no discoloration, having a longer shelf life, being thixotropic, water-soluble, bio-pleasant, having an appropriate look, and being translucent ^{14, 15, 16, 17}.

Leflunomide Treatment: The placement of Leflunomide in the DMARD therapy sequence in RA isn't usually standardized, and it's left to the discretion of the individual rheumatologist. Leflunomide was prescribed in the manufacturer's recommended dose, i.e., a loading dose of 100 mg daily for three days, followed by 20 mg every day ¹⁸.

Mechanism of Action: Leflunomide is an immunomodulatory medication that works by blocking the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which is involved in the production of the pyrimidine ribonucleotide uridine monophosphate from scratch (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at wavelengths (about 600 nm) that are reached during RA treatment ¹⁹.

Anti-inflammatory Actions: Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting cyclooxygenase (COX), the enzyme responsible for the production of prostaglandins (PGs). They all have the same negative side effects, such as gastrointestinal and renal toxicity, to a greater or lesser extent. According to a recent study, there are at least two COX isozymes. COX-1 is a constitutive enzyme that produces PGs, which protect the stomach and kidneys from harm. COX-2 is activated by inflammatory stimuli, such as cytokines, and generates PGs that contribute to the discomfort and edoema associated with irritation. As a result, selective COX-2 inhibitors should be anti-inflammatory while causing no adverse effects on the kidneys or the stomach. Selective COX-2 inhibitors, on the other hand, may have other adverse effects and healing abilities. COX-2 (rather than COX-1) is assumed to be involved in ovulation and labour.

Furthermore, aspirin's well-known anticancer effect may be due to an action on COX-2, which is expressed in this disease. Furthermore, NSAIDs delay the onset of Alzheimer's disease. As a result, selective COX-2 inhibitors may offer novel and important therapeutic benefits as anticancer agents, as well as preventing premature labour and maybe even slowing the progression of Alzheimer's disease ²⁰.

Pharmacokinetics: After oral administration, leflunomide is rapidly metabolized in the gut wall, plasma, and liver to its active form A77 1726. The parent chemical is only found in trace amounts in the plasma. After oral administration of leflunomide, peak plasma levels of A77 1726 are attained 6-12 hours later. Using a high-fat meal has no effect on the bioavailability of A77 1726. It has a narrow range of distribution because it is >99% protein-specific. The fact that A77 1726 traverses enterohepatic stream and biliary recycling may contribute to its lengthy elimination half-life (less than two weeks) A77 1726 is further metabolised and excreted as an oxalinic acid offshoot in the urine, as well as in the unaltered form in the faeces ^{20, 21}.

Drug Interaction: Few reports on leflunomide drug interactions are known. Leflunomide and methotrexate no longer exhibit a substantial pharmacological interaction, according to in-vivo drug interaction studies. Leflunomide levels rise after receiving numerous doses of rifampin ⁸. The enzyme CYP2C9, which is responsible for the metabolism of many NSAIDS, is suppressed by A77 1726. However, no clinically relevant interactions were observed in clinical trials with patients using leflunomide and NSAIDs, commonly used in RA treatment. There were no known interactions with oral contraceptives, which were used by a substantial number of people in the scientific trials ^{22, 23}.

Long-time Period Efficacy and Protection of Leflunomide: Kalden et al. confirmed that the early efficacy of leflunomide [ACR20, ACR50, ACR70] response rates and health assessment questionnaire (HAQ) scores visible at 1 year in patients with RA were maintained for up to five years in an open-label, non-controlled extension study. The long-term protective profile was no longer unique to previous studies. During the evaluation, no new adverse events were discovered, and the majority of patients' liver characteristics were normal. The participants who were included in this extension study were those who had completed all 24 months of leflunomide treatment in the previous two Phase III studies ^{24, 25}.

Adverse Drug Effects: The principal unfavorable events in the medical trials blanketed gastrointestinal signs (diarrhoea, dyspepsia, nausea, abdominal ache, oral ulcers), accelerated liver function checks, skin rash/allergic reactions, alopecia, infections, weight loss, and hypertension. Only GI symptoms, alopecia, and high blood pressure have been determined to be considerably more within the leflunomide institution as compared to MTX ²⁶.

Dosage and Administration: Leflunomide remedy is initiated orally with a loading dose of a hundred mg/day administered as soon as each day for 3 days to hasten the regular state concentration (Css) and protection dose of 20 mg/day. If the dose of 20 mg/day is not properly tolerated, then the dosage is reduced to 10 mg/day. Dosages more than 20 mg/day aren't encouraged ^{26, 27}.

Monitoring: Patients taking leflunomide to need to have an entire haemogram and ALT (SGPT), monitored at baseline and month-to-month for six months following initiation of therapy, if solid each 6 to 8 weeks thereafter. In addition, if leflunomide and MTX are given concomitantly, American College of Rheumatology (ACR) suggestions for monitoring methotrexate-prompted liver toxicity should be observed²⁷.

Contraindication: There are no records regarding leflunomide's safety in kids with RA, and it isn't always advocated for sufferers < 18yrs of age. It is contraindicated in people with hepatic insufficiency. Caution wants to be exercised in patients with continual renal insufficiency as plasma degrees of A77 1726 are multiplied with impaired kidney function. Reproductive Adverse Effects ²⁸:

• Women taking leflunomide need to use birth control and communicate to their rheumatology crew earlier than attempting for an infant.
• You might be cautioned to stop taking leflunomide and have a washout remedy earlier than trying to turn out to be pregnant. You’ll normally be cautioned to carry on the usage of birth control until blood checks display the drug is absolutely from your machine.
• If you decide not to have the washout treatment, you'll be advised to retain the use of contraception for up to 2 years after preventing leflunomide.
• If you end up pregnant at the same time as taking leflunomide, talk to your health practitioner or a member of your rheumatology team right away. You will probably be advised to prevent taking your leflunomide and feature a washout treatment as soon as viable.
• If this occurs to you, leflunomide will not likely damage your baby if you act quickly and make contact with your rheumatology crew.
• You are cautioned to keep away from taking leflunomide until you have stopped breastfeeding due to the fact it can skip into your milk.
• Men need to be excellent at taking leflunomide if they are trying for a child with their companion, but the research is restrained, so you have to talk this along with your doctor.

Drug Elimination Procedure: If there are indications to stop the drug due to unfavorable reactions, overdosage or reproductive problems, the following is undertaken to gain non-detectable plasma ranges (less than zero.02 mg/L or 0.02 µg/mL). Administer cholestyramine eight g three instances daily for eleven days. (The eleven days do no longer need to be consecutive until there may be a want to lower the plasma degree hastily.) Verify plasma degrees much less than zero.02 mg/L (0.02 µg/mL) with the aid of separate assessments as a minimum 14 days apart. If plasma degrees are higher than zero.02 mg/L, additional cholestyramine remedy ought to be considered. Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for twenty-four hours) in addition to the above, if speedy decreasing of the drug stages is indicated ²⁸.

Role of Leflunomide in the Management of Rheumatoid Arthritis: The efficacy and protection of leflunomide as monotherapy is corresponding to that of first-line DMARDs-MTX and SSZ. However, rheumatologists have differing opinions concerning the exact region of leflunomide inside the hierarchy of DMARDs for RA. Presently, leflunomide is taken into consideration for use within the following scientific situations ²⁹-

• As monotherapy in place of MTX or SSZ when the latter drugs are poorly tolerated or contraindicated.
• Refractory RA patients- In combination (add-on therapy) with MTX for patients with persistent active RA despite recommended doses of MTX.
• Further studies and longer follow-up periods are required before it can be advocated as first-line therapy for use in combination with other DMARDS.

Constraints of Leflunomide Therapy with Respect to Indian Patients: The treatment has a high value compared to set up DMARDs. Lack of facilities to reveal blood degrees at some point of drug elimination processes when indicated. We report an Indian (Asian) revel in from a prospective observational examination. Two hundred thirty affording sufferers with moderately severe energetic RA, often failing methotrexate (MTX), were began LEF (Aravatrade mark; 20 mg daily, post-loading a hundred mg OD x 3 days) in a health facility placing and accompanied often in an open cohort as consistent with wellknown of care exercise guidelines. One hundred forty-3 patients and 87 patients have been clinically assigned to the LEF monotherapy and LEF + MTX mixture, respectively; less than one 1/3 received prednisolone. We cognizance on 146 sufferers (64%) completing 1 year remedy ^{30, 31}.

CONCLUSION: The epidemiology, pathophysiology, clinical capabilities, diagnosis, and scientific route of rheumatoid arthritis (RA) and the function of disorder-editing antirheumatic tablets (DMARDs) in its remedy are reviewed. RA, a giant disorder affecting humans of all races and sexes around the sector, has an unknown and perhaps multifactorial etiology.

Conflicting proof supports an immune-complex, infectious, metabolic, or genetic foundation for RA. The sickness impacts arthrodial joints and starts as an immune reaction to unknown antigenic stimuli. A proliferative process ensues, leading to a vascular lesion called pannus, which then infiltrates into cartilage, subchondral bone, and tendon.

This detrimental segment ends in traditional RA signs of pain, the predicament of motion, swelling, warmth, and redness of the affected joint. Symptoms and laboratory checks form the basis for prognosis.

For maximum RA sufferers, a conservative remedy presents a significant advantage. More competitive intervention is vital to prevent everlasting incapacity in those sufferers who suffer from unrelenting and regularly negative sickness. The DMARDs are reserved for treatment of this institution of sufferers.

Leflunomide, DMARD anti-inflammatory residences, has been delivered to the armamentarium towards RA after more than 10 years of using established DMARDs. It has proven equivalent efficacy, protection, and tolerability compared with the prevailing first-line DMARDs - SSZ and MTX- in controlled medical trials. With extended experience in recurring scientific practice, it can be a primary preference when starting DMARD treatment for this revolutionary and disabling sickness. There are also encouraging consequences with weekly leflunomide therapy, which, if shown with large-scale blinded trials, might also bring about lesser value of remedy, much less side effects, and higher compliance without loss of efficacy.

ACKNOWLEDGMENT: I am thankful to my institute for providing all the facilities required to compile this article's literature, journals, and online sources.

CONFLICTS OF INTEREST: The authors declare no conflict of interest, financial or otherwise.

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    How to cite this article:

    Verma V and Easwari TS: Anti-inflammatory effect of disease modifying anti-rheumatic drug, leflunomide: a review. Int J Pharm Sci & Res 2022; 13(7): 2648-54. doi: 10.13040/IJPSR.0975-8232.13(7).2648-54.

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