Disease Modifying Anti Rheumatoid Drugs Research Articles

Case 316: Progressive Pseudorheumatoid Dysplasia.

A 10-year-old North Indian boy presented with swelling of multiple joints in his hands for the past 3 years. This swelling involved the small joints of his hands and some restriction of joint movement, without any associated tenderness or morning stiffness. No other joints were symptomatically involved. Prior to visiting our hospital, he had received disease-modifying antirheumatoid drugs for suspected juvenile idiopathic arthritis, without any clinical benefit. On examination, the metacarpophalangeal and interphalangeal joints were nontender but had swelling and flexion deformities. He also had a short stature (below the third centile) for his age. Inflammatory markers, including erythrocyte sedimentation rate (7 mm per hour; normal range, 0-22 mm per hour) and C-reactive protein level (1.5 mg/L; normal level, <10 mg/L), were normal, and the rheumatoid factor test result was negative. A skeletal survey of the patient was performed.

Cost–utility analysis of tapering strategies of biologicals in rheumatoid arthritis patients in the Netherlands

ObjectivesCurrent guidelines recommend tapering biological disease-modifying antirheumatoid drugs (bDMARDs) in rheumatoid arthritis (RA) if the disease is under control. However, guidelines on tapering are lacking. Assessing cost-effectiveness of different tapering...

Case 316

A 10-year-old North Indian boy presented with swelling of multiple joints in his hands for the past 3 years. This swelling involved the small joints of his hands and some restriction of joint movement, without any associated tenderness or morning stiffness. No other joints were symptomatically involved. Prior to visiting our hospital, he had received disease-modifying antirheumatoid drugs for suspected juvenile idiopathic arthritis, without any clinical benefit. On examination, the metacarpophalangeal and interphalangeal joints were nontender but had swelling and flexion deformities. He also had a short stature (below the third centile) for his age. Inflammatory markers, including erythrocyte sedimentation rate (7 mm per hour; normal range, 0-22 mm per hour) and C-reactive protein level (1.5 mg/L; normal level, <10 mg/L), were normal, and the rheumatoid factor test result was negative. A skeletal survey of the patient was performed and is shown in Figures 1-6.

Nanoparticulate drug delivery systems for the treatment of rheumatoid arthritis: A comprehensive review

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects 1% of the world's population. It is a progressive condition that causes joint inflammation, polyarticular synovitis, bone and cartilage destruction, bone erosion, and deformation, resulting in impairments, morbidity, and a lower quality of life. There is no curative therapy for rheumatoid arthritis because the complete pathogenesis is unknown. The treatment aim is to give symptomatic relief while preventing irreversible joint injury. The standard treatment involves glucocorticoids alone or in combination with nonbiologic and biologic disease-modifying anti-rheumatoid drugs (DMARDs). Treatment of RA with conventional dosage forms has limitations such as non-specificity, dose-escalation, increased frequency of administration, toleration, and systemic side effects. Through its application to medicine, nanotechnology has been able to address the drawbacks of conventional treatment and the complexity of the disease, thus offering new possibilities for the treatment of RA by achieving specificity to joints through active and passive targeting strategies, overcoming dose escalation, increased frequency of administration, and the adverse effects associated with it. This review entails a thorough understanding of various Nanoparticulate drug delivery systems, including polymeric nanoparticles such as polymeric micelles, nanocapsules, and dendrimers; lipid-based nanoparticles such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, Transferosomes, exosomes, nanoemulsions, ethosomes; and metallic nanoparticles such as gold and silver nanoparticles, quantum dots, siRNA, and peptide-based nanoparticulate delivery systems. A comprehensive review of the merits and drawbacks of nanoparticulate drug delivery systems is provided, as well as an update on their application on the pharmacotherapy, toxicity, clinical trial of Nanoparticles on rheumatoid arthritis and patents granted in this field.

Risk factors for rheumatoid arthritis-associated interstitial lung disease: a retrospective study.

The objective of this study was to assess clinical and imaging features of rheumatoid arthritis (RA) associated with interstitial lung disease (ILD), (RA-ILD) group, in comparison to RA without ILD (RA-C) and to identify the associated factors to ILD. This was a retrospective comparative study (from June 2015 to March 2022) including RA patients aged ≥18 years. The RA-C control group was matched according to age (±2 years), gender, and RA duration (±2 years). General data, RA characteristics, ILD features, and treatment modalities were recorded. Statistical analysis was performed to determine the predictive factors of ILD. A total of 104 patients were included (52 RA-ILD and 52 RA-C); sex ratio was 0.36. Mean age was 66.3±11 years (RA-ILD) versus 65.6±10.8 years (RA-C) (p=0.72). In comparison to RA-C, RA-ILD patients were significantly higher smokers (p=0.01) and physically inactive (p=0.01). Regarding RA features, RA-ILD patients have significantly increased positive anti-citrullinated peptide antibody (ACPA) (p=0.01), ACPA rate (p<0.001), erosive disease (p<0.001), and disease activity score (p<0.001). Mean time to ILD diagnosis was 5.85±7.16 years. Chest high-resolution computed tomography (HRCT) patterns of disease were identified: nonspecific interstitial pneumonia (NSIP) (28.8%), usual interstitial pneumonia (UIP) (17.3%), organizing pneumonia (OP) (25%), acute interstitial pneumonia (13.5%), and respiratory bronchiolitis (3.8%). Multivariate analysis identified smoking, high baseline DAS28 (disease activity score 28) and ACPA positivity as predictive factors of ILD. Our results confirmed the reported associated factors of ILD in RA (smoking, higher disease activity, ACPA positivity). Thus, we need to target the modifiable factors by supporting and educating RA patients to quit smoking and intensify disease modifying anti-rheumatoid drugs (DMARD) to reach remission.

Ozone Mixed Autologus Blood Used for Treatment of Rheumatoid Arthritis :A Case Report of two Patients

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder that primarily affects joints and can affect skin, eye, heart, lungs and blood vessels. Currently we are using Disease Modifying Anti-rheumatoid Drugs (DMARD) for RA1 . This time we used a different kind of treatment to alter autoimmunity in form of intramuscular injection of ozone mixed autologous blood with encouraging results Keywords: DAMRD, RA, VAS

The Effects of Intra-articular Platelet-Rich Plasma Injections in Rheumatoid Arthritis: A Narrative Review.

Platelet-rich plasma injections have been a therapeutic option with exponential growth in several pathologies in the last decades, particularly musculoskeletal for their effect on improving pain and functionality. Rheumatoid arthritis is a chronic joint disease, which involves inflammation of the synovial membrane with cartilage and juxta-articular bone destruction. Conventional and biological disease-modifying anti-rheumatoid drugs are the cornerstone of the treatment of this disease. However, the use of intra-articular glucocorticoids is often necessary and the role of platelet-rich plasma injections in these patients remains uncertain.A literature review was carried out through the PubMed database, Cochrane and Google Scholar for the search terms “rheumatoid arthritis” and “platelet-rich plasma”. Eleven studies have been included in this review: two of these are in vitro studies, five are animal studies, one case report, two case series and one randomized controlled trial. Most of the studies demonstrated a decrease in pain and inflammatory mediators and improvement of functional outcomes, with no severe adverse effects reported.However, the quantity and quality of literature about the effects and safety of plasma-rich plasma injections in rheumatoid arthritis patients are still scarce. It is essential that well-designed randomized controlled trials are made on this topic to understand if platelet-rich plasma may be useful as a coadjuvant therapy in rheumatoid arthritis.

Overlapping rheumatoid arthritis and antisynthetase syndrome with secondary Sj\xf6gren\u2019s syndrome: a case report\xa0and review of the\xa0literature

BackgroundOverlap syndromes account for about 25% of autoimmune diseases. They are many possible combinations of known autoimmune diseases increasingly diagnosed with the identification of of a large number of autoantibodies. In this case report, we present a patient with rare overlapping rheumatoid arthritis–antisynthetase syndrome with associated secondary Sjögren’s syndrome atypically presenting without interstitial lung disease.Case presentationA 52-year-old Sinhalese female, a known patient with type 2 diabetes mellitus, presented with a history of symmetrical inflammatory-type polyarthritis with significant morning stiffness, proximal muscle weakness, pain, and roughening of the fingertips with associated sicca symptoms of 5 months duration. Examination revealed features of active joint inflammation, mechanic’s hand, xerostomia, and left-sided breast lump. Investigations confirmed the presence of rheumatoid arthritis with strongly positive rheumatoid factor (202 U/ml) and anti-cyclic citrullinated peptide antibody (717 U/ml). Antisynthetase syndrome was also diagnosed with borderline-positive anti-aminoacyl-tRNA antibodies but without interstitial lung disease. Sjögren’s syndrome was confirmed by the clinical history and histology and considered a secondary disorder. As her breast lump proved to be benign, no further interventions were done. She was started on sulfasalazine and methotrexate with steroid bridging therapy and achieved remission and had good control of the disease without any joint deformity or flare-up on 6-month clinic follow-up.DiscussionOverlapping rheumatoid arthritis–antisynthetase syndrome is a very rare disease with disabling complications. Early identification of the atypical presentations of the overlap syndromes, by thorough investigations, helps physicians to prescribe proper disease-modifying antirheumatoid drugs and biological drugs. It also helps predict the prognosis of the patients before they develop complications.

Bilateral idiopathic club foot in baby of a rheumatoid mother: A rare case report and its management

Congenital clubfoot has a multifaceted etiology, with several hypotheses offered in its etiopathogenesis. The clubfoot has rarely been reported in babies born to women who have rheumatoid arthritis (RA). We present a rare case of a 31-year-old lady with RA on disease-modifying anti-rheumatoid drugs who delivered a child with bilateral congenital clubfoot. She had previously been using Methotrexate, Hydroxychloroquine, and Sulfasalazine regularly, but Methotrexate was stopped seven months before pregnancy. A full-term female baby was born through the cesarean section with bilateral clubfoot deformity and a modified Pirani score of eight out of 10. The deformity correction was done with the Ponseti serial casting method. The final modified Pirani score was two out of ten. In newborns born to rheumatoid arthritis mothers, the club foot deformity was effectively treated with serial Ponseti corrective casts, as was idiopathic clubfoot in babies born to non-rheumatoid mothers. Our findings validate the Ponseti serial casting method for these kinds of patients.

A Review on Comparison of Effectiveness and Safety of Disease Modifying Anti-Rheumatoid Drugs Used in Patients with Rheumatoid Arthritis

Objective: To compare the safety and effectiveness of monotherapy as well as combination therapy with disease modifying anti rheumatoid drugs (DMARDs) in rheumatoid arthritis patients. Data sources: Study works limited to the English language and more concentrated to adults by using Google Scholar, PubMed and The Cochrane library. Summary: Some head to head trial works, retrospective studies and prospective cohort studies were used to compare the safety and effectiveness of the therapy. Here we go through the comparison in between each disease modifying anti rheumatoid drug (DMARD) monotherapy, combination with monotherapy and also combination with combination therapy. Conclusion: Among the synthetic DMARDs monotherapy, methotrexate would be the preferred DMARD. Biological DMARDs have more efficacy than synthetic agents and have comparable safety profile. Rituximab would be the preferred agent among the bDMARDs. Since synthetic agents are more economical as compared to biologicals, hence these are preferred over biological agents. Combinations of biological DMARDs with methotrexate have improved efficacy and safety than methotrexate monotherapy. Combination of biological DMARDs have no advantage over biological monotherapy, there was an increased safety risk and no therapeutic benefit. Combination of biological DMARDs with methotrexate have better efficacy than monotherapy with either bDMARDs or methotrexate alone. A triple combination therapy of synthetic DMARDs (methotrexate, sulfasalazine and hydroxychloroquine) had better safety, effectiveness and high tolerability than double combination therapy or monotherapy. Keywords: Rheumatoid arthritis, disease modifying antirheumatoid drugs

Is fibromyalgia frequency increasing in axial spondyloarthritis? Association with fibromyalgia and biological therapies.

Fibromyalgia (FM) is known a common painful syndrome and its frequency is increased in inflammatory rheumatic diseases. We aimed to assess FM frequency in axial spondyloarthritis (AxSpA) patients and age- and sex-matched healthy controls with the 2011 ACR FM criteria. We evaluated the association between receiving biologic disease-modifying antirheumatoid drugs (bDMARD) and presence of FM. 127 patients with Ax-SpA and 73 age- and sex-matched controls were included. Individuals were assessed according to modified 2011 ACR diagnostic criteria for FM. The pain was evaluated by visual analog scale (VAS). Disease activity was assessed by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activation Score (ASDAS). Spinal limitation, quality of life, and functionality were assessed. Drug therapies were noted. AxSpA and control group had similar FM rates. 43 (33.9%) patients in AxSpA group and 22 (30.1%) patients in control group had FM diagnosis (p = 0.589). Age, gender, BMI, and CRP values were similar in the AxSpA patients with and without FM, while global VAS and ASDAS scores were higher in patients with FM. Biologic DMARD use was higher in the AxSpA patients with FM; however, the difference was not statistically significant. In conclusion, FM frequency does not increase in AxSpA patients as compared to healthy controls. FM awareness is one of the key points to determine the appropriate treatment due to the influence on disease activity.

To study the effect and mechanism of dimethyl fumarate [DMF] in adjuvant induced arthritis model in rats

Currently available disease modifying anti-rheumatoid drugs have limitations like dose-dependent toxicity and tolerance.Dimethyl fumarate has demonstrated anti-inflammatory and immunomodulatory properties in various animal models. Thus, thepresent study aimed to evaluate the effects and mechanism of DMF in a murine model of adjuvant-induced arthritis.A total of 84 rats were divided into early treatment groups (n=48) and late treatment groups (n=36). There were 8 subgroupsand 6 subgroups (n=6 in each group) in the early and late treatment groups, respectively. Experimental rheumatoid arthritis(RA) was induced in Wistar rats by injecting complete Freund's adjuvant (CFA) intradermally at the base of the tail. Antirheumatic effects were evaluated by arthritis and histopathological scoring of ankle joints. To evaluate anti-oxidant properties,GSH, catalase, SOD, and lipid peroxidation were measured. ESR, WBC count, TNF-α and IL-6 levels were measured to evaluatethe immunomodulatory properties of DMF. DMF demonstrated anti-inflammatory effects by decreasing arthritis andhistopathological scores compared to the CFA control group, though the difference was not statistically significant. DMFexhibited immunomodulatory properties as decreases in TLC count, serum TNF-α, and plasma IL-6 levels were observed. In allthe above-mentioned parameters, the best response was achieved with the early combination therapy of DMF 30 mg/kg andmethotrexate [Mtx] 0.1 mg/kg. In the present study, DMF demonstrated antirheumatoid effects in a rat model of CFA-inducedarthritis. The best antirheumatoid effect was achieved with the early combination of DMF and Mtx.

Impact of Chronic DMARD Therapy in Patients With Rheumatoid Arthritis Undergoing Surgery of the Craniovertebral Junction: A Multi-center Retrospective Study.

A multi-centered retrospective review from five institutions. The aim of this study was to determine whether continuing or withholding disease-modifying antirheumatoid drugs (DMARDs) in the perioperative period affect outcomes in rheumatoid arthritis (RA) patients undergoing arthrodesis at the craniovertebral junction SUMMARY OF BACKGROUND DATA.: RA is a chronic systemic inflammatory disease that affects the cervical spine and is treated with DMARDs. Some advocate withholding DMARDs in the perioperative period due to concern for the cytotoxic effects of these medications. However, the impact of DMARDs in the perioperative period is not well understood. A multicenter retrospective study from five affiliated institutions was performed. Adult patients with RA on chronic DMARDs undergoing posterior arthrodesis of the craniovertebral junction (occipital-cervical or atlanto-axial arthrodesis) were identified. Patients were stratified based on whether DMARD therapy was continued (C group) or discontinued (DC group) in the perioperative period. The primary outcome was the need for reoperation and reason for reoperation. Thirty-nine patients met inclusion criteria, 19 in C group and 20 in DC group. Average follow-up time was 42 months. Four patients (three in DC group and one in C group) required reoperation. Two patients from the DC group required readmission secondary to RA flare-up. Our cohort of RA patients who underwent occipital-cervical and C1/C2 posterior arthrodesis showed no significant differences in surgical complications when DMARD therapy was continued or discontinued in the perioperative period. The decision to continue or discontinue DMARD therapy in the perioperative period is at the discretion of the treating physician, but we encourage physicians to counsel patients regarding this theoretical risk and their tolerance of the medications as well as the risk of RA flare-up. Factors such as overall health, disease burden, nutrition, bone quality, smoking status, and other comorbid conditions are likely to have a larger influence on perioperative complications. 3.

Quantification of health-related quality of life among patients with rheumatoid arthritis: An institution-based study in Kolkata, West Bengal.

Context:Rheumatoid arthritis (RA) is a known chronic debilitating disease accounting for a large percentage of disability globally. Pain and stiffness, decreased work function, depression and emotional state alteration, fatigue, disability, and social handicaps are some patient reported outcomes, which if considered with priority the health-related quality of life (HRQOL) of patients with RA could improve.Aims:This study was conducted with the aim to assess the HRQOL of the patients with RA and the determinants related to it.Settings and Design:This was a cross-sectional study conducted at Rheumatology Department of a tertiary care hospital, Kolkata.Subjects and Methods:A total of 252 patients with RA were selected in this study through systematic random sampling.Statistical Analysis Used:Data were analyzed using appropriate statistical measures with Statistical Package for the Social Sciences(SPSS) version 16.0 (Armonk, NY: IBM Corporation) software program, version 16.0. Univariate and multivariable logistic regression were carried out.Results:In the study, the mean age of the patients was 43.1 years (mean age ±SD: 43.05±10.63 years). The proportion of female subjects was 84.5%. Unsatisfactory QOL was found in 59.9% study participants. In multivariable logistic regression unsatisfactory quality of life was significantly associated to moderate to high functional disability [AOR: 6.04, CI: 2.86, 12.78], disease activity moderate to high [AOR: 5.41, CI: 1.87, 15.69], presence of comorbidity [AOR: 2.90, CI: 1.39, 6.04], extra-articular manifestations [AOR: 3.14, CI: 1.41, 6.96] and delay in starting Disease-Modifying Anti-Rheumatoid Drugs (DMARDs) [AOR: 1.24, CI: 1.08, 1.42].Conclusion:Findings of this study clearly indicate the presence of high proportion of unsatisfactory QOL among the patients with RA. Early identification and prompt referral are the key strategies to prevent any permanent damage. Regular follow-up of the patients should be carried out to prevent or delay the disability progression and provide high-quality physical and mental health.

PBI48 EQUALITY IN ACCESS TO DMARDS IN TURKEY

Equality in healthcare is one of the main objectives of the health systems all over the World. Access to Disease-Modifying Anti-rheumatoid Drugs (DMARDs) especially biologic drugs are important for patients diagnosed with rheumatoid arthritis. The purpose of this study was to examine how equality in access to DMARDs in Turkey impacts outcomes in rheumatoid arthritis. Research is a based on expert opinion. A Delphi panel was conducted together the information Equality in Access to DMARDs in TURKEY. The hypothesis of the study was tested through opinions from experts in rheumatology in Turkey by employing the modified Delphi method to generate a consensus. Turkish Social Security (SS) covers 98,5% of the Turkish population. SS Institution reimburses cost of registered drugs for covered population including DMARDs. Under the current system of SS, there are provisions in the Turkish laws to procure medications, if they lack marketing authorization and are not available in the country. However, procuring such medications need to be supported by prescriptions for a treating specialist physician and further approved by the Ministry of Health. In many cases, to reduce the waiting times, the Turkish Ministry of Health has developed a list of pre-approved medicines for procurement from abroad (referred as “Abroad Drug List”), for which individual permissions from the Ministry of Health is not required. The Turkish Parliament passed a new law removing the requirement that the Turkish Pharmacists Union be the only institution to procure medicines from abroad which did not have a marketing authorization in Turkey. In Turkey, there is no distinction or discrimination between individuals generally for access to medicines and this is no different when it concerns the access to DMARDs for treating RA. Everyone has equal access to medicines. Equality and access to quality healthcare is assured to the citizens within the Turkish Constitution.

Reactivation of latent tuberculosis associated with methotrexate therapy

Tuberculosis is highly prevalent in developing world. Post primary tuberculosis occurs in the setting of depressed immunity commonly affecting the lungs. Reactivation of tuberculosis concomitantly at different non-pulmonary sites is very uncommon. Here we report an immunocompetent male with rheumatoid arthritis presented with reactivation of cutaneous and meningeal tuberculosis while on low dose methotrexate therapy. The case report highlights the fact that the treating clinician should be vigilant enough to suspect reactivation of latent tuberculosis even with non biological disease modifying anti rheumatoid drugs therapy in tropical world.

Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis

Background:Rheumatoid arthritis (RA) is an autoimmune disorder characterized by involvement of multiple small and large joints with multisystem extra-articular manifestations. Peripheral neuropathy is known extra-articular manifestation of RA with the incidence of around 39.19% as per previous studies. Early diagnosis and treatment of peripheral neuropathy has been shown to improve both physical and functional disabilities of patients with RA.Objectives:The primary objective was to study prevalence and patterns of peripheral neuropathy in patients with RA. The secondary objective was to study demographic, clinical parameters, disease severity, and extra- articular manifestations in patients with RA with and without peripheral neuropathy.Materials and Methods:Consecutive patients of RA were recruited. Detailed clinical examination and electrophysiological tests were done to diagnose peripheral neuropathy. The demographic and clinical parameters were noted and tabulated. Student's t-test was used to analyze continuous variable, whereas Chi-square test was used for analysis of categorical variables.Results:Of 89 patients with RA, 75.28% (n = 67) patients had peripheral neuropathy electrophysiologically, whereas 20.89% (14 patients of 67) had superficial touch sensory loss on examination. Subclinical neuropathy was present in 50.74% (n = 34) of patients. Statistically significant association between the presence of neuropathy and age of the patients, disease duration, use of disease-modifying antirheumatoid drugs, disease severity (disease activity score-28), and presence of subcutaneous nodules (P < 0.05).Conclusion:Patients with RA, especially elderly patients, should undergo electrophysiological testing to rule out peripheral neuropathy. Electrophysiological study is a diagnostic and gold standard tool to diagnose subclinical neuropathy in patients with RA. Presence of peripheral neuropathy in these patients has been found to be significantly associated with deteriorating health status, pain scores, and presence of extra-articular manifestations.

Safety and efficacy of abatacept among patients with refractory rheumatoid arthritis: Experience from a North Indian Tertiary Care Hospital

Background: T-cells are pathogenic in rheumatoid arthritis (RA) and have an important role in persistent synovitis, even in established disease. Modulation of T-cell activity by blocking of costimulatory signals has been known to suppress inflammation and improves prognosis in RA. This study aims to assess the effect of costimulation blockade with Abatacept in patients with RA who were refractory to conventional synthetic/biological disease modifying anti-rheumatoid drugs (csDMARDs, bDMARDs). Methods: In this prospective study, 63 patients with active disease, measured by the European League Against Rheumatism (EULAR) disease activity score (DAS28-erythrocyte sedimentation rate [ESR]) ≥3.2, who had failed conventional therapy with at least 2 csDMARDs and/or antitumour necrosis factor (anti-TNF) agents (Infliximab/Etanercept) either standalone, or in combination, were initiated on Abatacept in fixed doses, which was given on days 1,15, and 29 and repeated every 28 days for 11 months, after taking informed consent. Biomarkers comprising ESR and DAS28-ESR score were measured at baseline and repeated at the end of 3, 6, and 12 months. The primary end-point was the achievement of remission as defined by DAS28-ESR score ≤ 2.6. Results: Sixty-three patients completed 6 monthly follow-up whereas 57 patients completed 12 months follow-up (90% follow-up rate). DAS28-ESR declined significantly at 3 months (P = 0) and improvements were sustained at 6th and 12th month. Treatment was discontinued in three patients due to inadequate response, and three patients were lost to follow-up. Nearly 52.6% patients achieved primary end-point. Most common adverse effects reported during the study period were headache (14.2%) and upper respiratory tract infection (9.5%). Conclusions: Abatacept is an effective and well-tolerated treatment option for Indian RA patients with an inadequate response to csDMARDs and TNF antagonists.

Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5-49% HCQ and 53.4-66.8% of NSAIDs were recovered in 8.5-10h in blood. Urine and feces samples pooled over a period of 24h exhibited 2.3-3.5% and 0.75-0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.

DESIGN AND SYNTHESIS OF SOME NEWER IMIDAZOLYL HETEROCYCLES AS POTENT BTK INHIBITORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

Objective: The rheumatoid arthritis as a global health problem over the past few decades, Emphasizes the need for discovery of new therapeutic disease modifying anti-rheumatoid Arthritis drugs (DMARD’s). Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor, tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in the development, differentiation and proliferation of B-lineage cells, thus making BTK an efficient therapeutic target for the treatment of rheumatoid arthritis. This prompted us to synthesise a novel series of Imidazolyl Heterocycles as potent BTK (Bruton’s Tyrosine Kinase) inhibitors with alleged Anti-Rheumatoid Arthritis properties. Methods: Newer BTK inhibitors containing one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic features based on that pharmacophore model for BTK were designed. The designed compounds were sorted by applying ADMET properties, Lipinski rule of five, molecular docking and Novelty prediction to refine the designed ligands. Finally, different five compounds containing Imidazole as the heterocyclic nucleus have been synthesized and characterized by different analytical methods like Chromatographic data, Elemental analysis and Spectral studies by IR, 1H NMR, 13C NMR, GC-MS. Molecular docking studies were performed against BTK using GLIDE 10.2. Results: Several important hydrogen bonds with BTK were revealed, which include the gatekeeper residue Glu475 and Met477 at the hinge region. Conclusion: Overall, this study suggests that the proposed ligands are found to be more effective BTK inhibitor as Anti-Rheumatoid arthritis agents.