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Title of Thesis

Jawed Altaf Baig
Institute/University/Department Details
University of Karachi/ Department of Biochemistry
Number of Pages
Keywords (Extracted from title, table of contents and abstract of thesis)
rheumatiod arthritis, synovitis, disease modifying antiheumatic drugs (dmard), non-steroidal antinflammatory drugs (nsaids), methotrexate

Rheumatiod arthritis is a chronic, autoimmune, inflammatory disorder in which the joints are primarily affected with synovitis causing the articular destruction. About 1% of the world population and 0.1-0.2% of Pakistani population is affected with RA. It is hypothesized that the genetically susceptible individuals, after exposure to arthritogenic antigen, under go for inflammatory reaction leading to joint destruction

The etiology of RA is unknown, therefore, the curative treatment is not yet established. However, the current treatment is to suppress the inflammatory response to ameliorate the symptoms thereby preventing the damage to articular structure. To achieve these goals several therapies have been used

The disease modifying antiheumatic drugs (DMARD) with non-steroidal antinflammatory drugs (NSAIDs) are being extensively used to provide the best possible relief to RA patients

Among the DMARDs, the methotrexate (MTX), is being extensively used in low doses (7.5 mg – 15 mg/day) in the treatment of RA. Its popular use in RA is due to its reasonably rapid ant inflammatory action with minimum side effects and low cost. In spite of its extensive use in RA, the mechanism of ant inflammatory action of MTX still not known

Since RA is quite common in Pakistan, we embarked on investigating the role of MTX in patients with RA in Pakistani population

The study had following four objectives: i). To observe the effectiveness and tolerability of MTX in our RA population. ii). To observe the effects of commonly used NSAIDs on disposition of MTX in our RA patients. iii). To observe the frequency distribution of HKLA-DRBI and HLA-DQB1 alleles and to see if there is any relationship between clinical response to MTX and HLA-DR and HLA-DQ genotypes in these RA patients. iv). To investigation whether the ant inflammatory effect of MTX in RA is through suppression of pro-inflammatory neuropeptides (substance P and calcitonin gene related peptide).

The important findings of the study are: MTX despite its adverse effects in some patients, was found to be a very effective (83% of the patients showing good to excellent response after one year treatment) in RA. There was no significant pharmacokinetic interaction between MTX and various NSAID (naproxen, diclofenac, ibuprofen, aspirin, and indomethacin), indicating that MTX can be safely given along with above mentioned NSAIDs. The susceptibility to develop RA, in most of the Pakistani population, appeared to be associated with HLA-DRBI*15/DQ1*16 genotype. However, there was a lack of association between HLA-DRB1? DQB1 genotypes and clinical response to MTX. MTX suppresses the expression of pro-inflammatory neuropeptides (SP and OGRP) at the site of inflammation and at the level of lymphoid organs. Therefore pro-inflammatory neuropeptides do appear to have a role in RA and one of the mechanisms of anti-inflammatory action of MTX could be due to suppression of these neuropeptides.

Download Full Thesis
1405.9 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents 0
137.8 KB
2 1 General Introduction 1
159.47 KB
  1.1 Arthritis 2
  1.2 Rheumatiod Arthritis 2
  1.3 Pathogenesis 5
  1.4 Pharmacotherapy 8
  1.5 Methorexate 10
  1.6 Involvement Of Nervous System In Ra 14
  1.7 The Aims & Objective Of The Project 14
3 2 To Study The Effectiveness And Tolerability Of MTX In A Population Of Pakistani Patients Suffering From Rheumatoid Arthritis 18
174.94 KB
  2.1 Introduction 19
  2.2 Patients And Methods 20
  2.3 Assessment Of Clinical Outcome 21
  2.4 Results 22
  2.5 Discussion 34
  2.6 Summary 37
4 3 Pharmacokinetics Of MTX In RA Patients In The Presence Of Non-Steroidal Anti-Inflammatory Drug 39
243.35 KB
  3.1 Introduction 40
  3.2 Patients And Methods 42
  3.3 Estimation MTX In Plasma 44
  3.4 Data Analysis 45
  3.5 Results 46
  3.6 Discussion 64
  3.7 Summary 66
5 4 HLA-DR And HLA_DQ Genotype In Pakistani Patients With Rheumatoid Arthritis And Clinical Response To Mthotroxate 67
191.46 KB
6 5 Introduction 68
712.55 KB
  5.1 Patients And Methods 70
  5.2 Methods 71
  5.3 Statistical Analysis 75