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BACKGROUND: The protein tyrosine phosphatase non receptor type 22 (PTPN22) gene inhibits T-cell activation. A functional single nucleotide polymorphism (SNP) Arg620Trp (rs2476601), resulting from a C→T substitution at nucleotide position 1858, is a significant risk factor for rheumatoid arthritis (RA) in European populations. The variant allele results in a gain of function that alters the threshold for T-cell signalling and abnormal T regulatory cell function. AIM: To investigate the role of the PTPN22 R620W polymorphism in disease susceptibility and severity in Black South Africans (BSA) with RA. METHODS: A cohort of 187 BSA patients with RA and 93 ethnically matched Black and 60 White controls with no history of RA or other autoimmune diseases were studied. Genotyping was performed by the polymerase chain reaction and pyrosequencing. RESULTS: The rs2476601 SNP was nonpolymorphic in both Black patients and Black control subjects with total absence of the variant ‘T’ allele. In White control subjects the frequency of the ‘T’ allele was 0.092, with T/T, C/T and C/C genotype frequencies of 0.00, 0.183, and 0.817, respectively. CONCLUSION: This study shows that the rs2476601 SNP of the PTPN22 gene is nonpolymorphic in BSA and therefore not associated with RA but the minor ‘T’ allele frequency in White South Africans is similar to that in other European populations. However, since variations in the rest of the gene were not investigated, these results do not exclude other PTPN22 polymorphisms from playing a role in RA susceptibility in BSA.

M.Sc.(Med.), Faculty of Health Sciences, University of the Witwatersrand, 2009 / Introduction Foot involvement is common in rheumatoid arthritis (RA). Foot pain, instability and deformity affect ambulation and impacts on health-related quality of life. The aim of this study was to determine the nature, extent and functional impact of rheumatoid foot problems in established RA. Patients and Methods One hundred RA patients were studied. Functional status was evaluated using the modified Health Assessment Questionnaire (mHAQ) and Foot Health Status Questionnaire (FHSQ). Foot deformity and footwear suitability was assessed using the Foot Problems Survey (FP Survey) and Footwear Suitability Scale (FWS Scale). Results In this predominantly female group of 95%, with a mean (± SD) disease duration of 12.2 (7.9) and moderate functional disability [mHAQ: 1.3 (0.6)], the FP Survey showed all patients had one or more foot deformity. Foot function was impaired with a mean (± SD) FHSQ score of 41.3 (12.4) and the FWS Scale showed that 93% wore unsuitable footwear. A strong correlation was observed of the global FHSQ (r=-0.5489, p<0.0001), its pain domain (r=-0.472, p<0.0001) and foot function domain (r=-0.599, p<0.0001), with the global mHAQ score. Despite the high frequency of foot problems observed only 27% had visited a podiatrist. Conclusion In conclusion foot problems and foot function disability is common in Black South African patients with established RA. Furthermore the strong correlation between mHAQ and FHSQ showed that foot functional disability was a major driver of overall functional disability in RA.

Objectives: To determine the impact of human immunodeficiency (HIV) infection on rheumatoid arthritis (RA) disease activity. Patients & Methods: Retrospective record review of RA patients who HIV sero-converted, compared to a HIV negative RA control group. DAS28-ESR and -CRP scores were collected at the initial presentation (T0), time when HIV diagnosis made (TH) and the last clinic visit (TL). Results: Forty three HIV positive RA patients were included. At TL disease activity was similar between the groups, despite methotrexate (MTX) being continued in only 11.6% of the HIV group (vs. 83.7% in the control group, p=0.0002). In the HIV group, all clinical parameters improved except the ESR, which accounted for the significantly higher DAS28-ESR compared to the DAS28-CRP at TL (p=0.004). At TL only 13.9% HIV patients had ongoing moderate to high disease activity. Conclusion: Overall disease activity improved with HIV seroconversion in spite of stopping MTX in the majority of patients. The DAS28-ESR overestimated disease activity compared to DAS28-CRP following HIV seroconversion.

Li, Martin. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 187-208). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Despite the success of current biological agents, achievement of broader efficacy and improved safety profile remains an unmet need in rheumatoid arthritis therapy. Neovasculogenesis plays a vital role in the progression and perpetuation of rheumatoid arthritis and significant evidence has demonstrated molecular heterogeneity within the endothelium (MVE) of different tissues. The heterogeneity of the synovial MVE can be exploited for the development of organ-specific therapeutic and diagnostic reagents. A novel recombinant antibody fragment, scFv A7, with specificity for human arthritic synovium, was isolated in our laboratory following in vivo phage display. The aim of the project described in this thesis is to characterise the antibody reactivity and develop a novel tissue specific therapeutic. The scFv A7 antibody proved to specifically target the microvasculature of human arthritic synovium with no detectable reactivity in a comprehensive range of normal tissues. Furthermore, the detected reactivity was not a common feature of chronic inflammatory conditions. Hence, the A7 antibody represents a unique and versatile tool with great potential for the development of diagnostic and/or therapeutic agents. The unique properties of A7 were combined with the anti-TNF Adalimumab, forming a bispecific antibody with neutralising activity and synovial homing properties. The new construct was able to retain the synovial specificity and showed comparable TNF binding kinetics and biological activity to the parent Adalimumab antibody in vitro. In conclusion, these results demonstrate that scFv A7 reactivity is specific to the microvasculature of human arthritic synovium, suggesting that the target molecule may have potential as a biomarker in arthritis and applications as an immunotherapeutic target. The bispecific antibody format developed showed unaltered TNF blocking capacity and synovial specificity that may allow reduction in the dosage and/or administration frequency, with the ultimate goal to reduce the systemic exposure, achieve a better therapeutic index and decreasing health care costs.