Biological disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of Rheumatoid Arthritis, particularly TNF-α inhibitors, have been shown to improve patient outcome by slowing or halting radiographic damage. However, similar to most immunemodulators, there is an increased risk of infections co-incident with Tumour necrosis factor (TNF)-α inhibitor use, particularly the risk of activated latent tuberculosis infection (LTBI). Therefore, local and international guidelines recommend pre-screening for tuberculosis (TB) prior to the initiation of TNF-α therapy in rheumatoid arthritis (RA) patients. Also of critical importance in South Africa is the need for clinicians to be aware of environmental risk factors such as TB being highly endemic. Thus, a qualitative analysis was performed to investigate rheumatologists’ perceptions of TB co-incident with TNF-α inhibitors. Method: Physicians (n=18) practising rheumatology in the private and public healthcare sectors in Gauteng were interviewed to obtain their perceptions and attitudes related to TB co-incident with TNF-α inhibitor use. Interviews were audio-recorded and the transcripts analysed using thematic content analysis. Results: The determinants of health equity: Affordability, accessibility and availability of medicines (specifically TNF-α inhibitors) was reported to be different for the public care versus the private care patient. The high cost of TNF-α inhibitors warranted funding predominantly by the private medical schemes. A higher occurrence of latent TB infection was reported by physicians practising in the public or combined practice compared to the occurrence of LTBI in the private sector (21.4%versus 1.5%). The majority of study participants advocated pre-screening of TB, prior to the initiation of TNF-α inhibitors, in RA. However, it was suggested that because of the high occurrence of LTBI in the public sector, Isoniazid preventative therapy (IPT) should be compulsory, irrespective of the patient’s TB status, for the duration of TNF-α therapy. Most study participants supported local South African Rheumatism and Arthritis Association (SARAA) guideline recommendation to re-screen for TB by chest x-ray (CXR), every 6 months. However, the value of re-screening using diagnostic tools, purified protein derivative (PPD) skin test or interferon-gamma release assays (IGRAs) was queried due to the possibility of false readings. The occurrence of associated active TB in RA patients on TNF-α inhibitors was reported to be 0.07% in the private or combined practice versus 3.00% in the public sector. Forty percent of TB cases were reported to be extra-pulmonary. Despite active vigilance, some physicians reported that active TB month occurred months after the cessation of TNF-α inhibitor therapy. [Similar findings were observed from the British Society for Rheumatology Biologics Register (BSRBR)]. The majority of patients that developed TB co-incident with TNF-α inhibitors were treated successfully with TB chemotherapy. Only 1 of 12 patients died of extra-pulmonary TB, following compassionate use of infliximab in public care. Conclusion: Physicians practising rheumatology in Gauteng were of the opinion that there is a TB risk associated with the use of TNF-α inhibitors for the management of rheumatoid arthritis, as South Africa is a TB endemic country. Most acknowledged that these biological DMARDs were efficacious in slowing or halting radiographic progression in rheumatoid arthritis, but emphasised the need to take steps to prevent TB reactivation in the immuno - compromised RA patients and to remain overtly vigilant for active TB. In clinical practice, physicians mentioned that the monitoring and management of TB associated with TNF-α inhibitors appears to follow the socio-economic status of the RA patient and that distinct recommendations should be made for the public healthcare as well as the private healthcare sectors. Different opinions emanated from different physicians relating to the adequacy of local SARAA guidelines for the prevention of TB associated with TNF-α inhibitors. Some physicians mentioned that local guidelines were sufficient, whilst other physicians mentioned that the diagnostic tools were inadequate in the South African setting and that additional precautions should be taken in the form of IPT for the full duration of TNF-α therapy for all candidates, irrespective of TB status determined during pre-screening. As the science of biological DMARDs evolves with the rapid development of new medicinal therapies, physicians showed a preference to consider alternative non TNF-α biological DMARDs that had a lower risk of associated TB, specifically in high-risk RA patients. Physicians’ overall perception of the management of RA with TNF-α inhibitor therapy was that the risk-benefit assessment of these interventions, as well as patient preference and economic considerations should be taken into account.

The societal burden of autoimmune diseases and donor organ transplant rejection in developed countries reflects the lack of effective immune suppressive drugs. The main objective of my thesis was to develop novel fusion proteins targeting receptors linked to autoimmunity; strategies that will allow the suppression of autoreactive cells while sparing resting lymphocytes. Interleukin (IL) 15 has been demonstrated to exert its effects mainly on activated T-cells triggered via their T-cell receptor (TCR). Since we found that the fusion of granulocyte-macrophage colony stimulating factor (GMCSF) to IL15 - aka GIFT15 - paradoxically leads to aberrant signalling downstream of the IL15R and blocks interferon (IFN)-gamma secretion in a mixed lymphocyte reaction (MLR), we hypothesized to use this fusokine in proof-of-principle cell transplantation models and shown that GIFT15 can indeed block the rejection of allogeneic and xenogeneic cells in immunocompetent mice. Additionally, we found that ex vivo GIFT15 treatment of mouse splenocytes lead to the generation of regulatory B-cells (Bregs). These Bregs express high levels of MHCII, IL10 and are capable to block antigen (Ag)-presentation in vitro as third party bystander cells. Moreover, a single injection of these GIFT15-generated Bregs in mice with pre-developed experimental autoimmune encephalomyelitis (EAE) leads to long lasting remission of disease. / Along those lines, we also found that mesenchymal stromal cells (MSCs) lead to the paracrine conversion of CCL2 to an antagonist form capable of specifically inhibiting plasma cells and activated Th17 cells. This mechanistic insight informed the design of a second class of suppression fusokine. Namely, the fusing of antagonist CCL2 to GMCSF - aka GMME1. We tested its potential use in autoimmune diseases such as EAE and rheumatoid arthritis (RA). We demonstrated that GMME1 leads to asymmetrical signalling and inhibition of plasma cells as well as Th17 EAE/RA-reactive CD4 T-cells. The net outcome of these pharmacological effects is the selective depletion of CCR2-reactive T-cells as demonstrated both in vitro and in vivo. / Overall, our data support the use of our fusion proteins as part of a powerful and specific immunosuppressive strategy either as directly injectable protein biopharmaceuticals or through the ex vivo generation of autologous Bregs in the case of GIFT15.

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