Dr Lauren Host- Ken Muirden Fellowship

Recipient: Dr Lauren Host- Ken Muirden Fellowship
Intended department: Royal Free Hospital and University College Medical School, London, England

Centre of Rheumatology and Connective Tissue Diseases- Funded by ARA & Roche Products

 

Project:

 

Clinical and biological significance of altered IL-7 expression in systemic sclerosis

 

With the support of Arthritis Australia, the Australian Rheumatology Association and Roche, I have completed a 12 month fellowship as an honorary fellow in the Department of Rheumatology and Connective Tissue Diseases, University College London (UCL) Division of Medicine, Royal Free Hospital, under the supervision of Professor Christopher Denton. The Royal Free Hospital (RFH) is a large University Teaching Hospital in the National Health Service (NHS), and a major European centre for the management of systemic sclerosis and related connective tissue diseases. Systemic sclerosis (SSc) commonly known as ‘scleroderma’ is an autoimmune condition that affects blood vessels and connective tissues. It causes hardening of the skin and can result in scarring of internal organs. Systemic Sclerosis is divided into two major subtypes; diffuse and limited disease. These subtypes are differentiated based on the distribution and amount of skin that is involved. These subtypes have different clinical manifestations and outlooks. It is important to identify which form of scleroderma a patient has in order to ensure optimal monitoring and management. Scleroderma is a condition that to date has no cure and unfortunately can cause significant functional impairment and a reduction in life expectancy. My research has focussed on this condition and I have been involved in both basic science and clinical research during my fellowship. My main area of investigation while completing my fellowship was to look into any relationships between a protein called:Interleukin-7 (IL7) and scleroderma. IL7 is a cytokine, these are small proteins produced and released by cells in the body that act as messengers between cells. IL7 was chosen to study as it plays a role in the functioning of the immune system, and has been shown in recent studies to be implicated in autoimmune diseases.

As a first step in introducing myself to this project I assisted in the genetic analysis of a group of scleroderma patients for differences in IL7 and IL7 receptor genes in a candidate gene association study. Genes are the building blocks of everyone’s individual genetic code (or DNA). Candidate gene association studies target a selection of genes that have been identified by previous research as being potentially implicated in a particular disease. We aimed to identify if specific changes within genes known as single nucleotide polymorphisms (SNPs) where related to scleroderma disease features.

The initial part of the study included 728 scleroderma patients and 260 without scleroderma. This study found a significant difference between scleroderma patients who had an antibody usually associated with the diffuse form of the disease (known as anti-topoisomerase I antibody [ATA]) versus those that did not have this antibody, in five areas (four SNPs in the IL7 receptor region and one in IL7 gene). We wished to see if these findings held true in a second, different genetic group of patients. We tested a further 256 scleroderma patients and 106 healthy people for the SNPs that were significant in the first stage. The association with the antibody ATA remained present for two SNPs when both groups were combined. Association of one SNP with pulmonary arterial hypertension, a disease characteristic affecting some scleroderma sufferers, was found in the second stage. These results are important in suggesting a potential genetic significance of IL7 in determining how scleroderma patients will present. We wished to look further for any associations between IL7 and the subtype of scleroderma (limited or diffuse), other disease characteristics and its profile over the disease time course. Our aim was to explore if IL7 was associated with the subtype of scleroderma that people develop, and could be a useful test for discriminating between the forms.

We looked at the levels of IL7 in the blood of 153 patients with scleroderma and 47 people without. We included patients with up to five blood samples available, representing different times in their disease. IL7 levels did not significantly change across time. We found a meaningful association between pulmonary arterial hypertension and mean IL7 levels.  We also discovered that IL7 levels were significantly higher in scleroderma patients compared with patients who didn’t have scleroderma. There was no significant difference in IL7 levels across all scleroderma subtypes, although levels were numerically higher in diffuse scleroderma and levels in limited scleroderma remained significantly higher compared with people without scleroderma. This project represents the largest cohort in this area to date. We have shown increased IL7 levels in scleroderma patients. In addition, IL7 levels are elevated in scleroderma patients developing pulmonary arterial hypertension. However, IL7 levels did not change significantly over time and we did not identify a difference in IL7 levels when analysed across all scleroderma subtypes. The importance of this suggests that IL7 levels may be a marker of someone’s susceptibility to scleroderma, or a factor in which type of scleroderma you develop, rather than having a role in causing the disease itself.  The implications of these findings are that IL7 would therefore not likely be a good test in scleroderma for differentiating disease subtype, nor would it be a good target for drug trials in scleroderma. This research is important for scleroderma sufferers as it has largely excluded IL7 as a causative cytokine in scleroderma and thus further research should be directed towards other potential targets. Finally, I had the opportunity to explore a potential link between exposure to proton pump inhibitors (PPIs), medications used for the treatment of reflux, and calcinosis in scleroderma sufferers.  Calcinosis is the deposition of calcium hydroxyapatite in the skin and subcutaneous tissues and occurs in around 25% of patients with scleroderma. The cause remains unclear and to date there are no proven effective treatments. Calcinosis can be a source of much distress for scleroderma patients. We assessed PPI exposure and the presence and extent of calcinosis in 216 patients seen at our clinic. We found an association of calcinosis with disease duration and antibody profile. The most striking finding from this study was that that even after correcting for disease duration and antibody status, we found that higher exposure to PPI (> 10 years) remained a significant predictor of calcinosis. To our knowledge work from our centre is the first to identify an association between PPI use and calcinosis in scleroderma patients. Given the clinical impact of calcinosis on scleroderma sufferers, and the lack of available efficacious treatments, this finding of a potentially adjustable risk factor is very important and warrants further investigation. As demonstrated above, we have answered all research questions set out during my fellowship. There will be further publications forthcoming from this research. I am confident that the research that I have been involved in, particularly my work in PPI and calcinosis, will lead the way for further studies.  Furthermore, through my fellowship I have gained laboratory skills, experience in research methodology including formation of research questions and implementation of studies, practice in writing abstracts for submission for international conferences, and producing and presenting posters at international conferences. Most importantly I have gained much knowledge in the management of patients with connective tissue diseases and learnt many skills that will benefit not only my career, but the patients I am to care for in the future.