A consecutive series of 280 Charnley low-friction arthroplasties, performed between 1966 and 1978, on 192 patients, who were less than 40 years of age at the time of operation, were followed up for an average duration of 20.1 years. Patients were divided into four groups based on underlying disease process, and only three patients (5 hips) could not be traced. Patients with rheumatoid arthritis had significantly lower rates of acetabular component loosening, migration and revision (all p< 0.05), and patients with developmental dysplasia of the hip had the highest rates as well as a significantly higher rate of combined clinical and radiological component failure (p < 0.05). Patients with degenerative arthrosis had the highest rates of femoral implant loosening, revision and failure (all p < 0.05), and patients with ankylosing spondylitis and rheumatoid arthritis had the lowest. Age (< 30 years or 30 to 40 years at operation), gender, heterotopic ossification, hypertrophy of the femoral cortex at the tip of the prosthesis or development of changes in the medial femoral calcar were not associated with an increased risk of component failure or revision (all p > 0.05). The average annual rate of wear of revised components, in each of the four groups and the series as a whole, was significantly higher than the rate in surviving original components (p < 0.04), and the development of osteolysis, and increasing wear of the acetabular component were associated with failure and revision of both the acetabular and femoral components (both p < 0.01). Cox regression analysis confirmed that increasing average annual acetabular wear was the most significant factor determining the outcome of the arthroplasty (p < 0.001). For each additional millimetre of wear observed, the risk of component failure or revision in any one year increased significantly (p < 0.02). The 25-year survivorship of implants with an average acetabular wear rate of less than 0.1 mm/yr (117 arthroplasties) was greater than 90% but no arthroplasties with a rate in excess of 0.2 mm/yr survived 25 years, and only 40% survived 20 years.

HLA-B27 and ERAP1 are the two strongest predisposing genetic factors to Ankylosing Spondylitis (AS). As a key aminopeptidase in MHC class I presentation, ERAP1 potentially contributes to AS pathogenesis through altering HLA-B27 peptide presentation. In this thesis, I first studied the effect of AS-associated ERAP1 variation on its enzyme activity in vitro. Trimming of two N-terminally extended HLA-B27 epitopes was decreased by K528R mutation; the effect of R725Q was however substrate-dependent. I also investigated the effects of ERAP1 silencing on the repertoire of peptides bound to HLA-B27 and on peptide presentation to Cytotoxic T lymphocytes (CTLs). In both HeLa.B27 and C1R.B27 cells, the proportion of 9mer peptides, the canonical MHC class I peptide length, was decreased by ERAP1 silencing whereas the percentage of longer peptides (11-13mer) was increased. Surprisingly, following ERAP1 silencing, C-terminally extended versions of 9mer and 10mer peptides were readily identified. In both HeLa.B27 and mouse fibroblasts expressing HLA-B27, ERAP1 silencing/knockout reduced recognition by KK10-specific HLA-B27-restricted CTLs following recombinant vaccinia viral infection or transfection with minigenes expressing KK10 precursors. Interestingly, KK10 CTL recognition following extended KK10 minigene transfection was reduced in the presence of the AS protective variant, K528R-ERAP1 compared to wildtype ERAP1. The effects of ERAP1 inhibition (Leucinethiol), silencing (siRNA & shRNA) and introduction in ERAAP-/- cells on cell surface HLA-B27 expression were also studied. My finding validates the role of ERAP1 and HLA-B27 interaction in AS pathogenesis indicated by GWAS. ERAP1 inhibition could potentially be used for treatment in AS and other ERAP1-associated diseases.

Possession of the Major Histocompatibility Complex (MHC) allele, HLA-B27 (B27), strongly predisposes to the development of spondyloarthritis. Furthermore, B27 exists as polymorphic variants, with some subtypes (such as B*2705) being more strongly associated with disease than others (B*2709). The immunological function of MHC molecules is to present peptides in a heterotrimeric complex with beta-2-microglobulin (β2m); however, B27 has also been observed to form non-classical (β₂m –free) homodimers at the cell surface. It has been suggested that there may be a pathogenic role for cell surface B27 homodimer interactions with Natural Killer (NK) cell receptors, such as Leukocyte Immunoglobulin like Receptors (LILRs). In this thesis I characterise these interactions and investigate molecular differences between two B27 subtypes. Here I show that the B*2705 subtype forms homodimers more readily than the B*2709 subtype, but once formed, B27 homodimers of the 2 different subtypes exhibit comparable binding specificities and affinities to the NK receptors. On the other hand, I show significant differences in the binding specificities and affinities of these receptors to B27 homodimers and heterotrimers. LILRB1 does not bind B27 homodimers, but does bind B27 heterotrimers. LILRB2 binds B27 heterotrimers with a KD of 22μM, whereas LILRB2 binds B27 homodimers more strongly with a KD of 2.5μM. In addition to these main findings, I have characterised the specificity and affinity of candidate B27 homodimer-specific antibodies. I have performed epitope-mapping experiments and developed a model for binding to the B27 homodimer. Finally, I have identified crystallisation conditions for the B27 homodimer in complex with a Fab, allowing for X-ray crystallography studies. In this thesis, I have characterised for the first time the molecular interactions of the B27 homodimer with NK cell ligands and show that they are different from those with the B27 heterotrimer. This work supports a hypothesis of B27 homodimer induced pathology involving NK receptors.

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BACKGROUND: The Spondyloarthritis Research and Treatment Network (SPARTAN), together with the American College of Rheumatology (ACR) and the Spondylitis Association of America (SAA), published treatment recommendations for ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) in 2016. The extent to which these recommendations are being followed in clinical practice is unclear. We performed a retrospective chart review focusing on disease activity monitoring, back exercises and DXA scanning in adults with AS. METHODS: We reviewed electronic medical records at a single academic hospital network. The cohort for this study was derived from an existing population of 775 patients identified as having AS or nr-axSpA based on imaging studies, all of whom had 3 or more ICD- 9 or 10 codes for AS (720.x or M45.x). Patients were included if they had at least one rheumatology clinic visit for AS during a three-year study period from July 1, 2016 to June 30, 2019. Data were recorded for the first and last clinic visit within the study period. RESULTS: 358 patients met inclusion criteria. The study population was predominantly male (72.6%) with a mean age of 48.1 years (SD=15.5 years); 84.9% had AS based on review of pelvic or spine radiographs. A total of 661 clinic visits were analyzed. A clinical disease activity measure was recorded at 110/661 (16.6%) visits. RAPID3 was the most frequently used score (57.3%) followed by BASDAI (33.6%) and ASDAS (9.1%). CRP and/or ESR was ordered at 346/661 (52.3%) visits. AS-specific physical therapy (PT) or home exercises for the back were documented in 103/661 (15.6%) visits. A discussion of general exercise unrelated to the back was documented in an additional 153/661 (23.1%) visits. 303/358 patients had two or more visits during the study period. The use of disease activity measures or documentation of AS-specific PT or home exercises did not increase between the first and last visit. 65/358 (18.2%) patients had a DXA scan at any time prior to June 30, 2019. Patients with a DXA were significantly older than those without (58.7 vs. 45.7 years, p<0.001) and more likely to be female (31.6% vs. 13.1%, p<0.0001). 32/358 (8.9%) patients carried a diagnosis of osteoporosis, while 27/358 (7.5%) patients had a history of vertebral fracture. 48.1% of patients with a history of vertebral fracture had a DXA compared to 15.7% of patients without vertebral fracture (p<0.001). CONCLUSION: Monitoring with validated disease activity measures, treatment with AS- specific PT or home exercises, and osteoporosis screening with DXA were performed at low frequencies in our study population. Our data emphasize the need for more education of rheumatologists and the development of implementation strategies along with future updates of the AS/nr-axSpA treatment recommendations. / 2020-12-07T00:00:00Z

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

Title: Application of backstroke to a patient with ankylosing spondylitis Objectives: To evaluate the effectiveness of the application of backstroke with chosen parameters to a patient with ankylosing spondylitis. To compare the effectiveness of this swimming exercise programme with a traditional exercise programme held in a gymnasium. This work investigates whether it is suitable to recommend backstroke swimming to patients with ankylosing spondylitis as an effective form of physical exercise for improving range of movements and reducing pain. Methods: The effectiveness of a 9 week long swimming programme was evaluated using a range of movements of the glenohumeral and coxal joints and of the spine. The presence of pain was measured by the Bath Ankylosing Spondylitis Diasese Activity Index. The same parameters were measured for another patient with the similar activity of the disease who took part in group exercises in a gymnasium. At the end of the programmes the parameters were compared and evaluated. Results: The swimming programme has improved the patient's posture and has strengthened back muscles. Pain was reduced in some parts of the back and also general pain measured by BASDAI. The range of movements of both glenohumeral joints improved in all measured directions. The range of movements...

Osteoporosis and fragility fractures are recognized complications of inflammatory rheumatic diseases. This is thought to result from the effects of chronic inflammation, relative immobility and corticosteroid use. A rare syndrome of osteoporosis in a patient with coeliac disease has been described which results from production of neutralizing antibodies to the bone protective protein osteoprotegerin (OPG). The aim of my thesis is to evaluate prevalence and clinical predictors of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis (RA) and to investigate the role of OPG autoantibodies in the pathogenesis of osteoporosis in rheumatic diseases. In a retrospective cohort study, I found that the overall prevalence of osteoporosis in patients with RA was 29.9% which is in keeping with older reports that recorded a prevalence rate between 17% and 36%. In our contemporary cohort osteoporosis was significantly more common than in a gender and age matched control cohort (17.4%). Further analysis showed that only age and BMI were independent predictors of osteoporosis in RA. A predictive tool based on age and BMI was developed which had 91.4% sensitivity for the detection of osteoporosis in an independent RA population. I went on to screen for the presence of autoantibodies to OPG in patients with various rheumatic diseases. In a study of 75 patients with rheumatoid arthritis and 199 healthy controls OPG autoantibodies were detected in two controls (1%) compared with seven patients with RA (9.3%). The RA patients with detectable OPG antibodies had a longer disease duration, higher DAS28 scores and higher levels of the bone resorption marker CTX than RA patients who did not have autoantibodies. Purified IgG from patients with high levels of OPG antibodies blocked the ability of recombinant OPG to inhibit RANKL induced NFκB activation in a HEK293 cell based assay indicating that they were functional. In a further study of 134 patients with ankylosing spondylitis (AS), 16 patients (11.9%) had detectable OPG antibodies. The presence of OPG-Ab was independently associated with reduced hip bone mineral density and an increased risk of fractures in this population. In patients with a longer disease duration we have also observed that there was a higher discrepancy between spinal and hip BMD in OPG-Ab positive patients compared with OPG ab negative patients (p=0.003). In order to investigate if OPG antibodies affected measurement of serum RANKL concentrations as detected by ELISA using OPG as the capture reagent, I measured OPG ab and free RANKL concentrations in 55 rheumatic disease patients. Surprisingly there was a significant positive correlation between free RANKL and OPG Ab concentrations (r=0.430, p=0.001) which was the opposite to what I had expected. These findings reject the hypothesis that OPG ab block binding of synthetic OPG to RANKL in the ELISA. In conclusion, I have shown that osteoporosis is a common complication in RA and I have developed a new risk prediction tool for the use in clinical practice. I have also found that OPG antibodies are produced more commonly in patients with RA and AS than in healthy controls and that antibody levels correlate with bone resorption markers in RA and bone mineral density in AS patients. In vitro studies have shown that some OPG antibodies have functional effects on RANKL signalling. These findings raise the possibility that OPG antibodies may contribute to the pathogenesis of local and systemic bone loss in rheumatic diseases and signal the need to study the relationship between these antibodies and bone disease in large-scale longitudinal studies.

Background: Psoriatic arthritis (PsA) is a chronic heterogenous inflammatory arthritis with five phenotypes. The two least studied phenotypes are investigated in this thesis, including: psoriatic spondyloarthropathy (PsSpA) and psoriatic arthritis mutilans (PAM). The aims of this thesis were to determine the prevalence, clinical characteristics and radiographic characteristics of PsSpA and PAM in a cohort of PsA patients, and serum-soluble bone- turnover biomarkers of these phenotypes. Aims: Comparisons were made with PsA patients without axial disease (pPsA), and ankylosing spondylitis (AS) patients. Methods: A prospective single-centre cross-sectional study was conducted of PsA and AS patients. Serum on psoriasis-only patients (PsC) and healthy controls (HC) were also obtained. Multivariate clinical, radiographic, genetic and serum biomarker comparisons were made between these five groups of subjects. Results: The study enrolled 201 PsA and 201 AS patients, who were then reclassified as 118 PsSpA, 127 pPsA and 157 AS cases, alongside 200 PsC and 50 HC subjects. Several clinical biomarkers, imaging biomarkers, serum-soluble biomarkers and genetic biomarkers were identified that differentiate PsSpA from pPsA and AS. PsSpA affected a significant proportion of PsA patients, and was not a milder version of AS. PsSpA involvement was as disabling and clinically impactful as AS. PAM was found to be associated with PsSpA, and clinical biomarkers of PAM occurrence and radiographic progression were identified. Conclusions: In conclusion, this thesis indicates that PsSpA is on a spectrum of musculoskeletal disease, in between pPsA and AS; with PsSpA comprising a continuum itself, and with a phenotype expression related to disease duration. These findings may prompt the inception of an international-consensus classification system for PsSpA, for which there is a great clinical need. Given that PsSpA has its own discrete clinical and biomarker signature, its clinical management and research should be tailored from that of pPsA and AS. Ultimately this may further the effort for stratified and personalised medicine.

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.