AbstractBackgroundAnkylosing Spondylitis Research Articles

Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis

BackgroundAnkylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS.MethodsUsing a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs).The results were analyzed using logistic regression (adjusted for age and sex).ResultsNine polymorphisms were associated with risk of AS (p < 0.05). The polymorphisms were in genes regulating a: the TNF-α pathway (TNF -308 G > A (rs1800629), and − 238 G > A (rs361525); TNFRSF1A -609 G > T (rs4149570), and PTPN22 1858 G > A (rs2476601)), b: the IL23/IL17 pathway (IL23R G > A (rs11209026), and IL18–137 G > C (rs187238)), or c: the NFkB pathway (TLR1 743 T > C (rs4833095), TLR4 T > C (rs1554973), and LY96–1625 C > G (rs11465996)).After Bonferroni correction the homozygous variant genotype of TLR1 743 T > C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48–4.51, p = 0.04), and TNFRSF1A -609 G > T (rs4149570) (OR: 1.79, 95% CI: 1.31–2.41, p = 0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G > A (rs1800629) (OR: 0.56, 95% CI: 0.44–0.72, p = 0.0002) were associated with reduced risk of AS.ConclusionWe replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-α, IL23/IL17, and NFkB pathways increase risk of AS.

Identification of ANKDD1B variants in an ankylosing spondylitis pedigree and a sporadic patient

BackgroundAnkylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis.MethodsWe used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient.ResultsWe identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort.ConclusionsTogether these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association.

Early anti-inflammatory intervention ameliorates axial disease in the proteoglycan-induced spondylitis mouse model of ankylosing spondylitis

BackgroundAnkylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression.MethodsPGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation.ResultsETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation.ConclusionsEarly intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.

The patient experience with fatigue and content validity of a measure to assess fatigue severity: qualitative research in patients with ankylosing spondylitis (AS)

BackgroundAnkylosing spondylitis (AS) is an autoimmune disorder characterized by inflammation of the spine and large joints. Fatigue is a common symptom that many AS patients find significantly impacts their health-related quality of life. The Worst Fatigue – Numeric Rating Scale (WF-NRS) assesses the severity of this symptom during the previous 24-hour period. The objective of this study was to perform qualitative research to support the development and content validity of the WF-NRS.MethodsPatients with AS were recruited from clinical sites in the U.S. for a qualitative study which first entailed concept elicitation interviews to gain understanding of the patients’ experience with AS and fatigue. Subsequently, cognitive debriefing interviews were undertaken to assess the understandability, clarity, and appropriateness from the patient’s perspective, of the content of a measure of fatigue severity.ResultsThirteen patients with AS participated in concept elicitation interviews and cognitive debriefing of the Brief Fatigue Inventory (BFI) fatigue severity subscale. The WF-NRS was developed from the worst fatigue item of the BFI as patients generally reported it to be understandable and covered an important concept, the completion instructions were modified, but the response scale remained as it was familiar and readily completed, and the recall period was appropriate.ConclusionsPatient responses resulted in the development of and supported the content validity of the WF-NRS. Further quantitative evaluation of the WF-NRS is warranted in order to assess its psychometric properties and confirm its usefulness as a clinical trial tool.

Biomechanical assessment of balance and posture in subjects with ankylosing spondylitis

BackgroundAnkylosing spondylitis is a major chronic rheumatic disease that predominantly affects axial joints, determining a rigid spine from the occiput to the sacrum. The dorsal hyperkyphosis may induce the patients to stand in a stooped position with consequent restriction in patients’ daily living activities. The aim of this study was to develop a method for quantitatively and objectively assessing both balance and posture and their mutual relationship in ankylosing spondylitis subjects.MethodsThe data of 12 healthy and 12 ankylosing spondylitis subjects (treated with anti-TNF-α stabilized), with a mean age of 51.42 and 49.42 years; mean BMI of 23.08 and 25.44 kg/m2 were collected. Subjects underwent a morphological examination of the spinal mobility by means of a pocket compass needle goniometer, together with an evaluation of both spinal and hip mobility (Bath Ankylosing Spondylitis Metrology Index), and disease activity (Bath Ankylosing Spondylitis Disease Activity Index). Quantitative evaluation of kinematics and balance were performed through a six cameras stereophotogrammetric system and a force plate. Kinematic models together with a test for evaluating balance in different eye level conditions were developed. Head protrusion, trunk flexion-extension, pelvic tilt, hip-knee-ankle flexion-extension were evaluated during Romberg Test, together with centre of pressure parameters.ResultsEach subject was able to accomplish the required task. Subjects’ were comparable for demographic parameters. A significant increment was observed in ankylosing spondylitis subjects for knee joint angle with the target placed at each eye level on both sides (p < 0.042). When considering the pelvic tilt angle a statistically significant reduction was found with the target placed respectively at 10° (p = 0.034) and at 30° (p = 0.019) less than eye level. Furthermore in ankylosing spondylitis subjects both hip (p = 0.048) and ankle (p = 0.029) joints angles differs significantly. When considering the posturographic parameters significant differences were observed for ellipse, center of pressure path and mean velocity (p < 0.04). Goniometric evaluation revealed significant increment of thoracic kyphosis reduction of cervical and lumbar range of motion compared to healthy subjects.ConclusionsOur findings confirm the need to investigate both balance and posture in ankylosing spondylitis subjects. This methodology could help clinicians to plan rehabilitation treatments.

Surgical outcome after spinal fractures in patients with ankylosing spondylitis

BackgroundAnkylosing spondylitis is a rheumatic disease in which spinal and sacroiliac joints are mainly affected. There is a gradual bone formation in the spinal ligaments and ankylosis of the spinal diarthroses which lead to stiffness of the spine.The diffuse paraspinal ossification and inflammatory osteitis of advanced Ankylosing spondylitis creates a fused, brittle spine that is susceptible to fracture. The aim of this study is to present the surgical experience of spinal fractures occurring in patients suffering from ankylosing spondylitis and to highlight the difficulties that exist as far as both diagnosis and surgical management are concerned.MethodsTwenty patients suffering from ankylosing spondylitis were operated due to a spinal fracture. The fracture was located at the cervical spine in 7 cases, at the thoracic spine in 9, at the thoracolumbar junction in 3 and at the lumbar spine in one case. Neurological defects were revealed in 10 patients. In four of them, neurological signs were progressively developed after a time period of 4 to 15 days. The initial radiological study was negative for a spinal fracture in twelve patients. Every patient was assessed at the time of admission and daily until the day of surgery, then postoperatively upon discharge.ResultsCombined anterior and posterior approaches were performed in three patients with only posterior approaches performed on the rest. Spinal fusion was seen in 100% of the cases. No intra-operative complications occurred. There was one case in which superficial wound inflammation occurred. Loosening of posterior screws without loss of stability appeared in two patients with cervical injuries.Frankel neurological classification was used in order to evaluate the neurological status of the patients. There was statistically significant improvement of Frankel neurological classification between the preoperative and postoperative evaluation. 35% of patients showed improvement due to the operation performed.ConclusionThe operative treatment of these injuries is useful and effective. It usually succeeds the improvement of the patients' neurological status. Taking into consideration the cardiovascular problems that these patients have, anterior and posterior stabilization aren't always possible. In these cases, posterior approach can be performed and give excellent results, while total operation time, blood loss and other possible complications are decreased.