Robert D Inman

University Health Network, Toronto, Ontario, Canada

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Publications (322)1891.66 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory arthritis affecting the spine in young adults. It is associated with excess cardiovascular and cerebrovascular morbidity. To determine whether patients with AS are at increased risk for cardiovascular and cerebrovascular mortality. Population-based retrospective cohort study using administrative health data. Ontario, Canada. 21 473 patients with AS aged 15 years or older and 86 606 comparators without AS, matched for age, sex, and location of residence. The primary outcome was a composite of cardiovascular and cerebrovascular death. Hazard ratios (HRs) for vascular death were calculated, adjusted for history of cancer, diabetes, dementia, inflammatory bowel disease, hypertension, chronic kidney disease, and peripheral vascular disease and, among those aged 66 years or older, relevant drug therapies. Independent risk factors for vascular mortality were identified in patients with AS. The mean age of patients with AS was 46 years, and 53% were male. Patients and comparators were followed for 166 920 and 686 461 patient-years, respectively. Adjusted HRs for vascular death in AS were 1.36 (95% CI, 1.13 to 1.65) overall, 1.46 (CI, 1.13 to 1.87) in men, and 1.24 (CI, 0.92 to 1.67) in women. Significant risk factors for vascular death were age; male sex; lower income; dementia; chronic kidney disease; peripheral vascular disease; and, among patients aged 65 years or older, lack of exposure to nonsteroidal anti-inflammatory drugs and statins. Diagnosis codes for AS were not validated in Ontario. Ankylosing spondylitis is associated with increased risk for vascular mortality. A comprehensive strategy to screen and treat modifiable vascular risk factors in AS is needed. The Arthritis Program, University Health Network, Toronto and The Arthritis Society, Canada.
    Annals of internal medicine 08/2015; DOI:10.7326/M14-2470 · 16.10 Impact Factor
  • N. Nigil Haroon · M.J. Paterson · P. Li · R.D. Inman · N. Haroon
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):757.1-757. DOI:10.1136/annrheumdis-2015-eular.2434 · 10.38 Impact Factor
  • I. Sari · R.D. Inman · J. Chan · A. Omar · R. Ayearst · N. Haroon
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):1146.2-1146. DOI:10.1136/annrheumdis-2015-eular.4844 · 10.38 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):149.1-149. DOI:10.1136/annrheumdis-2015-eular.3130 · 10.38 Impact Factor
  • A. Omar · I. Sari · R. Inman · N. Haroon
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):411.1-411. DOI:10.1136/annrheumdis-2015-eular.6284 · 10.38 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):743.1-743. DOI:10.1136/annrheumdis-2015-eular.4375 · 10.38 Impact Factor
  • J. Chan · I. Sari · D. Salonen · N. Haroon · R.D. Inman
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):756.3-757. DOI:10.1136/annrheumdis-2015-eular.3573 · 10.38 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):277.1-277. DOI:10.1136/annrheumdis-2015-eular.3179 · 10.38 Impact Factor
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    ABSTRACT: Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
    Nature Communications 05/2015; 6:7146. DOI:10.1038/ncomms8146 · 10.74 Impact Factor
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    ABSTRACT: Axial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family. HLA-B*27 genotyping and exome sequencing was performed on DNA collected from available family members. Variant frequency was assessed by mining publically available datasets and using fragment analysis of unrelated AxSpA cases and unaffected controls. Gene expression was performed by qPCR, and protein expression was assessed by western blot analysis and immunofluorescence microscopy using patient-derived B-cell lines. Circular dichroism spectroscopy was performed to assess the impact of discovered variants on secondary structure. This is the first report identifying two rare private familial variants in a multigenerational AxSpA family, an in-frame SEC16A deletion and an out-of-frame MAMDC4 deletion. Evidence suggests the causative mechanism for SEC16A appears to be a conformational change induced by deletion of three highly conserved amino acids from the intrinsically disordered Sec16A N-terminus and RNA-mediated decay for MAMDC4. The results suggest that it is the presence of rare syntenic SEC16A and MAMDC4 deletions that increases susceptibility to AxSpA in family members who carry the HLA-B*27 allele. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 05/2015; DOI:10.1136/annrheumdis-2014-206484 · 10.38 Impact Factor
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    ABSTRACT: The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. A survey was sent to the membership of the CRA to obtain an extended review that was used to finalize the recommendations. Guidelines for the management of SpA were created. Part I focuses on the principles of management of SpA in Canada and includes 6 general management principles, 5 ethical considerations, target groups for treatment recommendations, 2 wait time recommendations, and recommendations for disease monitoring. Also included are 6 modifications for application to juvenile SpA. These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that the implementation of these recommendations will promote best practices in the treatment of SpA.
    The Journal of Rheumatology 02/2015; 42(4). DOI:10.3899/jrheum.141000 · 3.17 Impact Factor
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    ABSTRACT: The Canadian Rheumatology Association (CRA) and the Spondyloarthritis Research Consortium of Canada (SPARCC) have collaborated to update the recommendations for the management of spondyloarthritis (SpA). A working group was assembled and consisted of the SPARCC executive committee, rheumatologist leaders from SPARCC collaborating sites, Canadian rheumatologists from across the country with an interest in SpA (both academic and community), a rheumatology trainee with an interest in SpA, an epidemiologist/health services researcher, a member of the CRA executive, a member of the CRA therapeutics committee, and a patient representative from the Canadian Spondylitis Association. An extensive review was conducted of literature published from 2007 to 2014 involving the management of SpA. The working group created draft recommendations using multiple rounds of Web-based surveys and an in-person conference. Recommendations for the management of SpA were created. Part II: Specific Management Recommendations addresses management with nonpharmacologic methods, nonsteroidal antiinflammatories and analgesics, disease-modifying antirheumatic drugs, antibiotics, tumor necrosis factor inhibitors, other biologic agents, and surgery. Also included are 10 modifications for application to juvenile SpA. These recommendations were developed based on current literature and applied to a Canadian healthcare context. It is hoped that implementation of these recommendations will promote best practices in the treatment of SpA.
    The Journal of Rheumatology 02/2015; 42(4). DOI:10.3899/jrheum.141001 · 3.17 Impact Factor
  • Aifeng Lin · Xiaoxin Guo · Robert D Inman · Jeremy M Sivak
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    ABSTRACT: HLA-B27 is a major histocompatibility complex class I (MHCI) allele that has been closely associated with the development of ankylosing spondylitis and acute anterior uveitis (AAU), the most common form of uveitis worldwide. We have been characterizing the phenotypes of transgenic mice carrying a human HLA-B27 allele, but that are deficient in endogenous mouse MHCI genes (H-2K(-/-) and H-2D(-/-) double knockout, or DKO) to create the HLA-B27/DKO line. In maintaining and expanding this colony, we observed a rare sporadic severe central keratitis that developed in transgenic animals, but that was not present in wild-type (WT) animals. The corneas of affected HLA-B27/DKO and DKO mice were compared to their WT counterparts by staining with standard histological methods for markers of inflammation and neovascularization. A model of experimental corneal inflammation was subsequently used to test the responses of each genotype to insult. We identified a previously unreported corneal pathology in naïve HLA-B27/DKO mice, and we describe significantly prolonged CD4(+)- and CD8(+)-associated inflammation in these animals following an experimentally induced corneal injury. These results demonstrate an increased T-cell response in B27/DKO corneas due to the expression of the HLA-B27 allele, suggesting that low MHCI expression in WT corneas is an important contributor to immune privilege.
    Molecular vision 02/2015; 21:131-137. · 2.25 Impact Factor
  • Qi Wu · Robert D Inman · Karen D Davis
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    ABSTRACT: Ankylosing spondylitis is associated with back pain and fatigue and impacts mobility but can be treated with tumor necrosis factor inhibitors (TNFi). The differential effects of TNFi treatment on multiple symptoms and the brain is not well delineated. Thus, we conducted a 2-part study. In study 1, we conducted a retrospective chart review in 129 ankylosing spondylitis patients to assess TNFi effects on pain, fatigue, motor function, mobility, and quality of life (QoL). After at least 10 weeks of TNFi treatment, patients had clinically significant improvements (>30%) in pain (including neuropathic pain), most disease and QoL factors, and normalized sensory detection thresholds. However, residual fatigue (mean = 5.3) was prominent. Although 60% of patients had significant relief of pain, only 22% of patients had significant relief of both pain and fatigue. Therefore, the preferential TNFi treatment effect on pain compared with fatigue could contribute to suboptimal effects on QoL. Part 2 was a prospective study in 14 patients to identify TNFi treatment effects on pain, fatigue, sensory and psychological factors, and brain cortical thickness based on 3T magnetic resonance imaging. Centrally, TNFi was associated with statistically significant cortical thinning of motor, premotor, and posterior parietal regions. Pain intensity reduction was associated with cortical thinning of the secondary somatosensory cortex, and pain unpleasantness reduction was associated with the cortical thinning of motor areas. In contrast, fatigue reduction correlated with cortical thinning of the insula, primary sensory cortex/inferior parietal sulcus, and superior temporal polysensory areas. This indicates that TNFi treatment produces changes in brain areas implicated in sensory, motor, affective, and cognitive functions.
    Pain 02/2015; 156(2):297-304. DOI:10.1097/01.j.pain.0000460310.71572.16 · 5.84 Impact Factor
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    ABSTRACT: Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembling the spinal changes seen in patients with ankylosing spondylitis (AS). The study of the histopathology of the feet of patients with tarsitis could help us understand the pathogenesis of bone formation in affected structures in the SpA. The objective of our study was to describe the histopathologic characteristics of the midfoot in patients with tarsitis associated with SpA. We obtained synovial sheaths, entheses, and bone samples from 20 patients with SpA with midfoot pain/tenderness and swelling. Tissue samples underwent H&E staining; immunohistochemistry for CD3, CD4, CD8, CD68, and CD20 cell identification; and immunofluorescence for bone lineage proteins, including osteocalcin, osteopontin, parathyroid hormone-related protein, bone sialoprotein, and alkaline phosphatase. Slight edema and hyalinization were found in some tendon sheaths, and few inflammatory cells were detected in the entheses. In bones, we found some changes suggesting osteoproliferation, including endochondral and intramembranous ossification, but no inflammatory cells. In entheses showing bone proliferation, we detected osteocalcin and osteopontin in cells with a fibroblastmesenchymal phenotype, suggesting the induction of entheseal cells toward an osteoblast phenotype. Osteoproliferation and abnormal expression of bone lineage proteins, but no inflammatory infiltration, characterize midfoot involvement in patients with SpA. In this sense, tarsitis (or ankylosing tarsitis) resembles the involvement of the spine in patients with AS. Ossification may be in part explained by the differentiation of mesenchymal entheseal cells toward the osteoblastic lineage.
    The Journal of Rheumatology 12/2014; 42(4). DOI:10.3899/jrheum.140218 · 3.17 Impact Factor
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    ABSTRACT: To use high density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients both with and without ankylosing spondylitis (AS). Method We genotyped 1,711 patients with AAU (either primary or with AAU and AS), 2,339 AS patients without AAU, and 10,000 controls on the Illumina Immunochip Infinium microarray. We also used data on AS patients from previous genomewide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by RT-PCR. Results Comparing all AAU cases with HC, strong association was seen over HLA-B corresponding to the HLA-B27 tag SNP rs116488202. Three non-MHC loci IL23R, the intergenic region 2p15 and ERAP1 were associated at genome-wide significance (P < 5x10(-8) ). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye related gene EYS, were also associated at a suggestive level of significance (P < 5x10(-6) ). A number of previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression was found to vary across eye compartments. Conclusion These findings, with both novel AAU specific associations, and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways. © 2014 American College of Rheumatology.
    09/2014; 67(1). DOI:10.1002/art.38873
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    ABSTRACT: Background and Object Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS. Methods A total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke’ Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates. Results We identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74×10−4) and rs1235192 [OR 1.92, p = 1.17×10−3]) adjusted by covariates. Conclusion This is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.
    PLoS ONE 08/2014; 9(8):e104966. DOI:10.1371/journal.pone.0104966 · 3.23 Impact Factor
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    ABSTRACT: Objectives. Long-term data on infection risk in axial SpA (axSpA) are sparse. TNF inhibitors (TNFis) are increasingly being used in axSpA, with infection being the most important adverse event. We aimed to investigate the frequency of infections in axSpA and to identify factors predisposing to infection. Methods. Data were extracted from a longitudinal observational cohort of patients with axSpA. Infection rates were calculated and multivariate analysis was performed to investigate the association of independent variables with infection. Results. Data were analysed for 440 patients followed for a total of 1712 patient-years (pys). A total of 259 infections, of which 23 were serious, were recorded in 185 patients. The overall rate of any infection was 15 (95% CI 13, 17)/100 pys and the serious infection rate was 1.3 (95% CI 0.9, 2.0)/100 pys. There was no significant difference in the rate of any infection or serious infection in patients on TNFis compared with patients never on biologic agents. In the multivariate analysis, DMARD treatment, but not TNFi treatment, was associated with risk of infection. Age, disease duration, smoking status, BASFI, BASDAI, co-morbidity score and hospitalization were not associated with an increased risk of infection. Conclusion. The serious infection rate in axSpA in this observational cohort is low when compared with rates reported in other rheumatic diseases. Biologic use was not a significant risk factor for serious infection.
    Rheumatology (Oxford, England) 08/2014; 54(1). DOI:10.1093/rheumatology/keu255 · 4.44 Impact Factor
  • Dinny Wallis · Robert D. Inman
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    ABSTRACT: In recent years the early identification of axial spondyloarthritis has become a high priority area of research. Evidence that therapy may slow radiographic progression of disease has heightened the importance of recognition of early disease. However, the concept of early axial spondyloarthritis and natural history of early disease are not fully understood. Future strategies to detect early and preclinical disease may incorporate clinical information, radiographic, serologic, and genetic testing. The risks and benefits of screening and early identification of disease need careful consideration. Copyright © 2014 Elsevier Inc. All rights reserved.
    Rheumatic Disease Clinics of North America 08/2014; 40(4). DOI:10.1016/j.rdc.2014.07.011 · 1.74 Impact Factor
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    ABSTRACT: To determine the heritability of spine curve using plain radiographs and to identify risk factors for spine curvature including age, body mass index, smoking, bone mineral density (BMD), and lumbar disc degeneration (LDD).
    European Spine Journal 07/2014; DOI:10.1007/s00586-014-3477-6 · 2.47 Impact Factor

Publication Stats

8k Citations
1,891.66 Total Impact Points

Institutions

  • 2002–2015
    • University Health Network
      • Department of Medicine
      Toronto, Ontario, Canada
  • 1986–2015
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • University of Toronto
      • • Division of Rheumatology
      • • Department of Medicine
      Toronto, Ontario, Canada
  • 2013
    • University of Colorado
      Denver, Colorado, United States
  • 2010
    • University of Bristol
      Bristol, England, United Kingdom
  • 2007–2009
    • University of Alberta
      • Department of Medicine
      Edmonton, Alberta, Canada
    • Memorial University of Newfoundland
      • Faculty of Medicine
      St. John's, Newfoundland and Labrador, Canada
  • 2008
    • Chonnam National University Hospital
      Sŏul, Seoul, South Korea
  • 2005
    • Hanyang University
      Sŏul, Seoul, South Korea
  • 1981–1984
    • Hospital for Special Surgery
      New York, New York, United States
  • 1982
    • Weill Cornell Medical College
      • Department of Medicine
      New York, New York, United States