Robert D Inman

University Health Network, Toronto, Ontario, Canada

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Publications (312)1760.39 Total impact

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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 · 9.27 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
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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: 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 01/2015; 6:7146. DOI:10.1038/ncomms8146 · 10.74 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 = 6.74x10(-4)) and rs1235192 [OR 1.92, p = 1.17x10(-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 · 3.53 Impact Factor
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    ABSTRACT: 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.
    Rheumatology (Oxford, England) 08/2014; 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
  • 69th Annual Meeting of the Canadian-Rheumatology-Association (CRA); 07/2014
  • 69th Annual Meeting of the Canadian-Rheumatology-Association (CRA); 07/2014
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    ABSTRACT: The concept of axial spondyloarthritis (axSpA) is new. Two recent trials on tumor necrosis factor (TNF) inhibitors for the treatment of axSpA using the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for study inclusion were unsuccessful in obtaining the FDA approval. On January 16th, 2014, the executive committee members of ASAS and Spondyloarthritis Research and Treatment Network (SPARTAN) met in Dusseldorf, Germany, to discuss the ramifications of this decision on the patients with non-radiographic axSpA (nr-axSpA) and also on the rheumatologists treating them. Sixteen propositions divided under nosology, diagnosis versus classification, and unmet clinical needs were discussed and consensus reached. This position paper presents the consensus statement by these two organizations on the concept of axial spondyloarthritis and suggests a way forward. © 2014 American College of Rheumatology.
    07/2014; DOI:10.1002/art.38776
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    ABSTRACT: Objective. There are unexplained sex-specific changes in the clinical expression of ankylosing spondylitis (AS). We sought to examine the potential effect of exogenous estrogen in the form of oral contraceptive pills (OCP) on AS initiation and severity. Methods. This cross-sectional study consisted of women with AS from the membership of the Spondylitis Association of America. Measures of disease severity included use of biological agents and hip replacement surgery, while Bath AS Functional Index (BASH) scores served as a surrogate marker of disability. Information was obtained using a patient questionnaire on patient demographics, OCP use, pregnancy history, AS duration, medication use, and hip replacement. Results. There were 571 women with AS who participated in our study, consisting of 448 OCP ever-users and 123 non-OCP users. The mean age of OCP users was 42.7 yrs (+/- 11.5) and of non-OCP users, 48.4 yrs (+/- 12.1). No difference was noted in the age at initial onset of back pain. However. OCP users were significantly younger at the time of diagnosis of AS (36.5 yrs vs 39.1 yrs. p = 0.02). There were no significant differences between the 2 groups in tumor necrosis factor inhibitor or opioid use. BASFI scores, pregnancy complications, or hip surgery. Conclusion. The use of exogenous estrogens in the form of OCP is not associated with a measurable effect on initiation or severity of AS. Biologic and social factors may contribute to earlier diagnosis of AS in OCP users. This is the largest study to date investigating the potential effect of exogenous estrogens in women with AS.
    The Journal of Rheumatology 06/2014; 41(7). DOI:10.3899/jrheum.130996 · 3.17 Impact Factor
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):1159-1159. DOI:10.1136/annrheumdis-2014-eular.4315 · 9.27 Impact Factor
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    ABSTRACT: Background: Genetic factors are of major importance in susceptibility to ankylosing spondylitis (AS). Currently there are 43 genetic loci associated with AS pathogenesis but these only explain a small proportion of the heritability which suggests that other rare genomic variants may contribute as risk factors. Given that AS is a subset of axial spondyloarthritis, it too is likely to have a strong genetic component. Objectives: To identify novel rare, highly penetrant mutations associated with AxSpA segregating within well-characterized families. Methods: Samples were collected from affected and healthy individuals from a large multigenerational, well-characterized family with AxSpA with Northern European Ancestry. All AxSpA patients satisfied the ASAS classification. Full exome sequencing was performed on eleven family members using the Agilent SureSelect Human All Exon kit V4 for library preparation and exome enrichment and sequencing was performed on an Illumina HiSeq 2000 instrument with TruSeq sequencing chemistry V3. Variants of interest identified by exome sequencing were confirmed using Sanger sequencing. Gene expression profiling was performed using a Taqman Gene Expression Assay (Cat#4331182, SEC16A-Hs00389570_m1, GAPDH-Hs99999905_M1) and protein expression was assessed using Western analysis using a commercial SEC16A antibody. Results: Our family-based exome sequencing analysis revealed a 9-bp in-frame deletion in SEC16A which segregated with AxSpA in the family. This deletion was confirmed in extended family members with 7/9 of the clinically diagnosed AxSpA members carrying the SEC16A deletion using Sanger sequencing. All healthy (i.e., not diagnosed with AxSpA) family members did not carry the deletion. The in-frame deletion had no significant impact on gene or protein expression. Conclusions: Full exome sequencing of a large multigenerational AxSpA family revealed a 9-bp deletion in SEC16A segregating in the majority of affected family members. Although this in-frame deletion had no significant impact on gene or protein expression, a detrimental impact on protein structure of SEC16A remains a possibility and is currently under investigation. The association of this deletion within the SEC16A gene with AxSpA is particularly interesting given that the gene product plays a role in protein transport from the endoplasmic reticulum (ER) to the Golgi and mediates COPII vesicle formation at the transitional ER. Disclosure of Interest: None declared DOI: 10.1136/annrheumdis-2014-eular.3327 Citation: Ann Rheum Dis 2014;73(Suppl2): 440 Session: Spondyloarthritis - etiology, pathogenesis and animal models
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):440-440. DOI:10.1136/annrheumdis-2014-eular.3327 · 9.27 Impact Factor
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    ABSTRACT: Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.
    The Application of Clinical Genetics 05/2014; 7:105-15. DOI:10.2147/TACG.S37325
  • Mohamed K Bedaiwi, Robert D Inman
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    ABSTRACT: The gut microbiome plays an integral role in the development and maintenance of the host immune system. Expanding knowledge about this microbial microenvironment has raised the possibility of new treatments based on this knowledge. In this review, we describe the recent evidence of the impact of the gut microbiome on arthritis and possible novel therapeutic approaches to alter the gut flora.
    Current opinion in rheumatology 05/2014; DOI:10.1097/BOR.0000000000000075 · 5.07 Impact Factor

Publication Stats

7k Citations
1,760.39 Total Impact Points

Institutions

  • 2009–2015
    • University Health Network
      • Department of Medicine
      Toronto, Ontario, Canada
  • 1987–2015
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1986–2015
    • University of Toronto
      • • Division of Rheumatology
      • • Department of Medicine
      Toronto, Ontario, Canada
  • 2014
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 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
      St. John's, Newfoundland and Labrador, Canada
  • 2008
    • Chonnam National University Hospital
      Sŏul, Seoul, South Korea
  • 2005
    • University of the Pacific (California - USA)
      Stockton, California, United States
    • 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