Robert D Inman

University Health Network, Toronto, Ontario, Canada

Are you Robert D Inman?

Claim your profile

Publications (258)1357.18 Total impact

  • [Show abstract] [Hide abstract]
    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; · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    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).
    07/2014;
  • [Show abstract] [Hide abstract]
    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.
    Arthritis & Rheumatology. 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    The Journal of rheumatology. 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endoplasmic reticulum-associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383-391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383-391 epitope in influenza A (flu)-infected B27/ERAP(-/-) mice. With the use of tetramer staining, the number of naive CD8(+) T cells expressing TCR Vβ8.1 in B27/ERAP(-/-) transgenic mice is significantly lower than that seen in B27/ERAP(+/+) mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP(-/-) mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP(+/+) mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP(-/-) transgenic mice. The B7-restricted NP418-426 CTL response in flu-infected B7/ERAP(-/-) and B7/ERAP(+/+) mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition.
    Journal of immunology (Baltimore, Md. : 1950). 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with an increased risk of osteoporosis and fractures. TNF inhibitors have been used to treat AS, but their effect on bone is unclear. Thus, we conducted a meta-analysis to study the effect of TNF inhibitors on spine and hip BMD in patients with AS.
    Seminars in arthritis and rheumatism. 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the effects of golimumab therapy on achieving inactive disease or major improvement, as assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS), and improvements in health-related quality of life (HRQOL) and productivity through 2 years in patients with AS. In the phase III GO-RAISE trial, 356 patients were randomized to placebo with crossover to golimumab 50 mg at Week 24 (n = 78), golimumab 50 mg (n = 138), or golimumab 100 mg (n = 140) at baseline and every 4 weeks. The proportions of patients with ASDAS major improvement (improvement ≥ 2.0) or inactive disease (score < 1.3) were determined. HRQOL was assessed using the 36-item Medical Outcomes Study Short Form-36 physical/mental component summary (SF-36 PCS/MCS) scores (normal score ≥ 50). The effect of disease on productivity was assessed by visual analog scale (0-10). Regression analyses on the association of disease activity and HRQOL were performed. The final assessment was at Week 104. Significantly greater proportions of golimumab-treated patients achieved ASDAS major improvement or inactive disease at weeks 14 and 24 versus placebo. Through Week 104, patients who achieved ASDAS inactive disease or major improvement had significantly greater improvements in SF-36 PCS and MCS scores and productivity than did patients not meeting these targets. Among all patients, achieving ASDAS inactive disease at weeks 52 and 104 was associated with normalized SF-36 PCS/MCS scores and significant improvements in work productivity. Greater proportions of golimumab-treated patients achieved ASDAS major improvement or inactive disease and improved HRQOL versus placebo. Achieving an inactive disease state by ASDAS criteria (< 1.3) was associated with normalized HRQOL through 2 years.
    The Journal of Rheumatology 04/2014; · 3.26 Impact Factor
  • Eric Gracey, Nigil Haroon, Robert D Inman
    Arthritis & rheumatology (Hoboken, N.J.). 04/2014; 66(4):783-5.
  • [Show abstract] [Hide abstract]
    ABSTRACT: To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10(-5)), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10(-3)). There was no observed association between radiographic severity and HLA-B*27. These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-α (IL-6Rα), in patients with ankylosing spondylitis (AS). Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety. Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints.The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred. The ALIGN study shows that IL-6Rα blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile.
    Annals of the rheumatic diseases 02/2014; · 8.11 Impact Factor
  • Qi Wu, Robert D Inman, Karen D Davis
    [Show abstract] [Hide abstract]
    ABSTRACT: Fatigue is one of the cardinal features of ankylosing spondylitis (AS) and contributes substantially to the disability associated with this disease. The mechanisms underlying fatigue in AS remain poorly understood, and this has hampered the development of targeted, effective treatment of this disabling feature of AS. The current study was undertaken, therefore, to investigate the brain networks underlying fatigue in AS. Twenty patients with back pain secondary to AS (15 men and 5 women; mean ± SD age 34.8 ± 11.9 years) and 20 age- and sex-matched controls consented to participate in the study. Patients underwent clinical assessment of AS using the Fatigue Severity Scale, the Affect Intensity Measure, and the McGill Pain Questionnaire. Brain gray matter and white matter connectivity was assessed using 3T magnetic resonance imaging. The patients with AS had significant fatigue that correlated with measures of their emotional strength and spinal mobility. Individual fatigue scores were negatively correlated with the amount of gray matter in areas of the dorsal and ventral attention networks, the somatosensory cortices, and the caudate nucleus, but were positively correlated with gray matter within the executive control network and putamen. Moreover, in patients with high fatigue scores, white matter tracts connecting these brain structures (e.g., inferior fronto-occipital fasciculi, superior/inferior longitudinal fasciculi, and corticothalamic tracts) exhibited low fractional anisotropy (indicative of decreased white matter tract integrity). These data indicate that fatigue in AS involves sensory salience and attention brain networks.
    Arthritis & rheumatology (Hoboken, N.J.). 02/2014; 66(2):295-303.
  • [Show abstract] [Hide abstract]
    ABSTRACT: A significant proportion of patients with juvenile spondyloarthritis (JSpA) are refractory to treatment with established medications. The objective of this study was to assess long-term efficacy of treatment with anti-TNF agents in patients with JSpA. An observational study of 16 patients with JSpA from 3 centres treated with infliximab (n=10) and etanercept (n=6) was performed, with a median follow-up period of 7.2 years. Prospective data was collected according to a standardized protocol. Outcomes examined were TEC, TAJC, markers of inflammation (ESR, CRP), functional assessments (C-HAQ, BASDAI, BASFI), and ongoing requirement for anti-TNF treatment. 13/16 patients (83%) had achieved clinical remission 6 months into the treatment. Improvement was sustained over time, with a median TAJC and TEC of 0 at any time point after 6 weeks. 6/16 patients (38%) showed a flare of arthritis after a median of 3.5 years. Two patients with hip disease prior to treatment required an arthroplasty 3 and 8 years post anti-TNF initiation. Patients showed progression of sacroiliitis with median modified New York score of 1 (range 0-3) at time of diagnosis and 3 (range 0-4) at last follow-up (p=0.002). Median BASDAI at last follow up was 1.6, median BASFI 3.1. Two patients developed transient reactions (one generalised, one local); no patient developed other adverse effects during the study. Anti-TNF treatment in JSpA refractory to standard treatment results in good long-term disease control except for pre-existing hip disease. However, radiographic evidence suggests inferior efficacy for control of sacroiliac joint disease.
    Clinical and experimental rheumatology 01/2014; · 2.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    PLoS ONE 01/2014; 9(8):e104966. · 3.73 Impact Factor
  • Dinny Wallis, Robert D. Inman
    Rheumatic Disease Clinics of North America 01/2014; · 2.10 Impact Factor
  • [Show abstract] [Hide abstract]
    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 01/2014; 7:105-15.
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the features of ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA) in a Canadian cohort of 639 patients with AS and 73 patients with nr-axSpA. Clinical and laboratory data were compared for patients with AS and nr-axSpA enrolled in a longitudinal SpA cohort. The proportion of male patients was higher in AS than in nr-axSpA (76.2% vs 47.9%; p < 0.0001). There was no difference in the presence of HLA-B27 between AS (78.9%) and nr-axSpA (72.5%) patients, nor in age at the time of diagnosis, although AS patients were younger at the time of symptom onset (23.9 yrs vs 26.4 yrs; p = 0.03). Disease duration at the time of last clinic visit was longer for AS than for nr-axSpA patients (17.7 yrs vs 12.1 yrs; p = 0.0002). Acute-phase reactants were higher in AS than in nr-axSpA (C-reactive protein 11.4 vs 5.2, p < 0.0001; erythrocyte sedimentation rate 13.7 vs 9.9, p = 0.02). The Bath Ankylosing Spondylitis Metrology Index was higher in patients with AS (2.84 vs 1.35, p < 0.0001). Patients with nr-axSpA were more likely to be female and to have lower inflammatory markers than patients with AS. When restricted to female patients only, acute-phase reactants did not differ significantly between AS and nr-axSpA. The evidence provides indirect support for the concept that nr-axSpA may represent an early form of AS, but that also has features of a distinct disease entity with significant burden of symptoms.
    The Journal of Rheumatology 11/2013; · 3.26 Impact Factor
  • Ali Akram, Robert D Inman
    [Show abstract] [Hide abstract]
    ABSTRACT: It is recognized that host response following viral infection is characterized by immunodominance, but deciphering the different factors contributing to immunodominance has proved a challenge due to concurrent expression of multiple MHC class I alleles. To address this, we generated H2-K(-/-) /D(-/-) (DKO) transgenic mice expressing either one or two human MHC-I alleles. We hypothesized that co-expression of different allele combinations figures critically in immunodominance and examined this in influenza-infected, double Tg MHC-I mice. In A2/B7 or A2/B27 mice, using ELISpot assays with the A2-restricted M1.58-66, the B7-restricted NP418-426 or the B27-restricted NP383-391 flu epitopes we observed the expected recognition of both peptides for both alleles. In contrast, in flu-infected B7/B27 mice a significantly reduced level of B27/NP383-restricted CTL response was detected while there was no change in the B7/NP418-restricted CTL response. Flu-specific tetramer studies revealed a partial deletion of Vβ8.1(+) NP383/B27-restricted CD8(+) T cells, and a diminished Vβ12(+) CD8(+) T-cell expansion in B7/B27 Tg mice. Using HLA Tg chimeric mice we confirmed these findings. These findings shed light on the immune consequences of co-dominant expression of MHC-I alleles for host immune response to pathogens. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 09/2013; · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is an unacceptable delay in the diagnosis of axial spondyloarthritis (axSpA) in its early stages among patients at high risk, in particular those with inflammatory bowel disease (IBD). Our objectives were to develop a sensible and reliable questionnaire to identify undetected axSpA among patients with IBD. Literature was reviewed for item generation in the Toronto axSpA Questionnaire on IBD (TASQ-IBD). Sensibility of the questionnaire was assessed among healthcare professionals and patients. This assessment was related to purpose and framework (clinical function, clinical justification, and clinical applicability), face validity, comprehensiveness [oligo-variability (limiting the questionnaire to important items) and transparency], replicability, content validity, and feasibility. The test-retest reliability study was administered to 77 patients with established IBD and axSpA. Kappa agreement coefficients and absolute agreement were calculated for items. Three domains included IBD, inflammatory back symptoms, and extraaxial features. The entry criterion required a patient to have IBD and back pain or stiffness that ever persisted for ≥ 3 months. Iterative sensibility assessment involved 16 items and a diagram of the back. Kappa coefficients ranged from 0.81-1.00 for each item. Absolute agreement across all items ranged from 91% to 100%. TASQ-IBD is a newly developed, sensible, and reliable case-finding questionnaire to be administered to patients with IBD who have ever had chronic back pain or stiffness persisting for ≥ 3 months. It should facilitate identification and timely referral of patients with IBD to rheumatologists and minimize the delay in diagnosis of axSpA. Consequently, it should assess the prevalence of axSpA in IBD.
    The Journal of Rheumatology 09/2013; · 3.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The primary objective of this study is to identify novel copy number variations (CNVs) associated with familial ankylosing spondylitis (AS). A customized genome-wide microarray was designed to detect CNVs and applied to a multiplex AS family with six (6) affected family members. CNVs were detected using the built-in DNA analytics aberration detection method-2 (ADM-2) algorithm. Gene enrichment analysis was performed to observe the segregation. Subsequent validation was performed using real time quantitative fluorescence polymerase reaction (QF-PCR). The frequency of copy number variation for the UGT2B17 gene was then performed on two well-defined AS cohorts. Fisher exact test was performed to quantify the association. Our family-based analysis revealed ten gene-enriched CNVs that segregate with all six family members affected with AS. Based on the proposed function and the polymorphic nature of the UGT2B17 gene, the UGT2B17 gene CNV was selected for validation using real time QF-PCR with full concordance. The frequency of two copies of the UGT2B17 gene CNV was 0.41 in the Newfoundland AS cases and 0.35 in the Newfoundland controls (OR = 1.26(0.99-1.59); p < 0.05)), whereas the frequency of two (2) copies of the UGT2B17 gene CNV was 0.40 in the Alberta AS cases and 0.39 in the Alberta controls (OR = 1.05(95% CI: 0.83-1.33); p < 0.71)). A genome-wide microarray interrogation of a large multiplex AS family revealed segregation of the UGT2B17 gene CNV among all affected family members. The association of the UGT2B17 CNV with AS is particularly interesting given the recent association of this CNV with osteoporosis and the proposed function as it encodes a key enzyme that inhibits androgens. However, two copies of the UGT2B17 gene CNV were only marginally significant in a uniplex AS cohort from Newfoundland but not in a uniplex AS cohort from Alberta.
    BMC Genetics 08/2013; 14(1):67. · 2.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. To develop and validate a reference image module aimed at calibration of readers using the modified Stoke Ankylosing Spondylitis Spine Score to assess radiographic progression in spondyloarthritis. Methods. Our working group comprised 6 rheumatologists and 3 musculoskeletal radiologists.. The following developmental steps were conducted: 1. Review of the literature to identify aspects of the mSASSS requiring methodological clarity. 2. Independent assessment of baseline and 2 year radiographs from 25 patients using the mSASSS (pilot exercise). 3. Development of a training module (the SPAR module) that clarifies definitions, rules and scoring methodology, and a set of reference radiographic images. 4. Scoring exercise 1 by 6 readers on 39 patients where baseline and 2 year radiographs were scored blinded to time point. 5. Revision of SPAR module followed by scoring exercise 2 conducted by the same 6 readers on 35 patients. Reliability of status and 2-year change scores was assessed by the intraclass correlation method (ICC). Results. ICC for change scores for the radiologist reader pair improved from 0.46 to 0.62 after minimal calibration with the SPAR module. Recalibration from exercise 1 to exercise 2 with the SPAR module led to substantial improvement in inter-reader reliability for change in mSASSS score from ICC (range) = 0.44 (0.31-0.62) to ICC = 0.62 (0.34-0.84). Simultaneous assessment of AP and lateral lumbar radiographs did not enhance reliability or detection of progression. Conclusion. Calibration according to the SPAR module led to improved reliability in the scoring of the mSASSS even for expert readers. © 2013 American College of Rheumatology.
    Arthritis care & research. 08/2013;

Publication Stats

5k Citations
1,357.18 Total Impact Points

Institutions

  • 2000–2014
    • University Health Network
      • • Department of Rheumatology
      • • Department of Medicine
      Toronto, Ontario, Canada
  • 1987–2014
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2013
    • Translational Research Institute
      Sydney, New South Wales, Australia
    • University of Colorado
      Denver, Colorado, United States
  • 2012
    • Mount Sinai Hospital
      New York City, New York, United States
  • 1987–2012
    • University of Toronto
      • • Division of Rheumatology
      • • Department of Medicine
      Toronto, Ontario, Canada
  • 2011
    • Singapore General Hospital
      • Department of Rheumatology and Immunology
      Tumasik, Singapore
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
    • Johnson & Johnson
      New Brunswick, New Jersey, United States
    • University of South Florida
      • Division of Rheumatology
      Tampa, FL, United States
  • 2010
    • Oregon Health and Science University
      Portland, Oregon, United States
    • University of Texas Health Science Center at Houston
      • Division of Rheumatology and Clinical Immunogenetics (Internal Medicine)
      Houston, TX, United States
    • University of Bristol
      Bristol, England, United Kingdom
  • 2008–2010
    • The University of Western Ontario
      • Department of Surgery
      London, Ontario, Canada
    • Royal National Hospital For Rheumatic Diseases NHS Foundation Trust
      Bath, England, United Kingdom
    • Memorial University of Newfoundland
      St. John's, Newfoundland and Labrador, Canada
    • University of Queensland
      Brisbane, Queensland, Australia
  • 2005–2010
    • University of Alberta
      • Department of Medicine
      Edmonton, Alberta, Canada
    • University of the Pacific (California - USA)
      Stockton, California, United States
  • 2009
    • Hanyang University Medical Center
      Sŏul, Seoul, South Korea
  • 2008–2009
    • Chonnam National University Hospital
      Sŏul, Seoul, South Korea
  • 2005–2009
    • SickKids
      • • Program in Cell Biology
      • • Division of Rheumatology
      Toronto, Ontario, Canada
  • 2004–2009
    • Hanyang University
      • Major in Internal Medicine
      Sŏul, Seoul, South Korea
  • 2006
    • London Health Sciences Centre
      • Department of Surgery
      London, Ontario, Canada
  • 1996
    • Arthritis Research Centre of Canada
      Richmond, British Columbia, Canada
  • 1984
    • Devry College of New York, USA
      New York City, New York, United States
  • 1982
    • Hospital for Special Surgery
      New York City, New York, United States
    • Cornell University
      • Department of Medicine
      Ithaca, New York, United States