Magnetic Resonance Imaging in High Risk Patients for the Development of Diffuse Idiopathic Skeletal Hyperostosis (DISH)

Diffuse idiopathic skeletal hyperostosis (DISH) is a poorly understood, systemic condition characterized by progressive calcification and ossification of ligaments and entheses. The current classification criteria allow diagnosing the disease in its late course, when significant bony overgrowth already involves the vertebral column and the appendicular skeleton. The research of the pathogenic mechanisms in DISH, is significantly hampered by the late diagnosis resulting from this definition.Based on recent MRI studies in both axial spondyloarthritis (axSpA) and in DISH, it seems that changes similar to the classical early inflammatory changes described in axSpA, can be detected in patients with DISH. We therefore hypothesize, that patients with metabolic syndrome without radiographic evidence for spinal DISH, might exhibit early MRI changes. If this hypothesis proves to be correct, early diagnosis and research of the possible pathogenetic mechanisms at this early stage might be very rewarding in investigations of the early aberrations of the entheses homeostasis and eventually early, more targeted therapeutic interventions. The study will examine MRI changes in patients, in their 5th decade of life, with high risk for the development of DISH (ie diabetes mellitus, metabolic syndrome) compared with patients who don't have this risk.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus; Metabolic Syndrome; Hyperostosis, Diffuse Idiopathic Skeletal
• Intervention / Treatment: Diagnostic test: Thoracic spine x-rays+whole spine MRI; Diagnostic test: blood tests; Other: constitutional and demographic data collection

Detailed Description

Patient's selection- Patients will be recruited from obesity/metabolic/diabetes clinics and from bariatric surgeries clinics. All patients will have the diagnosis of metabolic syndrome National Cholesterol Education Panel III (NCEP). Patients in their 5th decade of life will be recruited for the study. This study group will have to meet the NCEP 3 criteria for metabolic syndrome and/or have type 2 diabetes mellitus (9). An age and sex matched individuals who do not meet these pre-requisits will serve as a control group.

All asymptomatic patients will undergo postero-anterior and lateral x-rays of the thoracic spine, unless they have postero-anterior or lateral thoracic spine or chest x-rays in the year preceding the recruitment. For patients with back pain, addition of cervical or lumbar spine radiographs will be permitted based on the physician judgement. Patients recruited for the study will have a total spine and sacroiliac MRI (see below) read by radiologists and rheumatologists, expert in musculoskeletal imaging, who will be blinded for the patient's data. The readings of the radiographs and the MRI will be performed in a random order.

All patients and controls will undergo postero anterior and lateral thoracic spine X-rays and MRI of the entire spine and their sacroiliac joints (Spine: sagittal T1-weighted and T2 with fat suppression sequences, SIJ semicoronal T1-weighted and T2 with fat suppression sequences) at study entry.

An accepted scoring system for the interpretation of the MRI studies will be employed for both the spine and the sacroiliac joints.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Reuven Mader, MD; Phone Number: 972-4-6494354; Email: mader_r@clalit.org.il
• Study Contact Backup: Name: Irina Novofastovski, MD; Phone Number: 972-4-6494354; Email: Irina_no@clalit.org.il

Study Locations

• Israel
  • Afula, Israel, 18101
    • Recruiting
    • HaEmek MC and Chaim Sheba MC
    • Contact: Reuven Mader, MD; Phone Number: 972-4-6494354; Email: mader_r@clalit.org.il
    • Contact: Irina Novofastovski, MD; Phone Number: 972-4-6494354; Email: Irina_no@clalit.org.il
    • Sub-Investigator: Irina Novofastovski, MD
    • Sub-Investigator: Abdallah Fawaz, MD
    • Sub-Investigator: Amir Bieber, MD
    • Sub-Investigator: Iris Eshed, MD
    • Principal Investigator: Reuven Mader, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 49 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meet the NCEP 3 criteria for metabolic syndrome and/or have type 2 diabetes mellitus (9).

Age 40-49 years

Exclusion Criteria:

• ESR and CRP levels above common levels adjusted for age, gender, and weight.(I have ref for the determination of common CRP levels).

Positive HLA B-27 Personal or family history of Spondyloarthritis, psoriasis or inflammatory arthritis (past or present) Inflammatory back pain as defined by the ASAS definition (age at onset <40y, insidious onset, improvement with exercise, no improvement with rest, pain at night with improvement upon getting up = IBP if 4/5 items are present) (Ref) History of uveitis Plain radiographs with evidence for DISH

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: study group; Thoracic spine x-rays+whole spine MRI blood tests constitutional and demographic data collection	Diagnostic test: Thoracic spine x-rays+whole spine MRI; PA radiographs of the thoracic spine and MRI of the whole spine and sacroiliac joints; Other Names: imaging; Diagnostic test: blood tests; blood chemistry including total cholesterol, LDL HDL, CBC, HbA1C, fasting glucose, TG, and insulin levels, HLA-B27, 2 vials of frozen serum for future studies.; Other Names: laboratory; Other: constitutional and demographic data collection; demographics, concomitant diseases (in particular type 2 DM, hypertension, hyperlipidemia) concomitant medications, height and weight (BMI), waist circumference; Other Names: data
Active Comparator: control group; Thoracic spine x-rays+whole spine MRI blood tests constitutional and demographic data collection	Diagnostic test: Thoracic spine x-rays+whole spine MRI; PA radiographs of the thoracic spine and MRI of the whole spine and sacroiliac joints; Other Names: imaging; Diagnostic test: blood tests; blood chemistry including total cholesterol, LDL HDL, CBC, HbA1C, fasting glucose, TG, and insulin levels, HLA-B27, 2 vials of frozen serum for future studies.; Other Names: laboratory; Other: constitutional and demographic data collection; demographics, concomitant diseases (in particular type 2 DM, hypertension, hyperlipidemia) concomitant medications, height and weight (BMI), waist circumference; Other Names: data

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory changes in the spine and/or sacroiliac joints	inflammatory bone marrow edema lesions and fatty lesions and the anterior and posterior corners of the spine (Berlin score) as well as for the presence of enthesitis on the posterior elements. The sacroiliac joints will also be scored according to the Berlin scoring method for the presence of acute and structural inflammatory lesion, including BME, fat metaplasia, erosions, sclerosis, ankylosis. Anterior and posterior extraarticular enthesitis will also be registered	6 months

Collaborators and Investigators

• Sponsor: HaEmek Medical Center, Israel
• Collaborators: The Chaim Sheba Medical Center
• Investigators: Principal Investigator: Reuven Mader, MD, HaEmek MC

Publications and helpful links

General Publications

• Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97. doi: 10.1001/jama.285.19.2486. No abstract available.
• Mader R, Verlaan JJ, Buskila D. Diffuse idiopathic skeletal hyperostosis: clinical features and pathogenic mechanisms. Nat Rev Rheumatol. 2013 Dec;9(12):741-50. doi: 10.1038/nrrheum.2013.165. Epub 2013 Nov 5.
• Mader R, Novofestovski I, Adawi M, Lavi I. Metabolic syndrome and cardiovascular risk in patients with diffuse idiopathic skeletal hyperostosis. Semin Arthritis Rheum. 2009 Apr;38(5):361-5. doi: 10.1016/j.semarthrit.2008.01.010. Epub 2008 Mar 4.
• Mader R, Buskila D, Verlaan JJ, Atzeni F, Olivieri I, Pappone N, Di Girolamo C, Sarzi-Puttini P. Developing new classification criteria for diffuse idiopathic skeletal hyperostosis: back to square one. Rheumatology (Oxford). 2013 Feb;52(2):326-30. doi: 10.1093/rheumatology/kes257. Epub 2012 Sep 29.
• Weiss BG, Bachmann LM, Pfirrmann CW, Kissling RO, Zubler V. Whole Body Magnetic Resonance Imaging Features in Diffuse Idiopathic Skeletal Hyperostosis in Conjunction with Clinical Variables to Whole Body MRI and Clinical Variables in Ankylosing Spondylitis. J Rheumatol. 2016 Feb;43(2):335-42. doi: 10.3899/jrheum.150162. Epub 2015 Dec 15.
• Mader R, Novofastovski I, Iervolino S, Pavlov A, Chervinsky L, Schwartz N, Pappone N. Ultrasonography of peripheral entheses in the diagnosis and understanding of diffuse idiopathic skeletal hyperostosis (DISH). Rheumatol Int. 2015 Mar;35(3):493-7. doi: 10.1007/s00296-014-3190-0. Epub 2014 Dec 13.
• Arad U, Elkayam O, Eshed I. Magnetic resonance imaging in diffuse idiopathic skeletal hyperostosis: similarities to axial spondyloarthritis. Clin Rheumatol. 2017 Jul;36(7):1545-1549. doi: 10.1007/s10067-017-3617-6. Epub 2017 Mar 31.
• Julkunen H, Heinonen OP, Pyorala K. Hyperostosis of the spine in an adult population. Its relation to hyperglycaemia and obesity. Ann Rheum Dis. 1971 Nov;30(6):605-12. doi: 10.1136/ard.30.6.605. No abstract available.
• 8. Mader R, Fawaz A, Bieber A, Novofastovski I. Diffuse idiopathic skeletal hyperostosis (DISH) of young adults: lessons to be learnt. Austin J Orthopade & Rheumatol. 2016; 3(4): 1043.
• Landewe RB, Hermann KG, van der Heijde DM, Baraliakos X, Jurik AG, Lambert RG, Ostergaard M, Rudwaleit M, Salonen DC, Braun J. Scoring sacroiliac joints by magnetic resonance imaging. A multiple-reader reliability experiment. J Rheumatol. 2005 Oct;32(10):2050-5.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Anticipated): December 30, 2022
• Study Completion (Anticipated): December 30, 2022

Study Registration Dates

• First Submitted: July 30, 2017
• First Submitted That Met QC Criteria: August 1, 2017
• First Posted (Actual): August 2, 2017

Study Record Updates

• Last Update Posted (Actual): August 9, 2022
• Last Update Submitted That Met QC Criteria: August 6, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Musculoskeletal Diseases; Insulin Resistance; Hyperinsulinism; Spinal Diseases; Bone Diseases; Spinal Osteophytosis; Metabolic Syndrome; Hyperostosis; Hyperostosis, Diffuse Idiopathic Skeletal
• Other Study ID Numbers: 0102-17-EMC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Other researchers are expected to perform the study in their own countries. If they perform the study, unidentified data from the present study will be processed with the other parties data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No