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  • 1. Nephrogenic Systemic Fibrosis History, Diagnosis & The Registry Shawn E. Cowper, MD Associate Professor of Dermatology and Pathology Yale University New Haven, CT
  • 2. January 1997
  • 3. Philip LeBoit, MD
  • 4. AJDP, October 2001
  • 5. Pink Plaques Superficial Dermal Involvement
  • 6. Reticulated Lesions Superficial Dermal Involvement
  • 7. Severe Contractures Ankles and toes locked
  • 8. Deep Involvement Severe Contractures
  • 9. Registry population characteristics (n=345)
  • 10. Age at NSF onset, Registry cases
  • 11. Renal status at NSF onset, Registry Dialysis (79%) Hemodialysis (52%) Peritoneal Dialysis (16%) End Stage Renal Disease (11%) Non-Dialysis (17%) Acute Kidney Injury (10%) Renal Insufficiency (8%) Stage IV CKD (1.5%) Stage V CKD (3%) Post-Transplant (3%)
  • 12. 2003
  • 13. JAAD, January 2003 • Scleral plaques in NFD patients
  • 14. Archives of Dermatology, July 2003 • Known history of anti- thrombin III and Factor II deficiency • Patient elected to discontinue dialysis due to intolerable morbidity • Findings included fibrosis of proximal esophagus, diaphragm, and psoas muscle
  • 15. Involved skeletal muscle tissue from a patient with NSF
  • 16. Involved cardiac (heart) muscle from a deceased NSF patient
  • 17. Involved cardiac (heart) muscle from a deceased NSF patient
  • 18. AJDP, August 2003
  • 19. Tissue localized fibrocytes in NSF (red=procollagen I/brown=CD34)
  • 20. Current Opinion in Rheumatology, October 2003
  • 21. Thrombosis and Surgery What do these have in common?
  • 22. 2005
  • 23. Nephrology Dialysis Transplantation, January 2006 First published association of NSF with gadolinium administration
  • 24. Strength of Association, Presence and Magnitude J Am Acad Dermatol. 2007 Jan;56(1):21-6. Epub 2006 Nov 9 J Am Acad Dermatol. 2007 Jan;56(1):27-30. Epub 2006 Nov 15
  • 25. Gadolinium particles in NSF tissue
  • 26. Temporal: NSF latency n Weeks post Gd exposure before symptom onset
  • 27. GBCA dose/exposure, Registry cases (n=78)
  • 28. Animal and ex-vivo tests Courtesy Bayer-Schering Pharma J. Pathol. Vol.214, 5 Pages: 584-593
  • 29. Nephrogenic Systemic Fibrosis Clinical Scoring
  • 30. NSF - Major Criterion Patterned Plaques Red to violaceous, hyperpigmented, thin plaques showing polygonal to reticular morphologies on the upper extremities
  • 31. NSF - Major Criterion Joint contractures Often with edema of the fingers and wrists, toes and ankles [absence of signs of scleroderma]. Loss of range of motion of fingers, wrists, elbows
  • 32. NSF - Major Criterion “Cobblestoning” Deep induration showing a pattern of bumpiness over the upper arms and/or thighs
  • 33. NSF - Major Criterion Marked Induration/Peau d’orange Unpinchable, firm, shiny, often hyperpigmented bound down skin over extremities. Peau d’orange dimpling
  • 34. NSF - Minor Criterion Puckering/Linear Banding Focal areas/linear bands of bound-down skin on an upper extremity or proximal lower extremity (thigh)
  • 35. NSF - Minor Criterion Superficial NSF Hyperpigmented, pink or flesh colored macules coalescing into patches or thin plaques on the upper extremities (common) or trunk (rare). May have epidermal change (fine scale)
  • 36. NSF - Minor Criterion Dermal Papules Subtle, flesh-colored papules without epidermal changes
  • 37. NSF - Minor Criterion Scleral Plaques Patient < 45 years old
  • 38. Clinical Scoring • Major Criteria – Patterned Plaques – Joint Contractures – Cobblestoning – Marked Induration/Peau d’orange (upper extremity or above knee) • Minor Criteria – Puckering/Linear Banding – Superficial (Plaque/Patch) – Dermal Papules – Scleral plaques (pt <45 yo) • Scoring – > 1 Major Criterion Highly Consistent = 4 – 1 Major Criterion Consistent = 3 – > 1 Minor Criterion Suggestive = 2 – 0-1 Criterion Inconsistent = 1 – Another Diagnosis Excluded = 0
  • 39. Nephrogenic Systemic Fibrosis Pathological Scoring
  • 40. Increased Dermal Cellularity
  • 41. CD34+
  • 42. CD34+ (“Tram-Tracks”)
  • 43. Thick and Thin Collagen Fibers
  • 44. Preserved Elastic
  • 45. Septal Involvement
  • 46. “Lollipop” Sign
  • 47. Pathology Scoring • Increased Cellularity (+1) • CD34+ Tram-tracks (+1) • Thick and thin collagen fibers (+1) • Elastic preservation (-1 if elastic absent) • Septal involvement (+1) • Lollipop Sign (+3) • Highly Consistent (Score = 4 or 5) • Consistent (Score = 3) • Suggestive (Score = 2) • Inconsistent (Score = 1) • Excluded (Score = 0)
  • 48. Diagnostic Grid
  • 49. Nephrogenic Systemic Fibrosis The Registry and the Future
  • 50. NSF Registry case sources
  • 51. US Distribution of Registry cases (n=320)
  • 52. Patient impact, Registry data (n=345)
  • 53. NSF onset dates, Registry cases Cumulative < 304 n Calendar Year
  • 54. Temporal association with NSF onset (n=78)
  • 55. International Center for NSF Research Supported by a grant from the General Clinical Research Center at Yale http://www.icnsfr.org Yale University Additional thanks… Philip Boyer, MD PhD (U Colorado) Carol Hribko (Registry Coordinator) Dirk Elston, MD (Geisinger MC, PA) Whitney High, MD (U Colorado) Ali Abu-Alfa, MD (Nephrology) Emanuel Kanal, MD (U Pittsburgh) Richard Bucala, MD PhD (Rheumatology) Ira Krefting, MD (US FDA) Richard Edelson, MD (Dermatology) Phillip Kuo, MD PhD (U Arizona) Michael Girardi, MD (Dermatology) Philip E. Leboit, MD (UCSF) Avery LaChance (Research Assistant) Sameh Morcos (Sheffield, UK) Priti Patel, MD (CDC&P, Atlanta) Mark Perazella, MD (Nephrology) Georges Saab, MD (U Missouri) Jeffrey Weinreb, MD (Radiology) Lyndon Su, MD (U Michigan) Jonathan Kay, MD (U Massachusetts) Charles Bennett, MD PhD (Northwestern U) And the many patients, family, physicians, attorneys and friends who have been instrumental in bringing this work together!
  • 56. Use of GBCAs in Clinical Practice • Purpose – Provide background concerning use of GBCAs in day to day practice and the possible implications of any limitations of their use • Outline – Clinical Utility – Current Practice – Impact on Patients jeffrey.weinreb@yale.edu
  • 57. Use of GBCAs in Clinical Practice • Clinical Utility – Improve • detection (sensitivity) • characterization (specificity) – Disruption of “blood-brain barrier” Without GBCA • staging (margins, number) • confidence level • reliability & exam time (eg. MRA) With GBCA
  • 58. GBCA-enhanced MRI plays an essential role in modern medical diagnosis
  • 59. “Off-label” use of GBCAs has been common • None are FDA approved for use in the; – Heart – Breast – Musculoskeletal System – Intra-articular or intra-arterial • Only one is approved for CE-MRA (AIOD only) – >1,000,000 GBCA-MRA procedures are performed each year using GBCAs not approved for MRA • All not approved for higher doses, faster injection rates, or pediatric patients
  • 60. MRI Scans in the US 40000 35000 Scans (000's) G BCA (000's) 30000 25000 20000 15000 10000 5000 0 1999 2001 2003 2005 2007 25% 25% 26% 26% 27% 28% 28% 28% 28% 29% % Scans with GBCA Source: Arlington Medical Research (AMR)
  • 61. GBCA Utilization 39% Brain/Brain Stem 4% Face/Orbit/Neck 20% Spinal Canal & Contents 2% Breast 5% Abdomen (complete) 3% Pelvis 3% Other 13% Angiography (MRA) 10% Extremities Source: Arlington Medical Research (AMR)
  • 62. MRA = MRI of Blood Vessels MRI Magnetic Resonance Angiography Magnetic Resonance Imaging Magnetic Resonance Imaging
  • 63. MRA Magnetic Resonance Angiography 1993 1994 2009 Non-CE-MRA “High dose” CE-MRA Non-CE-MRA
  • 64. GBCA-MRA Procedures and GBCA Volume 1400 1200 CE-M RA (000's) Volume (cc's) 1000 800 600 400 200 0 1999 2001 2003 2005 2007 23 22 23 24 25 26 28 27 25 24 Average GBCA Volume Per CE-MRA Procedure (ml/procedure) Source: Arlington Medical Research (AMR)
  • 65. Contrast-induced Nephropathy (CIN/CIAKI) Prior to link with NSF, GBCAs were commonly (and often preferentially) used in patients with renal insufficiency because they are less likely to harm the kidneys than iodinated contrast agents used for CT Rofsky NM, et al. Radiology 1991;180:85–89. Haustein J, et al. Invest Radiol 1992;27:153–156. Niendorf HP, et al. Invest Radiol 1994;29(suppl 2):S179–S182. Prince MR, et al. Radiology 1996;6:162–166. Thomsen HS. Eur Radiol 2004;14:1654–1656. Thomsen HS. AJR 2003;181:1463–1471. Elmståhl B, et al. Acad Radiol 2004;11:1219–1228. Gemery J, et al. AJR 1998;171:1277–1278. Nyman U, et al. Radiology 2002;223:311–318.
  • 66. SevereAdverse Events Are Rare Adverse Events • The majority of AEs resulting from both iodinated agent and GBCA exposure are mild • More common with iodinated agents – 0.15–0.7% with iodinated agents – 0.03%–0.2% with GBCAs Examples: Among 456,930 contrast doses, AEs occurred in 0.15% with low-osmolar iodinated agent vs 0.04% with GBCA In a pediatric population, 0.18% incidence of acute allergic-like reaction to low- osmolality nonionic iodinated contrast compared with 0.04% with GBCAs Among 78,353 GBCA injections, acute allergic-like reactions occurred in 0.07%, of which 19% were moderate and 7% severe Cochran ST, et al. AJR 2001;176:1385–1388 . Murphy KP, et al. Acad Radiol 1999;6:656–664. Dillman JR, et al. AJR 2008;190:187–190. Li A, et al. Br J Radiol 2006;79:368–337. Dillman JR, et al. AJR 2007;188:1643–1647. Jordan RM, Mintz RD. AJR 1995;164:743–744. Murphy KJ, et al. AJR 1996;167:847–849. Mortelé KJ, et al. AJR 2005;184:31–34. ACR. Manual on Contrast Media. Version 6, 2008. Hunt CH, et al. AJR 2009;193:1124-1127.
  • 67. CIN Contrast Extravasation Anaphylactoid Reaction Nonanaphylactoid Reaction MR CT 2005
  • 68. Choice of GBCA • Prior to link with NSF, most radiologists believed that all brands of extracellular GBCAs were very similar in mechanism of action, efficacy and risk of adverse events – Even if they knew about differences in chemical structure, measure of stability, viscosity,ionicity, etc….. • Purchasing decisions were based primarily on pricing, GPO contracts, and personal preferences – Magnevist and Omniscan dominated the market
  • 69. June 8, 2006 There appears to be an association between GBCAs and NSF
  • 70. FDA Boxed Warning May 27, 2007 May 27, 2007
  • 71. Guidelines/Recommendations • FDA All recommend screening • US Professional Organizations for renal dysfunction – American College of Radiology • Guidance Document for Safe MR Practices • Manual on Contrast Media – National Kidney Foundation • Laminated Reference Tool – NKF/ACR – Individual Medical Centers and MRI Facilities • Outside the US Outside of US, all indicate that – Europe (EMEA, ESUR) the risk for NSF varies between – Canadian Association of types of GBCAs Radiologists – Japan – Australia
  • 72. Use of GBCAs in Clinical Practice • Current Practices: How have they changed since NSF? – Fewer patients with dialysis and known CKD referred for GBCA-MRI – Some reluctance to use GBCAs (anecdotal) • Some MRI facilities no long administer GBCAs • Some MRI facilities will not administer GBCAs to patients with CKD 3 or any risk factors for CKD (eg. diabetes, hypertension) • Some patients are being “turfed” to other facilities (especially hospitals) – Alternative imaging tests (e.g. non-contrast MRI/MRA, low dose contrast-CT) • Reassessment of the risk of clinically relevant CIN from intravenous iodinated contrast agents
  • 73. Adverse Events with Contrast Enhanced Imaging CIN NSF MR CT 2006
  • 74. CIN Contrast Extravasation Anaphylactoid Reaction Nonanaphylactoid Reaction NSF MR CT 2009
  • 75. Alternative Imaging Algorithm • 40 yo obese f with ADPCKD and eGFR < 30 • Ultrasound showed a 2 cm echogenic mass in the right kidney • Request imaging to evaluate for renal cell carcinoma • Volume expansion with saline (hydration) • Premedication with N-acetlycysteine before and after and isotonic sodium bicarbonate (3cc/kg/hr for 1 hr prior) • Non-C CT •If fat present in mass, stop (benign AML) •If no fat, perform low dose CE-CT with low-osmolality or iso-osmolality iodinated agent • CE-MRI with macrocyclic or low dose high relaxivity GBCA • Diffusion-weighted MRI (no GBCA)
  • 76. Sometimes GBCA-MRI is the best exam, even in patients with compromised renal function ! • 25 yo m with suspected intramedullary spinal cord tumor • eGFR 28 ml/min/1.73m2 • Request imaging to determine type and extent of mass • GBCA-enhanced MRI • MRI better that CT • Non-contrast MRI not sufficient •Use lowest diagnostic dose of macrocyclic or low dose high relaxivity GBCA
  • 77. Screening results in increased time, costs, and Use of GBCAs in Clinical Practice inconvenience • Current Practices: How have they changed since NSF? – Screening for CKD/risk factors for CKD is much more common • Enterprise-wide EMR • Require referring MD to provide eGFR or submit CKD risk factor form prior to scheduling GBCA-MRI • Patient questionnaire prior to exam – Ranges from one question (“Do you have a problem with your kidneys) to series of questions about risk factors for CKD • Point-of-service eGFR (based on serum creatinine) in every patient.
  • 78. Use of GBCAs in Clinical Practice • Current Practices: How have they changed since NSF? – Change in GBCA Usage • Decreased use of linear non-ionic GBCA(s) • “High dose” (>FDA approved dose) MRI/MRA less common • “Low dose” (< FDA approved dose) MRI more common • Patients with compromised renal function less likely to get repeat doses of GBCA at short time intervals
  • 79. Use of GBCAs in Clinical Practice • Current Practices: How have they changed since NSF? – More common to weigh patient and administer dose based on patient weight – Documentation of dose and specific GBCA used
  • 80. Diagnostic/Optimal Dose of GBCA • Not always known • Depends; • specific GBCA • patient characteristics • type of MRI exam • MR scanner software/hardware • magnetic field strength Krautmacher C et al. Radiology. 2005;237:1014-1019. Desai NK, et al Top Magn Reson Imaging 2003;14:360-364 Brekenfeld C, et al. Invest Radiol 2001;36:266-275 Kuhl CK et al. Radiology. 2008;247:16-35.
  • 81. Contrast Dose and Field Strength Effects in Lesion Visualization • No significant difference between field strengths for lesions greater than 20 mm • Small lesion visualization at low field strength improves with higher contrast Low field (0.2T) Low field (0.2T) Low field (0.2T) High field (1.5T) Single dose Double dose Triple dose Single dose Visualization of metastatic disease in one patient. Desai NK, et al. Top Magn Reson Imaging 2003;14:360-364. 2003;14:360- Brekenfeld C, et al. Invest Radiol. 2001;36:266-275. Radiol. 2001;36:266- Slide courtesy Lawrence Tanenbaum, Mt Sinai
  • 82. Use of GBCAs in Clinical Practice • Impact on patients – Questions: • Are diagnoses being missed? • Are patients receiving suboptimal care because of concern for NSF? – Answer • Unknown (has not been studied) – Concern • In effort to limit risk of NSF, some may be using suboptimal or non-diagnostic dose in some instances (don’t know what they are missing)
  • 83. Summary • GBCA-enhanced MRI plays (and will likely continue to play) an essential role in modern medical diagnosis • Off-label use (dose and clinical application) is common • FDA policy and other education efforts have resulted in changes in clinical practice in the United States – Including marked decrease of new cases of NSF • Effect on patient care?
  • 84. Acknowledgements • Ali Abu-Alfa: Yale University • Shawn Cowper: Yale University • Philip Kuo: Yale/University of Arizona • Emanual Kanal: University of Pittsburgh • Kenneth Maravilla: University of Washington • Lawrence Tanenbaum: Mount Sinai • Staff at Yale-New Haven Hospital