Does Fibronectin Aggrecan Complex Predict Response to Epidural Steroid Injection?

1. Does Fibronectin Aggrecan Complex Predict Response to Epidural Steroid Injection? Lisa Huynh MD Matthew Smuck MD, Agnes Martinez-Ith, David J. Kennedy MD Department of Orthopaedic Surgery, PM&R Section, Stanford University, Redwood City, CA AAPM&R Annual Assembly November 16, 2014

2. DISCLOSURES • Lisa Huynh, MD • Nothing to disclose • Matthew Smuck, MD • Cytonics Corporation (Research Support) • North American Spine Society (Travel, Honoraria) • The Spine Journal (Executive Editorial Board) • Agnes Martinez-Ith • Cytonics Corporation (Research Support) • David J. Kennedy, MD • Cytonics Corporation (Research Support) • North American Spine Society (Travel, Honoraria) • PM&R (Editorial Board)

3. BACKGROUND • Extensive research on degenerative disc disease, yet much remains to be learned • Radicular pain secondary to mechanical compression and inflammatory pathways • ESI is an effective treatment for lumbar radicular pain, but only in a proportion of patients1 • Need a reliable approach to determine good candidates for ESIs • Not without risk • Cost containment 1. Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med 2010;11:1149-1168

4. BACKGROUND • Inflammatory cytokines and protein biomarkers are being studied as diagnostic indicators and potential therapeutic targets1 • Elevated levels of metallomatrix proteases, nitric oxide, prostaglandin-E, (IL)-6, (TNF)-α , amongst others have been implicated in disk degeneration2,3 Golish SR, Hanna LS, Bowser RP, et al. Outcome of lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan from epidural lavage. Spine 2011;36:1464-9. Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine 1996;21:271-2. Kobayashi S, Baba H. Uchida K, et al. Effect of mechanical compression on the lumbar nerve root: localization and change of intraradicular inflammatory cytokines, nitric oxide, and cyclooxygenase. Spine 2005;30:1699-705

5. BACKGROUND • Fibronectin • Large extracellular glycoprotein • Contains a number of domains to bind various ligands including fibrin, collagen, glycosaminoglycans, and various cytokines1 • Ability to cleave aggrecan2 • Aggrecan • Major proteoglycan in extra-cellular matrix component of articular cartilage3 Potts JR, Campbell ID. Structure and function of fibronectin molecules. Matrix Biol 1996;15(5):313-20. Homandberg GA, Davis G, Maniglia C, et al. Cartilage chondrolysis by firbonectin fragments causes clevage of aggrecan at the same site as found in osteoarthritic cartilage. OsteoarthrCartil 1997;5(6):450-453. Abrams GD, Safran MR, Shapiro LM, et al. Fibronectin-aggrecan complex as a marker for cartilage degradation in non-arthritic hips. Knee Surg Sports TraumatolArthrosc 2014;22(4):768-73

6. BACKGROUND • Fragmentation of fibronectin and aggrecan seen in degenerative joint conditions and articular cartilage damage1 • May facilitate signaling of inflammatory cascade • Fibronectin-aggrecan complex (FAC) shown to be associated with inflammation and pain in degenerative joint and spine conditions1,2 • FAC predicts response to lumbar ESI for radiculopathy with HNP • Single-center, prospective, consecutive case series of 27 patients underwent epidural lavage prior to ESI • Primary outcome: PCS (of SF-36) >4.9 • Presence of FAC predicted clinically significant improvement in PCS after lumbar ESI Scuderi GJ, Golish SR, Cook FF, et al. Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury. J Bone Joint Surg Am 2011;93:336-40. Gajendran VK, Reuter M, Golish SR, et al. The fibronectin-aggrecan complex: Is it present in cervical disc disease? Phys Med Rehab 2011;3:1030-4. Golish SR, Hanna LS, Bowser RP, Montesano PX, Carragee EJ, Scuderi GJ. Outcome of lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan from epidural lavage. Spine (Phila Pa 1976). 2011 Aug 15;36(18):1464-9.

7. PURPOSE • To investigate the fibronectin-aggrecan G3 domain complex (FAC) as a biomarker to predict response to epidural steroid injections in patients with lumbar disc herniations

8. METHODS • Study Design • Prospective, consecutive cohort study at a university spine center • Patient Sample • Target: 100 patients • Screened consecutive patients scheduled for ESI • Inclusion: • lumbar radicular pain • positive physical exam findings • positive straight leg raise and/or diminished patellar or Achilles tendon reflex • MRI confirmed disc herniation • Exclusion: • negative lumbar MRI • ESI in previous 3 months • presence of any red flags • minors, pregnant, prisoners, not competent to make decisions

9. METHODS • Using fluoroscopic guidance, performed physiologic saline epidural lavage • Lavage sample collected prior to steroid administration • ELISA analysis to detect FAC • FAC positive if optical density was >0.06 at 450nm Scuderi GJ, Cuellar JM, Cuellar VG, Yeomans DC, Carragee EJ, Angst MS. Epidural interferon gamma-immunoreactivity: a biomarker for lumbar nerve root irritation. Spine (Phila Pa 1976). 2009 Oct 1;34(21):2311-7. Golish SR, Hanna LS, Bowser RP, Montesano PX, Carragee EJ, Scuderi GJ. Outcome of lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan from epidural lavage. Spine (Phila Pa 1976). 2011 Aug 15;36(18):1464-9.

10. METHODS • Outcomes Measures • Oswestry Disability Index (ODI) and Numeric Pain Rating Scale (NPRS) assessed at baseline and 6 weeks post-ESI • Criteria for success: • ”Responders”: • ODI improvement of 15 points, AND • NPRS reduction of 30% • “Nonresponders” • All remaining participants

11. METHODS • Analysis • Differences between group means evaluated using independent samples t-tests and two-by-two contingency table analysis.

12. Results • Age: 20-70 (mean 42.57 years) • Sex: 55.6% males, 44.4% females

13. RESULTS

14. RESULTS Primary Outcome • Sensitivity 26.7% (95% CI: 8-55.1%) • Specificity 91.1% (95%CI: 78.8%-97.5%) • p < 0.0982

15. RESULTS • Sensitivity 38.1% (95% CI: 18.2-61.6%) • Specificity 100% (95% CI: 90.9-100%) • p <0.0001

16. DISCUSSION • Greater improvement in NPRS and ODI at 6 weeks in the FAC (+) group compared to FAC (-) group • Presence of FAC in disc samples from patients with radiculopathy is associated with improvement in disability following ESI • FAC has a role in predicting response to ESIs

17. DISCUSSION • Limitations • Amount of lavage fluid sample was variable • Study was underpowered • Invasive sampling method with inherent risks which may limit diagnostic potential • Further studies needed to elucidate roles of inflammatory markers

18. CONCLUSION • FAC status predicts disability, but not pain outcomes 6-weeks after ESI in patients with lumbar disc herniations.

19. Thank You! Lisa Huynh, MD Interventional Spine Fellow Department of Orthopaedic Surgery, PM&R Division Stanford University Stanford University Spine Center