Does Fibronectin Aggrecan Complex Predict Response to

Epidural Steroid Injection?Lisa Huynh MD

Matthew Smuck MD, Agnes Martinez-Ith,

David J. Kennedy MDDepartment of Orthopaedic Surgery, PM&R Section, Stanford

University, Redwood City, CA

AAPM&R Annual Assembly November 16, 2014

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)

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 riskCost 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

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

1. 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.

2. 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.

3. 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

BACKGROUNDFibronectin

Large extracellular glycoproteinContains a number of domains to bind various

ligands including fibrin, collagen, glycosaminoglycans, and various cytokines1

Ability to cleave aggrecan2

AggrecanMajor proteoglycan in extra-cellular matrix

component of articular cartilage3

1. Potts JR, Campbell ID. Structure and function of fibronectin molecules. Matrix Biol 1996;15(5):313-20.2. 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. Osteoarthr Cartil 1997;5(6):450-453.3. Abrams GD, Safran MR, Shapiro LM, et al. Fibronectin-aggrecan complex as a marker for cartilage degradation in

non-arthritic hips. Knee Surg Sports Traumatol Arthrosc 2014;22(4):768-73

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

1. 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.

2. 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.

3. 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.

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

METHODSStudy Design

Prospective, consecutive cohort study at a university spine center

Patient SampleTarget: 100 patientsScreened consecutive patients scheduled for ESIInclusion:

lumbar radicular pain positive physical exam findings

positive straight leg raise and/or diminished patellar or Achilles tendon reflex

MRI confirmed disc herniationExclusion:

negative lumbar MRI ESI in previous 3 months presence of any red flags minors, pregnant, prisoners, not competent to make decisions

METHODSUsing fluoroscopic guidance, performed

physiologic saline epidural lavageLavage sample collected prior to steroid

administrationELISA analysis to detect FACFAC positive if optical density was >0.06 at

450nm

1. 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.

2. 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.

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, ANDNPRS reduction of 30%

“Nonresponders”All remaining participants

METHODS

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

ResultsTarget

N = 100

Screened N = 387

EnrolledN = 63

2 insufficient lavage samples

1 discontinued from hypotension

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

RESULTS

FAC Positive FAC Negative0

5

10

15

20

25

21

8

Oswestry Disability Index (ODI)

Mean O

DI

Score

Im

pro

vem

ent

FAC Positive FAC Negative05

1015202530354045

40

15

Numeric Pain Rating Scale (NPRS)

Mean %

NP

RS I

mpro

vem

ent

RESULTS

Sensitivity 26.7% (95% CI: 8-55.1%)Specificity 91.1% (95%CI: 78.8%-97.5%)p < 0.0982

Presence of FAC in Responders and Nonresponder Groups to ESI

Oswestry Disability Index and Numeric Pain Rating Scale at 6 weeks

Responders to ESI Nonresponders to ESI

FAC Positive 4 4

FAC Negative 11 41

Primary Outcome

RESULTS

Oswestry Disability Index Only at 6 weeksPresence of FAC in those with >15 point ODI

improvement versus those without

Responders to ESI Nonresponders to ESI

FAC Positive 8 0

FAC Negative 13 39

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

DISCUSSIONGreater 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

DISCUSSIONLimitations

Amount of lavage fluid sample was variableStudy was underpowered Invasive sampling method with inherent risks

which may limit diagnostic potentialFurther studies needed to elucidate roles of

inflammatory markers

CONCLUSIONFAC status predicts disability, but not pain

outcomes 6-weeks after ESI in patients with lumbar disc herniations.

Thank You!Lisa Huynh, MDInterventional Spine Fellow

Department of Orthopaedic Surgery, PM&R DivisionStanford University

Stanford University Spine Center