Arthroscopically Guided Jamshidi Needle Biopsy of Articular Cartilage: Potential Utility in the Evaluation of Disease Modifying Osteoarthritis Drugs (DMOADS)

Nathan Wei, MD, MD

Lanny L. Johnson

B. Lynn Seely, MD

Sheila K. Delauter, RN, CCRC

The Clinical Research Division, The Arthritis and Osteoporosis Center of Maryland, Frederick, Maryland

The Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

KEY WORDS: Arthroscopy, biopsy, osteoarthritis, cartilage

Abstract

Purpose: Studies of disease-modifying osteoarthritis drug (DMOAD) safety and effectiveness have relied on surrogate markers of disease activity (medical history, physical examination, radiographs, and magnetic resonance imaging). These often have low interobserver reliability and provide no information about cartilage quality. Assessment of cartilage histomorphology is a potentially valuable method for evaluating the extent of osteoarthritis (OA) and the effect of DMOADS on OA. Data on 126 arthroscopically guided small diameter (2 mm) Jamshidi needle cartilage biopsies from 32 patients (63 procedures with 2 biopsies obtained at each procedure) are reported.

Type of Study: Retrospective analysis and description of technique.

Methods: One hundred and twenty-six arthroscopically guided Jamshidi needle biopsies of articular cartilage were performed in 32 volunteers (10 men, 22 women; age range, 43-81 years) with Kellgren-Lawrence radiographic stage 1-3 OA of the knee in a randomized double-blinded placebo controlled study of insulin-like growth factor (IGF-1). Biopsies were obtained before treatment and also after 13 weeks of intra- articular injections. Patients were randomized to one of the 3 treatment groups: IGF given weekly or biweekly or placebo. Biopsies were obtained from the weight-bearing portion of the medial femoral condyle using a 2-mm Jamshidi needle and consisted of 2-mm diameter plugs of cartilage and underlying subchondral bone.

Results: Adequate material for interpretation was obtained from the biopsies. The data obtained from the biopsies were comparable to the information obtained from larger conventional sections harvested in a companion study (wedge biopsies using a scalpel) before and after total knee arthroplasty. Ten cases of postprocedure hemarthrosis, all of which resolved spontaneously, were the only complications noted. The cases of hemarthrosis were seen only in the first 10 cases before strict complete non-weight-bearing restrictions were applied. Pain and WOMAC measurements worsened in fewer than 50% of patients during the 13 week course of the study. No other adverse clinical sequelae related to the study knee have been noted at between 24 to 48 months of follow-up.

Conclusions: Arthroscopically-guided Jamshidi needle biopsy of articular cartilage from the weight-bearing surface of the medial femoral condyle may have potential utility for assessing the efficacy of DMOADs.

Introduction

Evaluation of new drugs for osteoarthritis has been largely dependent on surrogate markers.1-9 Radiographs, and more recently magnetic resonance imaging, have been considered by some researchers as the "gold standard" for many clinical trials.10-23 These objective parameters have been supplemented by clinical measures such as range of motion, global assessments, and quality of life assessments.4-5

Despite the time-honored tradition associated with some of these measures as well as the painstaking attempts to validate others, all of these measures have their deficiencies.24-30 Cartilage histology is a potentially valuable and accurate method for assessing the extent of osteoarthritis and may have value in measuring the effects of disease-modifying drugs in osteoarthritis.32 This method has previously been reported for opportunistic biopsy of osteochondral lesions, but not in a controlled study with follow-up.33

The purpose of this paper is to present data collected at one center on the technique of Jamshidi needle cartilage biopsy in a clinical trial. This paper is not presented as a definitive analysis but rather as a description of a novel procedure used in a single clinical trial. The technique may have application in future evaluation of DMOAD drugs in osteoarthritis.

Materials and MethodS

Sixty-three arthroscopic procedures were performed in 32 volunteers (10 men; 22 women) ranging in age from 43 to 81 years. At each procedure, 2 biopsies of articular cartilage were obtained for a total of 126 biopsies. All patients had symptoms of knee pain and had radiographic evidence of osteoarthritis with Kellgren Lawrence stages 1 to 3. Radiographic studies were performed using standard standing views. Care was taken to ensure that all radiographic studies were performed in the same manner for all patients and for all follow-up studies. No patient had stage four disease.

All patients were participating in a randomized double-blind placebo-controlled study of insulin-like growth factor-1 (IGF-1) administered intra-articularly. Biopsies were obtained before treatment and at the end of 13 weeks of treatment with either active drug or placebo.

Clinical data in the form of Western Ontario McMaster Universities Activity Index (WOMAC) and visual analog scale (VAS) were assessed before the first arthroscopy and 13 weeks after the first arthroscopy, at the completion of therapy. In addition, follow-up radiographs were available in 27 of the 32 patients. Intervals between prearthroscopy and postarthroscopy radiographs ranged from 22 to 48 months. The same x-ray equipment, technique, positioning, and blinded reader were used.

Technique

Arthroscopic biopsies were performed using sterile technique with local anesthetic as previously described.34 A 2.9-mm arthroscope (Dyosite, Smith and Nephew Dyonics, Andover, MA) was used for all procedures. The arthroscope was inserted using a standard inferolateral portal in all cases. An 18-gauge spinal needle was used to assess proper portal placement. A peripatellar tendon inferomedial portal was used for 30 of the patients. A transpatellar approach was used for two patients. Special care was taken to avoid iatrogenic cartilage lesions with the spinal needle.

Before arthroscopic biopsy, a 2.9-mm full radius motorized instrument was used to remove overlying soft tissue obscuring the potential biopsy site. In a number of instances, 14 cases, the superior attachment of the infrapatellar fat pad was detached using the motorized instrument to gain better visualization.

A 2-mm Jamshidi biopsy needle was used for the biopsies (Fig. 1). All biopsies were obtained from the weight-bearing portion of the medial femoral condyle. A biopsy was obtained by flexing the knee to 90°, locating an osteoarthritic lesion, and performing a biopsy at a site adjacent to but not part of the lesion. Biopsies were performed by introducing the Jamshidi biopsy needle at a perpendicular angle to the area of interest. (Perpendicular orientation was assured by first using a number 18 spinal needle to gauge the angle of entry.) The Jamshidi needle was then gently pushed into the cartilage. With steady pressure against the needle a measured clockwise-counterclockwise motion was used to advance the needle into subchondral bone.

Once the needle was buried in subchondral bone, a gentle rocking motion was used to free the base of the plug. A 60 mL syringe attached to the other end of the needle was used to create suction and free up the biopsy piece.

Each biopsy consisted of a 2-mm cylindrical core of cartilage and underlying subchondral bone that was between 5 and 8 mm long. Two biopsy specimens were obtained at each arthroscopy. The location of all biopsy sites was recorded on a diagram in a case report form. All cases were videotaped and photographs were obtained of the biopsy site immediately after the biopsy (Figs. 2 and 3). Biopsies after treatment were obtained from the same quadrant of the condyle and as close as possible to the pretreatment biopsy sites. Reference to the case report form and video were made before follow-up arthroscopy to ensure the same site was not rebiopsied. Biopsies were placed in numbered (to identify biopsy sequence) formalin-filled containers and sent to a central processing laboratory.

Results

Adequate material for histologic interpretation was obtained in all biopsies (Figs. 4 and 5). The reading pathologist judged whether a biopsy was considered adequate. A significant finding was that the information provided by the Jamshidi biopsies was equivalent to the information provided by wedge resection cartilage specimens obtained from patients at the time of knee replacement in a companion study. Mankin scores were used as the histologic measurement.

Complications

Ten cases of postprocedure hemarthrosis, all of which resolved spontaneously, were noted. Patients experienced significant pain the evening of the procedure. Both hemarthrosis and pain occurred in the first 10 cases only. These complications were not seen after strict institution of complete non-weight-bearing with crutches for 24 to 48 hours supplemented by cryotherapy (Cold Gold, Instrument Makar, Okemos, MI) in the remaining cases. Propoxyphene was also used.

In 26 of 31 patients, the arthroscopist was unable to identify the previous biopsy sites at the time of second arthroscopy, indicating possible healing. In the other 5 cases, only a small "dimple" was seen. No adverse clinical sequelae have been noted at between 22 and 48 months of follow-up.

Data regarding patient discomfort and function related to the first arthroscopy before and 13 weeks after the procedure are presented in Table 1 Fifteen of the 32 patients had some worsening of WOMAC or VAS scores. However, 31 of the patients volunteered to undergo a second arthroscopy and biopsy. We also found that putting patients at complete non-weight-bearing in the immediate postarthroscopic period (24 to 48 hours) helped mitigate pain. There was not a significant difference in pain scores between patients who had infra-patellar fat pad detachment and those who did not. No long term adverse sequelae have been seen as a result of fat pad debridement.

Radiographic comparisons are demonstrated in Table 2. Of the 27 cases, one patient worsened a full grade; one case showed a 1-mm joint space improvement in the study knee; two patients had worsening of the nonstudy knee; and two patients had had the nonstudy knee replaced. No other adverse clinical sequelae have been noted at between 24 and 48 months of follow-up in the 27 of 32 patients available for follow-up.

Discussion

Osteoarthritis is the most common form of arthritis seen in clinical practice.25-37 Current evidence suggests that osteoarthritis is an inflammatory disease that is the end result of a complex interaction involving several cytokines and degradative enzymes.38-47 Clinical trials of DMOADS have relied on surrogate markers to establish proof of efficacy. These surrogate markers have enjoyed popularity despite deficiencies including low interobserver variability and lack of information regarding cartilage quality.3-7,11-16,20,21,23-26 None of these provide histologic evidence. This biopsy technique was chosen because of previous data indicating a high probability of safety with small diameter full thickness (into subchondral bone) biopsies.33,59-61

Cartilage biopsy studies in osteoarthritis have been reported previously. However, these studies from the orthopedic literature have evaluated the effects of proximal tibial osteotomy in patients with severe osteoarthritis.62,63 The results of this study show the utility of arthroscopically obtained small diameter (2 mm) Jamshidi needle cartilage biopsy for research purposes to evaluate DMOAD effect. There is the potential economic benefit of local anesthesia thereby avoiding the expense and potential complications associated with spinal and general anesthesia. The direct visualization by arthroscopy provides an opportunity to record the gross anatomy. The method harvests an intact osteochondral plug for histological evaluation. The complications were few, self limited, and limited to the first ten cases before strict precautions were instituted to prevent them.

Although sampling variability may represent a potential weakness of this technique, the same could be said for other techniques. Comparability of biopsies obtained at the same time during this study was excellent. Cartilage biopsy represents a unique opportunity to assess cartilage quality as well as quantity, a prime area of interest in the assessment of disease modifying agents in osteoarthritis.1,48-51 Cartilage biopsy also affords evaluation of subchondral bone, an area of interest in regards to pathogenesis of osteoarthritis.53

Of importance was the amount and quality of biopsy obtained using this technique. In all instances it was suitable for histological preparation and interpretation. The specimens were suitable for interpretation and evaluation by blinded pathologists for drug effect in this study.32

This technique requires an experienced arthroscopist. Potential technical difficulties include performance of arthroscopy under local anesthesia, adequate visualization, and identification of the lesion. The angle of approach of the biopsy needle must be perpendicular to the surface. The exposure is facilitated by adequate distention and optional release or resection of the membranous ligament. A locator No. 18 spinal needle placement identifies the angle of approach prior to biopsy needle insertion.

The unspoken concern is the long-term effect biopsies may have in escalating the development of osteoarthritis on the weight-bearing surface of the medial femoral condyle. Prior experience with cartilage abrasion procedures has shown that defects fill in with fibrocartilage that is less sturdy than hyaline cartilage.53-57 These defects though have generally been much larger than the 2-mm diameter biopsies performed in our series. Another confounding issue is the heterogeneity of cartilage response to injury.57,58

This biopsy technique was chosen because of previous data indicating a high probability of safety with small diameter full-thickness (into subchondral bone) biopsies.59-61 In the previous reports of cartilage biopsy for medial gonarthrosis, biopsies did not worsen progression of disease.62,63 The short term WOMAC and VAS data indicates pain may be a problem for some patients. Complete non-weight-bearing for a 24 to 48 hour period after the procedure is strongly recommended.

A significant flaw of this study is that WOMAC and VAS data was obtained only during the course of treatment with the study drug. Three points must be made. First, the objective of the sponsor in the study was to evaluate the short term effects of IGF on articular cartilage. As a result, this paper is meant to provide a description of a potentially useful technique that was used in this study and not meant as a definitive treatise on assessing cartilage in osteoarthritis. Second, it bears repeating that 31 of the 32 patients volunteered to undergo the second procedure. Third, short-term radiographic data also is encouraging; however, longer-term radiographic analysis is obviously needed.

Cartilage biopsy by itself also suffers from some of the same potential sampling error concerns as other measures.31,57 It might best be used in combination with other methods of cartilage scoring.64-66 The possibility that this biopsy technique might also provide material for cellular and cytokine analysis of cartilage is also intriguing.

If this technique is validated and passes long- term scrutiny in regards to safety, this technique may become the new "gold standard" for osteoarthritis clinical trials. This method may provide the ideal balance between the need to know and "do no harm" so critical in all human studies.

Acknowledgements

The authors wish to thank Biff Owen and Carl Yoshizawa of Chiron Corporation for allowing us to use the clinical data (WOMAC, VAS and microscopic biopsy section) referred to in the manuscript.

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Figure 1. Two-mm Jamshidi biopsy needle.

Figure 2. Biopsy needle advanced into subchondral bone. Note perpendicular orientation of biopsy needle to cartilage surface.

Figure 3. Biopsy site immediately after biopsy.

Figure 4. Gross view of two biopsy specimens.

Figure 5. Safranin O stained microscopic section of a biopsy specimen 10 X power. Proteoglycan staining (pink).

Table 1. WOMAC and VAS Data for Patients Who Underwent Pretreatment Biopsy

WOMAC VAS

Pain Stiffness Physical Function

Subject Visit Week Signal Joint Score Score Score

01/001 PRE-STUDY RIGHT 90 83 424 39.36

14 RIGHT 38 21 112 3.19

01/002 PRE-STUDY RIGHT 191 125 679 52.13

14 RIGHT 163 82 588 46.81

01/003 PRE-STUDY RIGHT 327 180 1159 95.74

14 RIGHT 237 97 628 58.51

01/004 PRE-STUDY RIGHT 112 71 416 29.79

14 RIGHT 14 6 56 3.19

01/005 PRE-STUDY RIGHT 129 68 407 15.96

14 RIGHT 89 28 207 21.28

01/006 PRE-STUDY RIGHT 358* 161* 1314* 72.34*

14 RIGHT 389* 178* 1426* 87.23*

01/007 PRE-STUDY LEFT 226* 114* 855* 51.06*

14 LEFT 352* 131* 1125* 81.91*

01/008 PRE-STUDY LEFT 52 0 127 3.19

14 LEFT 25 1 25 3.19

01/009 PRE-STUDY LEFT 136 97 578 65.96

14 LEFT 40 14 143 6.38

01/010 PRE-STUDY LEFT 248 141 925 44.68

14 LEFT 88 77 533 42.55

01/011 PRE-STUDY RIGHT 174 123 567 63.83

14 RIGHT 56 10 122 26.6

01/012 PRE-STUDY LEFT 68 28* 215 12.77*

14 LEFT 37 73* 227 35.11*

01/013 PRE-STUDY LEFT 348* 89* 1074* 45.74*

14 LEFT 400* 98* 1226* 52.13*

01/014 PRE-STUDY LEFT 396 161 1370 90.43

14 LEFT 193 76 1052 47.87

01/015 PRE-STUDY RIGHT 245* 169 1352 77.66*

14 RIGHT 354* 135 1330 94.68*

01/016 PRE-STUDY RIGHT 210* 108* 951* 79.79

14 RIGHT 290* 126* 1003* 47.87

01/017 PRE-STUDY RIGHT 172* 113 434* 14.89

14 RIGHT 251* 65 478* 9.57

01/018 PRE-STUDY RIGHT 90 34* 371* 15.96*

14 RIGHT 137 41* 414* 37.23*

01/019 PRE-STUDY RIGHT 314 146 1095 78.72

14 RIGHT 233 0 1061 61.7

01/020 PRE-STUDY RIGHT 106* 77 628 32.98

14 RIGHT 266* 72 564 4.26

Table 1 continued on pg. 334

Table 1. continued

WOMAC VAS

Pain Stiffness Physical Function

Subject Visit Week Signal Joint Score Score Score

01/021 PRE-STUDY LEFT 218* 106* 1000* 67.02

14 LEFT 295* 137* 1137* 52.13

01/022 PRE-STUDY RIGHT 254 104 838 4.26*

14 RIGHT 124 103 681 37.23*

01/023 PRE-STUDY LEFT 146 119 675 38.3

14 LEFT 127 22 654 29.79

01/024 PRE-STUDY RIGHT 243 134 978 68.09

14 RIGHT 159 64 870 56.38

01/025 PRE-STUDY RIGHT 242 93 533* 6.38*

14 RIGHT 112 92 546* 20.21*

01/026 PRE-STUDY RIGHT 120 80* 545 31.91

14 RIGHT 81 126* 405 19.15

01/027 PRE-STUDY RIGHT 44 26 277 27.66

14 RIGHT 15 9 150 9.57

01/028 PRE-STUDY RIGHT 418 180 1331 97.87

14 RIGHT 187 99 822 45.74

01/029 PRE-STUDY RIGHT 65 37 301 18.09

14 RIGHT 32 23 273 14.89

01/030 PRE-STUDY RIGHT 291 134 1093 64.89

14 RIGHT 136 64 450 31.91

01/031 PRE-STUDY LEFT 343 119* 1192* 82.98

14 LEFT 298 123* 1204* 67.02

01/032 PRE-STUDY RIGHT 292* 106* 577* 43.62*

14 RIGHT 300* 156* 1009* 53.19*

*Scores of patients who had symptomatic worsening after the initial biopsy.

Table 2. Radiographic Data for 27 of 32 Patients Available for Follow-up

Radiographic Radiographic Follow-up

stage at Stage at duration in

Gender Age Study Knee entrance Follow-up months Comments

Male 53 Right II II 30 months No change

Female 82 Right III III 22 months No change

Male 72 Right III III 24 months No change

Male 77 Left III III 32 months 1 mm

improvement

Female 66 Left II II 34 months No change

Female 61 Right II II 31 months Left knee

was II - now III

Female 58 Left III III 44 months Right knee

replaced

Female 55 Right III III 35 months No change

Male 75 Right II II 32 months No change

Female 51 Right II II 33 months No change

Male 74 Left III III 32 months No change

Female 69 Right III III 31 months No change

Male 77 Right II II 35 months No change

Female 49 Left III IV 36 months Changed

full grade

Female 58 Left III III 29 months No change

Female 44 Right I I 33 months Left slightly

worse

Female 55 Right III III 33 months Left knee

replaced

Female 53 Left II II 31 months No change

Female 50 Right II II 32 months No change

Female 82 Left IV IV 32 months No change

Female 49 Left II II 34 months No change

Female 48 Right II II 34 months No change

Male 49 Right III III 31 months No change

Male 58 Right III III 33 months No change

Male 61 Right III III 37 months No change