Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

BACKGROUND: Non-contact cranial cruciate ligament rupture (CrCLR) is an important cause of lameness in client-owned dogs and typically occurs without obvious injury. There is a high incidence of bilateral rupture at presentation or subsequent contralateral rupture in affected dogs. Although stifle synovitis increases risk of contralateral CrCLR, relatively little is known about risk factors for subsequent contralateral rupture, or whether therapeutic intervention may modify this risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal study examining survival of the contralateral CrCL in client-owned dogs with unilateral CrCLR in a large baseline control population (n = 380), and a group of dogs that received disease-modifying therapy with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline (n = 16), and were followed for one year. Follow-up in treated dogs included analysis of mobility, radiographic evaluation of stifle effusion and arthritis, and quantification of biomarkers of synovial inflammation. We found that median survival of the contralateral CrCL was 947 days. Increasing tibial plateau angle decreased contralateral ligament survival, whereas increasing age at diagnosis increased survival. Contralateral ligament survival was reduced in neutered dogs. Our disease-modifying therapy did not significantly influence contralateral ligament survival. Correlative analysis of clinical and biomarker variables with development of subsequent contralateral rupture revealed few significant results. However, increased expression of T lymphocyte-associated genes in the index unstable stifle at diagnosis was significantly related to development of subsequent non-contact contralateral CrCLR. CONCLUSION: Subsequent contralateral CrCLR is common in client-owned dogs, with a median ligament survival time of 947 days. In this naturally occurring model of non-contact cruciate ligament rupture, cranial tibial translation is preceded by development of synovial inflammation. However, treatment with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline does not significantly influence contralateral CrCL survival

Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis

BACKGROUND: Pain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome-measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 – transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen – non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication. RESULTS: Acute hyperthermia developed after ABT-116 treatment (P < 0.001). Treatment with carprofen (P ≤ 0.01) and tramadol (P ≤ 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment (P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups (P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (S(R) ≥ ±0.40, P ≤ 0.005). Placebo treatment effects were evident with all variables studied. CONCLUSION: Treatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs

Photomicrographs of stifle synovium from dogs with unilateral cranial cruciate ligament rupture and a contralateral stable stifle.

<p>(<b>A</b>) Unstable stifle of a five-year-old neutered male Golden Retriever. Proliferation of the synovial intima with villus formation can be seen. Widening of intima (arrows) and infiltration of the intima and sub-intima with mononuclear inflammatory cells can also be seen. (<b>B</b>) Unstable stifle of a five-year-old Chesapeake Bay Retriever. TRAP⁺ mononuclear cells (arrows) were identified in synovial villi in the intima and sub-intimal tissues. (<b>C</b>) Stable stifle from a six-year-old neutered male Golden Retriever. Proliferation of the synovial intima can also be seen, with accumulation of mononuclear inflammatory cells within the intima and the sub-intimal tissues (arrows). A,C – Hematoxylin and eosin stain; B – histochemical stain for tartrate-resistant acid phosphatase (TRAP). A – bar = 500 µm; B – bar = 200 µm; C – bar = 100 µm.</p

Tibial plateau angle (TPA) and age influence contralateral cranial cruciate ligament (CrCL) survival over time in dogs diagnosed with unilateral CrCL rupture.

<p>(<b>A</b>) Increasing TPA was associated with decreased contralateral CrCL survival, whereas increasing age at diagnosis was associated with increased contralateral CrCL survival (<b>B</b>). However, these effects appear minor, as the slope of the regression lines is small and data points are widely scattered.</p

Radiographic signs of stifle arthritis and synovial effusion in dogs with unilateral cranial cruciate ligament rupture after surgical stabilization and hyaluronic acid/doxycycline treatment.

<p>Data represent median (range). Diagnosis, n = 16; 12 weeks after surgery, n = 15; 1 year after surgery, n = 8. NS – not significant (<i>p</i>>0.05). Changes in composite score and synovial effusion were not significantly different over time. One dog was excluded from the analysis at the 10 week recheck, because of development of contralateral CCLR at 67 days after surgery, 5 dogs were excluded at long-term follow-up.</p

Canine oligonucleotide primers for quantitative real-time reverse-transcriptase polymerase chain reaction.

<p><b>Note</b>: TCR-Vβ – variable region of the beta chain of the T lymphocyte antigen receptor; TRAP – tartrate-resistant acid phosphatase; IL – interleukin; IFN – interferon; TNF – tumor necrosis factor.</p

Synovial inflammation in the unstable index and stable contralateral stifles of dogs with unilateral cranial cruciate ligament rupture.

<p><b>Note</b>: Synovitis was scored subjectively using arthroscopy using a compartmental numerical rating scale (NRS, score range 0–24) and a visual analogue scale (VAS). Histologic sections of synovium were also subjectively graded for inflammation and numbers of TRAP⁺ mononuclear cells using a visual analogue scale; severity scores ranged from 0 (no inflammation) to 100 (could not be more severely inflamed). NS – not significant.</p

Relative expression of immune response genes in synovial fluid from unstable index and stable contralateral stifles of dogs with unilateral cranial cruciate ligament rupture.

<p><b>Note</b>: TCR Vβ - beta chain of the canine T cell receptor; TRAP – tartrate-resistant acid phosphatase; IL – interleukin; IFN – interferon; TNF – tumor necrosis factor. Data represent median (range). Median values in bold indicate that gene expression is significantly different from the peripheral blood mononuclear cell internal control (<i>p</i><0.05).</p><p>*<i>p</i><0.05,</p><p>**<i>p</i><0.01 versus contralateral stifle.</p>##<p><i>p</i><0.01 versus same tissue at diagnosis. n = 15–16 at diagnosis, n = 14–15 at 10 week recheck, n = 5–7 at 1 year recheck.</p

Contralateral cranial cruciate ligament (CrCL) survival after post-operative treatment with provisional disease-modifying therapy.

<p>Kaplan-Meier plot for contralateral CrCL survival in a population of client-owned dogs treatment with oral doxycycline after TPLO stabilization of unilateral CrCLR. Arthroscopic examination and associated lavage of the contralateral stable stifle, together with intra-articular hyaluronic acid and oral doxycycline did not significantly influence CrCL survival (<i>p</i> = 0.87). Complete – dogs that experienced contralateral CrCLR during the study period; Censored – dogs that did not experience contralateral CrCLR during the study period.</p