Citations

SummaryRheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non‐associated alleles develop arthritis is still unexplained. The trans‐heterodimer between two RA non‐associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ α chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen‐specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen‐derived peptides that are not presented by an arthritis‐resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.

Background— A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. Methods and Results— Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in Ca V 1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions— Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.

Abstract Anterior shoulder instability is often accompanied by a Hill‐Sachs defect on the humeral head that can contribute to recurrent instability if not addressed at the time of surgery. We describe a method of performing arthroscopic remplissage to treat engaging Hill‐Sachs lesions in patients with glenohumeral instability. It has the benefits of being an efficient procedure that can be performed with minimal technical difficulty and can be used to augment other stabilization procedures such as labral repair. The indications for this technique include the presence of an engaging Hill‐Sachs defect in patients will little or no glenoid bone loss. In appropriately selected patients, arthroscopic remplissage has shown reduced rates of recurrent instability. Technique Video video See video under supplementary data.

Background: Patients with patellar instability and a tibial tubercle–trochlear groove (TT-TG) distance ≥20 mm may be candidates for distal tubercle realignment surgery. Although this variable has proven valuable in predicting recurrent dislocations, it is not individualized to patient size, bony structure, or patellofemoral mechanics. Purpose: To develop a patellar instability ratio (PIR) that predicts the risk of recurrent instability based on the TT-TG distance to patient-specific anatomy. Study Design: Cohort study; Level of evidence, 3. Methods: On magnetic resonance imaging scans of 59 knees with patellar instability, the TT-TG distance, tibial tubercle–posterior cruciate ligament (TT-PCL) distance, sagittal patellar length (PL), sagittal trochlear length (TL), axial patellar width (PW), and axial trochlear width (TW) were calculated by 2 observers in a blinded and randomized fashion. Patients were divided into 2 groups: those with a single dislocation and those with multiple (≥2) dislocations. The ability of the TT-TG and TT-PCL distances as well as the 8 different ratios to predict recurrent instability was assessed by calculating odds ratios (ORs), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each measure. Results: Twelve knees (20%) experienced a single dislocation, while 47 (80%) sustained multiple dislocations. A TT-TG distance ≥20 mm was predictive of recurrent instability, with a sensitivity, specificity, and PPV of 21%, 100%, and 100%, respectively. The OR for TT-TG ≥20 mm was 5.38 ( P = .29), while the highest ORs for recurrent instability were noted for a TT-TG/PW ≥0.4 (OR, 7.37; P = .02) and a TT-TG/TW ≥0.5 (OR, 8.88; P = .04). The sensitivity, specificity, and PPV of a TT-TG/PW ≥0.4 were 62%, 83%, and 94%, respectively, while those of a TT-TG/TW ≥0.5 were 45%, 92%, and 95%, respectively. Conclusion: Two novel PIRs (TT-TG/TW and TT-TG/PW) were identified and found to more effectively predict recurrent instability than the TT-TG distance alone. Each ratio takes into account patient-specific anatomy and can be measured in an accurate and reliable fashion by clinicians. These PIRs are a step toward overcoming some of the limitations of using the TT-TG distance in isolation. Further investigation into the clinical applications and utility of the TT-TG/TW is warranted.

Background: The lateral tibial posterior slope (LTPS) has been reported in multiple studies to correlate with an increased risk for native anterior cruciate ligament (ACL) tearing. To date, no study has examined the effect of an increased LTPS as measured on magnetic resonance imaging (MRI) on the likelihood of ACL graft failure. Hypothesis: An increased LTPS as measured on MRI would correlate with an increased risk for ACL graft failure. Study Design: Case-control study; Level of evidence, 3. Methods: Fifty-eight patients were initially identified who experienced graft failure after primary ACL reconstruction and underwent revision between 1998 and 2009. Exclusion criteria were clinical follow-up of less than 4 years, graft failure occurring greater than 2 years after primary surgery, skeletal immaturity, deep infection, lack of available preoperative MRI, and history of trauma to the proximal tibia. This left 35 patients with early (within 2 years) failure of primary ACL reconstruction. These patients were matched to 35 control participants who had undergone ACL reconstruction with a minimum of 4 years of clinical follow-up and no evidence of graft failure. Patients were matched by age, sex, date of primary surgery, and graft type. The LTPS was then determined on MRI in a blinded fashion. Results: The mean time to failure in patients in the study group was 1 year (range, 0.6-1.4 years). The mean follow-up of those in the matched control group was 6.9 years (range, 4.0-13.9 years). The mean LTPS in the early ACL failure group was found to be 8.4°, which was significantly larger than that in the control group at 6.5° ( P = .012). The odds ratio for graft failure considering a 2° increase in the LTPS was 1.6 (95% CI, 1.1-2.2) and continued to increase to 2.4 (95% CI, 1.2-5.0) and 3.8 (95% CI, 1.3-11.3) with 4° and 6° increases in the LTPS, respectively. No significant association was identified between graft type and graft failure. Conclusion: An increased LTPS is associated with an increased risk for early ACL graft failure, regardless of graft type. Orthopaedic surgeons should consider measuring the LTPS as part of the preoperative assessment of ACL-injured patients.

Objectives: Patients with patellar instability and tibial tubercle to trochlear groove (TT-TG) distances ≥ 20 mm are often considered to have pathologic lateralization of the tibial tubercle (TT) relative to the femoral trochlea and may be candidates for TT realignment surgery. Although this variable has proven valuable in predicting risk of recurrent dislocations, the measure is limited in that it is not individualized to the patient and does not consider patient size, bony morphology, or patellofemoral mechanics. The purpose of this study was to develop a Patellar Instability Ratio (PIR) that predicts the risk of recurrent instability based on the TT-TG distance relative to patient specific anatomy. Methods: Fifty-nine patients with a clinical diagnosis of patellar instability were included in the study. A number of measures were calculated on MRI by two observers (one staff orthopedic surgeon and one senior resident) in a blinded and randomized fashion. Variables analyzed included: TT-TG, tibial tubercle to posterior cruciate ligament distance (TT-PCL), sagittal patellar length (PL), sagittal trochlear length (TL), axial patellar width (PW), axial trochlear width (TW), sagittal patellofemoral engagement (SPE; SPE=TL/PL) and axial patellofemoral engagement (APE; APE=PW/TW). Patients were divided into two groups: those with ≤ 1 dislocation and those with ≥ 2 dislocations. Using these groups, the ability of TT-TG, TT-PCL, and 12 different ratios with cut-off values to predict recurrent instability was assessed by calculating odds ratios (OR), C-statistics, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the ratios. P values < 0.05 were considered significant. Results: Mean follow up was 6.6 years. Twelve patients (20%) did not experience recurrent instability while 47 (80%) sustained two or more dislocations during the study period. Pathologic TT-TG (≥ 20 mm) was predictive of recurrent instability with an OR of 5.38 (p=0.29). The highest OR's for recurrent instability were noted for TT-TG/PW ≥ 0.40 (OR > 7.37, p=0.02) and TT-TG/TW ≥ 0.5 (OR 8.88, p=0.04)(Table 1). PW was defined as the largest medial to lateral width of the articular surface of the patella. TW is defined as the largest articular width of the trochlea that is articulating with the patella and can be conceptualized as the “jump distance” that must be overcome for the patella to dislocate. The sensitivity and specificity of TT-TG/PW ratio ≥ 0.40 was 61% and 83% and that of TT-TG/TW ≥ 0.50 was 59% and 92%, respectively. PPV for TT-TG/PW ≥ 0.40 was 94% while that of TT-TG/TW ≥ 0.49 was 97%. Conclusion: Two distinct PIR (TT-TG/PW and TT-TG/TW) have been identified that predict recurrent patellar instability more accurately than TT-TG ≥ 20 mm with PPV's ≥ 94% and OR's > 7 for both measures. These ratios take into consideration the TT-TG relative to patient specific size and anatomy. Further research is needed to determine if patients with increased PIR benefit from TT osteotomy.

Objectives: Female athletes are an at-risk population for anterior cruciate ligament (ACL) injury, with rates of injury significantly higher than the general population. Few studies have reported on a second ACL injury for female athletes. The purpose of this study was to (1) report the rate of subsequent ACL injury (ACL graft rupture or contralateral ACL tear) in competitive female soccer players, (2) compare these rates to those of other female athletes of similar competitive level, and (3) determine risk factors for second ACL injury in this athletic population. Methods: The medical record at our institution was reviewed for patients treated with primary ACL reconstruction between 1998 and 2013. Female patients injured during a competitive athletic event were included for further review, and followed for an average of 7.1 years postoperatively (range 1.0 - 17.7 years). Chi-square analysis was used to compare rate of graft rupture and contralateral ACL injury based on pre-operative Tegner score, graft type, and injury side for soccer players vs. other female athletes. Wilcoxon rank-sum test was used to compare rate of subsequent ACL injury to patient age. Results: 337 patients met our inclusion/exclusion criteria (90 soccer players; 247 non-soccer playing athletes) with a mean age of 24.0 years. Of the 337 athletes, 6 were injured during professional competition, 43 were injured during collegiate athletics, 184 during high school play, and 136 during recreational athletics. No patient demographical differences were found at baseline between the soccer group and non-soccer group, including Tegner scores. Overall, 21 soccer players (23.3%) sustained a second ACL injury compared to 21 (8.5%) non-soccer athletes (P < 0.001). Soccer players had significantly more graft ruptures (10.0% vs. 2.0%, P = 0.003) and more contralateral ACL tears (13.3% vs. 6.5%, P = 0.04). Risk factors for ACL graft tear included young age (mean 16.0 vs 24.3 years; P < 0.0001) and higher Tegner Activity Level scores (mean 8.1 vs. 7.4, P = 0.049), but were not risk factors for contralateral ACL injury. Graft selection and injury side showed no statistical significance on graft rupture or contralateral injury. Conclusion: Female soccer players treated with ACL reconstruction had an increased rate of second ACL injury, including graft tear and contralateral ACL injury, compared to a similar group of non-soccer female athletes (23.3% vs. 8.5%, P < 0.001). In addition, young age and higher activity level were risk factors for graft rupture in this population.

Objectives: Arthroscopic treatment for femoroacetabular impingement (FAI) generally has good results, but the outcome can worsen with increasing arthritis, largely defined as joint space narrowing. There remains a subset of hips with maintained joint space but with subchondral edema and cystic change of the acetabulum on MRI, with unknown outcome. Therefore, the purpose of this study was (1) to determine if postoperative outcome was worse for patients with subchondral edema on preoperative MRI compared to a matched control group and (2) to identify risk factors on MRI leading to inferior outcome. Methods: A review of patients who underwent arthroscopic hip surgery for FAI between 2007 and 2013 identified 530 patients. Of these, 39 patients had evidence of subchondral edema or subchondral cyst on the preoperative MRI with maintained joint space on preoperative radiographs. Lesions were characterized by grade, location and type using an established radiographic MRI classification system. A matched cohort of patients without evidence of subchondral edema or cyst was identified, and 2:1 matching was based on patient age, surgeon, surgery year within one year, surgical procedure, Tegner activity score, and Tonnis grade osteoarthritis changes on preoperative x-ray. Outcome was compared using the Hip Outcome Score and Modified Harris Hip Score between the two groups. Risk factors were then analyzed for type of lesion, grade and location of bone marrow lesion. Results: Thirty-nine patients (20 males, 19 females) showed preoperative MRI evidence of subchondral edema, and were followed for a mean of 23 months postoperatively (range, 12 - 60 months). Patients had an average age of 41 years (range, 19 - 67) and a preoperative Tegner score of 3.8 (range, 1 - 9). 87% of patients with subchondral cystic change had evidence of a grade IV full thickness cartilage lesion at the time of hip arthroscopy. Average Modified Harris Hip Scores were inferior for the subchondral group (79.9 ± 18.7) compared to the control group (86.6 ± 12.5; p = 0.027). In addition, Sport sub-scales of the Hip Outcome Score showed significantly lower scores for the subchondral group for both score (69.1 ± 27.0 vs. 79.5 ± 21.4, p = 0.018) and rating (66.7 ± 27.5 vs. 78.0 ± 20.8, p = 0.044). No radiographic risk factors, including type, location, or size of lesion were significant predictors of outcome. Two patients in the subchondral group were later converted to a total hip replacement. Conclusion: The presence of a subchondral acetabular cyst on MRI is indicative of a full thickness cartilage lesion at the time of arthroscopy. These patients have inferior outcomes for arthroscopic treatment of FAI compared to patients with similar age and activity level without MRI subchondral changes. Therefore, we recommend caution with consideration of hip arthroscopy in this patient subset.