Hand joints without radiographic osteoarthritis maintain their joint space width over 4 years despite what's happening elsewhere in the hand.

OBJECTIVES: We aimed to determine if hand osteoarthritis is characterized by systemic cartilage loss by assessing if radiographically normal joints had greater joint space width (JSW) loss during four years in hands with incident or prevalent osteoarthritis elsewhere in the hand compared with hands without osteoarthritis. METHODS: We used semi-automated software to measure JSW in the distal and proximal interphalangeal joints of 3,368 participants in the Osteoarthritis Initiative who had baseline and 48-month hand radiographs. A reader scored 16 hand joints (including the thumb-base) for Kellgren-Lawrence (KL) Grade. A joint had osteoarthritis if scored as KL ≥ 2. We identified three groups based on longitudinal hand osteoarthritis status: 1) no hand osteoarthritis (KL < 2 in all 16 joints) at the baseline and 48-month visits, 2) incident hand osteoarthritis (KL < 2in all 16 joints at baseline and then ≥1 joint with KL ≥ 2 at 48-months), and 3) prevalent hand osteoarthritis (≥1 joint with KL ≥ 2 at baseline and 48-months). We then assessed if JSW in radiographically normal joints (KL = 0) differed across these three groups. We calculated unpooled effect sizes to help interpret the differences between groups. RESULTS: We observed small differences in JSW loss that are unlikely to be clinically important between radiographically normal joints between those without hand osteoarthritis (n = 1054) and those with incident (n = 102) or prevalent hand osteoarthritis (n = 2212) (effect size range: -0.01 to 0.24). These findings were robust when examining JSW loss dichotomized based on meaningful change and in other secondary analyses. CONCLUSIONS: Hand osteoarthritis is not a systemic disease of cartilage.

Increased Joint Space Narrowing After Arthroscopic Partial Meniscectomy: Data From the Osteoarthritis Initiative.

BACKGROUND: Arthroscopic partial meniscectomy (APM) is widely performed and remains an important therapeutic option for patients with a meniscal tear. However, it is debated whether or not APM accelerates the progression of osteoarthritis (OA) in the long term. PURPOSE/HYPOTHESIS: The purpose was to compare the progression of OA measured by the change in tibiofemoral joint space width (JSW)-a quantitative measure of OA radiographic severity-across 3 groups with a midterm follow-up: (1) patients undergoing APM; (2) those with a meniscal tear treated nonoperatively; and (3) those without a tear. We hypothesized that the reduction in JSW would be greatest in patients undergoing APM and least in those patients without a tear. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Using the Osteoarthritis Initiative cohort, a total of 144 patients were identified that underwent APM with at least 12 months of follow up and without previous knee surgery. Those with a meniscal tear who did not have APM (n = 144) and those without a tear (n = 144) were matched to patients who had APM by sex, age, Kellgren-Lawrence (KL) grade, and follow up time. Participants underwent magnetic resonance imaging at baseline. Knee radiographs to assess JSW were collected annually or biannually. The change in minimum medial compartment JSW was calculated using a validated automated method. A piecewise linear mixed effects model was constructed to examine the relationship between JSW decline over time and treatment group-adjusting for age, body mass index, smoking status, KL grade, and baseline JSW. RESULTS: All groups had comparable baseline JSW-ranging from 4.33 mm to 4.38 mm. The APM group had a rate of JSW decline of -0.083 mm/mo in the first 12 months and -0.014 mm/mo between 12 and 72 months. The rate of JSW decline in the APM group was approximately 27 times greater in the first 12 months than that in the nonsurgical group (-0.003 mm/mo) and 5 times greater than that in the no tear group (-0.015 mm/mo); however, there was no significant difference between groups for 12 to 72 months (nonsurgical group: -0.009 mm/mo; no tear group: -0.010 mm/mo). The adjusted JSW in the APM group was 4.38 mm at baseline and decreased to 2.57 mm at 72 months; the JSW in the nonsurgical group declined from 4.31 mm to 3.73 mm, and in the no tear group it declined from 4.33 mm to 3.54 mm. There was a statistically significant difference in JSW change between baseline and 72 months for the APM group compared with the other groups (P < .001), but not between the nonsurgical and no tear groups (P = .12). CONCLUSION: In the first postoperative year, APM results in a faster rate of joint space narrowing compared with knees undergoing nonsurgical management of meniscal tears. Thereafter, there are comparable rates of OA progression regardless of the chosen management. APM results in a persistent decrease in JSW over at least 72 months. An untreated meniscal tear does not contribute to radiographic progression-assessed by JSW-as compared with an intact meniscus.

Aminopyridine analogs selectively target metastatic pancreatic cancer.

Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are therapeutically actionable. Here we report a novel aminopyridine compound that targets a unique Phosphogluconate Dehydrogenase (PGD)-dependent metabolic adaptation in distant metastases from pancreatic cancer patients. Compared to structurally similar analogs, 6-aminopicolamine (6AP) potently and selectively reversed PGD-dependent metastatic properties, including intrinsic tumorigenic capacity, excess glucose consumption, and global histone hyperacetylation. 6AP acted as a water-soluble prodrug that was converted into intracellular bioactive metabolites that inhibited PGD in vitro, and 6AP monotherapy demonstrated anti-metastatic efficacy with minimal toxicity in vivo. Collectively, these studies identify 6AP and possibly other 6-aminopyridines as well-tolerated prodrugs with selectivity for metastatic pancreatic cancers. If unique metabolic adaptations are a common feature of metastatic or otherwise aggressive human malignancies, then such dependencies could provide a largely untapped pool of druggable targets for patients with advanced cancers.

Prevalence, Incidence, and Progression of Radiographic and Symptomatic Hand Osteoarthritis: The Osteoarthritis Initiative.

OBJECTIVE: To describe the prevalence, incidence, and progression of radiographic and symptomatic hand osteoarthritis (OA), and to evaluate differences according to age, sex, race, and other risk factors. METHODS: Participants were assessed for radiographic and symptomatic hand OA at baseline and year 4 to determine incident disease. A modified Poisson regression with a robust variance estimator was used to account for clustering of joints within fingers within persons to estimate the prevalence ratios and relative risk estimates associated with participant characteristics. RESULTS: Among 3,588 participants, the prevalence of radiographic hand OA was 41.4%, and the prevalence of symptomatic hand OA was 12.4%. The incidence over 48 months was 5.6% for radiographic hand OA and 16.9% for symptomatic hand OA. Over 48 months, 27.3% of the participants exhibited OA progression. We found complex differences by age, sex, and race, with increasing rates of prevalent hand OA with older age in both men and women, but with rates of incident disease peaking at ages 55-64 years in women. Women had higher rates of symptomatic hand OA, but only nonsignificantly higher rates of incident radiographic hand OA, than men. Women more frequently had distal interphalangeal joint disease, while men more frequently had metacarpophalangeal joint OA. Black men and women had lower rates of hand OA than White participants, but Black men had higher rates of prevalent hand OA than Black women at younger ages. CONCLUSION: Hand OA is a heterogeneous disease with complex differences by age, sex, race, hand symptoms, and patterns of specific joints affected. Further research investigating the mechanisms behind these differences, whether mechanical, metabolic, hormonal, or constitutional, is warranted.

Differences in the Lateral Compartment Joint Space Width After Anterior Cruciate Ligament Reconstruction: Data From the MOON Onsite Cohort.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction can effectively return athletes to the playing field, but they are still at risk of developing posttraumatic osteoarthritis (PTOA). No studies have used multivariable analysis to evaluate the predictors of radiographic PTOA in the lateral compartment of the knee at short-term follow-up after ACL reconstruction. PURPOSE: To determine the predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in a young, active cohort. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A nested cohort of 358 patients from the Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort who were aged ≤33 years, were injured playing a sport, and had never undergone surgery on the contralateral knee were followed up 2 years after ACL reconstruction with questionnaires and with weightbearing knee radiographs using the metatarsophalangeal (MTP) joint technique. The joint space width in the lateral compartment was measured using a semiautomatic computerized method, and multivariable predictive modeling was used to evaluate the relationship between meniscus treatment, cartilage injury, graft type, and joint space while adjusting for age, sex, body mass index, and Marx activity score. RESULTS: The mean lateral joint space width was 0.11 mm narrower on the ACL-reconstructed knee compared with the contralateral healthy knee (7.69 mm vs 7.80 mm, respectively; P < .01). Statistically significant predictors of a narrower joint space width on the ACL-reconstructed knee included lateral meniscectomy ( P < .001) and a Marx activity score less than 16 points ( P < .001). CONCLUSION: This study identifies lateral meniscectomy and a lower baseline Marx activity score to be predictors of radiographic joint space narrowing in the lateral compartment 2 to 3 years after ACL reconstruction in young, active patients without a prior knee injury.

Impact of Cane Use on Bone Marrow Lesion Volume in People With Medial Knee Osteoarthritis (CUBA Trial).

BACKGROUND: No effective cure exists for knee osteoarthritis (OA). Low-burden self-management strategies that can slow disease progression are needed. Bone marrow lesions (BMLs) are a source of knee pain and accelerate cartilage loss. Importantly, they may be responsive to biomechanical off-loading treatments. OBJECTIVE: The study objective is to investigate whether, in people with medial tibiofemoral OA, daily cane use for 12 weeks reduces the volume of medial tibiofemoral BMLs and improves pain, physical function, and health-related quality of life. DESIGN: This study will be an assessor-masked, 2-arm, parallel-group, multisite randomized controlled trial. SETTING: The community will serve as the setting for this study. PARTICIPANTS: The study participants will be people who are 50 years old or older and have medial tibiofemoral OA and at least 1 medial tibiofemoral BML. INTERVENTION: The participants will be allocated to either the cane group (using a cane daily whenever walking for 12 weeks) or the control group (not using any gait aid for 12 weeks). MEASUREMENTS: Outcomes will be measured at baseline and 13 weeks. The primary outcome will be total medial tibiofemoral BML volume measured from magnetic resonance imaging. Secondary outcomes will include BML volume of the medial tibia and/or femur, knee pain overall and on walking, physical function, participant-perceived global change, and health-related quality of life. Additional measures will include physical activity, cointerventions, adverse events, participation, participant demographics, cane training process measures and feasibility, barriers to and facilitators of cane use, and loss to follow-up. LIMITATIONS: People who are morbidly obese will not be included because of difficulties with magnetic resonance imaging. CONCLUSIONS: The findings of this study will help to determine whether cane use can alter disease progression in people with medial tibiofemoral OA and/or influence clinical symptoms. This study may directly influence clinical guidelines for the management of knee OA.

Comparison of radiographic joint space width and magnetic resonance imaging for prediction of knee replacement: A longitudinal case-control study from the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement. METHODS: Knees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression. RESULTS: One hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement. CONCLUSIONS: Discrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement. KEY POINTS: • Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement.

Longitudinal (one-year) change in cartilage thickness in knees with early knee osteoarthritis: A within-person between-knee comparison.

Objective: To test the hypothesis that cartilage displays significant longitudinal thickening in the external subregions of the central medial (ecMF) and lateral (ecLF) femur in knees with early radiographic osteoarthritis (ROA) compared with contralateral knees without ROA, and to explore differences in change in other subregions and in radiographic joint space width (JSW). Methods: 50 participants (50% women; age 61.1±9.7y; BMI 27.7±4.7kg/m2 ) were identified from the Osteoarthritis Initiative cohort with definite femorotibial osteophytes but no JSN in one knee (early ROA), and no osteophytes or JSN in the contralateral knee (non-ROA). A longitudinal within-person, between-knee comparison was performed using measures of subregional cartilage thickness based on analyses of sagittal DESSwe MR images obtained at baseline and 1-year. Medial JSW was evaluated from fixed flexion radiographs. Results: The change between baseline and 1-year was -6±94µm in ecMF and +18±91µm in ecLF in early ROA (p=0.78) vs. -1±68µm and +4±76µm in non-ROA knees (p=0.38). The variability of cartilage thickness change tended to be greater in early ROA than in non-ROA knees. Greater cartilage thickness loss in the lateral tibia and a greater reduction in minimum medial JSW was observed in early ROA vs. non-ROA knees. Conclusion: There was no direct evidence of longitudinal cartilage thickening in external subregions of the central femur in knees with early ROA compared with contralateral non-ROA knees. The observed greater variability in longitudinal thickness change in early ROA knees (but not in non-ROA knees) might be due to cartilage thickening and thinning occurring simultaneously in these knees.

Imaging of osteoarthritis.

Osteoarthritis (OA) is the most prevalent joint disorder in the elderly, and there is no effective treatment. Imaging is essential for evaluating the synovial joint structures (including cartilage, meniscus, subchondral bone marrow and synovium) for diagnosis, prognosis, and follow-up. This article describes the roles and limitations of both conventional radiography and magnetic resonance (MR) imaging, and considers the use of other modalities (eg, ultrasonography, nuclear medicine, computed tomography [CT], and CT/MR arthrography) in clinical practice and OA research. The emphasis throughout is on OA of the knee. This article emphasizes research developments and literature evidence published since 2008.

Cartilage thickening in early radiographic knee osteoarthritis: a within-person, between-knee comparison.

OBJECTIVE: To determine whether the presence of definite osteophytes (in the absence of joint space narrowing [JSN]) on radiographs is associated with (subregional) increases in cartilage thickness in a within-person, between-knee cross-sectional comparison of participants in the Osteoarthritis Initiative. Based on previous results, the external weight-bearing medial femoral condyle (ecMF) and external weight-bearing lateral femoral condyle (ecLF) subregions were selected as primary end points. METHODS: Both knees of 61 Osteoarthritis Initiative participants (n = 4,796) displayed definite tibial or femoral marginal osteophytes and no JSN in 1 knee, and no signs of radiographic osteoarthritis (OA) in the contralateral knee; this was confirmed by an expert central reader. In these participants, cartilage thickness was measured in 16 femorotibial subregions of each knee, based on sagittal double-echo steady-state with water excitation magnetic resonance images. Location-specific joint space width from fixed-flexion radiographs was determined using dedicated software. Location-specific associations of osteophytes with cartilage thickness were evaluated using paired t-tests and mixed-effects models. RESULTS: Of the 61 participants, 48% had only medial osteophytes, 36% only lateral osteophytes, and 16% bicompartmental osteophytes. The knees with osteophytes had significantly thicker cartilage than contralateral knees without osteophytes in the ecMF (mean ± SD +71 ± 223 µmoles, equivalent to an increase of +5.5%; P = 0.015) and ecLF (mean ± SD +64 ± 195 µmoles, +4.1%; P = 0.013). No significant differences between knees were noted in other subregions or in joint space width. Cartilage thickness in the ecMF and ecLF was significantly associated with tibial osteophytes in the same (medial or lateral) compartment (P = 0.003). CONCLUSION: The knees with early radiographic OA display thicker cartilage than (contralateral) knees without radiographic findings of OA, specifically in the external femoral subregions of compartments with marginal osteophytes.

Radiographic grading and measurement of joint space width in osteoarthritis.

The progression of osteoarthritis is traditionally measured using radiographic joint space width (JSW). Numerous knee radiograph protocols have been developed with various levels of complexity and performance as it relates to detecting JSW loss (ie, joint space narrowing). Sensitivity to joint space narrowing is improved when radioanatomic alignment of the medial tibial plateau is achieved. Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area, and JSW at fixed locations.

Multiple computer-based methods of measuring joint space width can discriminate between treatment arms in the COBRA trial -- Update of an ongoing OMERACT project.

Previously reported data on 5 computer-based programs for measurement of joint space width focusing on discriminating ability and reproducibility are updated, showing new data. Four of 5 different programs for measuring joint space width were more discriminating than observer scoring for change in narrowing in the 12 months interval. Three of 4 programs were more discriminating than observer scoring for the 0-18 month interval. The program that failed to discriminate in the 0-12 month interval was not the same program that failed in the 0-18 month interval. The committee agreed at an interim meeting in November 2007 that an important goal for computer-based measurement programs is a 90% success rate in making measurements of joint pairs in followup studies. This means that the same joint must be measured in images of both timepoints in order to assess change over time in serial radiographs. None of the programs met this 90% threshold, but 3 programs achieved 85%-90% success rate. Intraclass correlation coefficients for assessing change in joint space width in individual joints were 0.98 or 0.99 for 4 programs. The smallest detectable change was < 0.2 mm for 4 of the 5 programs, representing 29%-36% of the change within the 99th percentile of measurements.

Radiographic-based grading methods and radiographic measurement of joint space width in osteoarthritis.

Accurate and highly reproducible measurements of the rate of progression of osteoarthritis is crucial to assessing structural change, and requires adherence to exacting standards of positioning, which include specifications for flexion and rotation of the joint, and angulation of the x-ray beam. The progression of osteoarthritis traditionally has been measured using radiographic joint space width (JSW). Over the past two decades, numerous knee radiographic protocols have been developed with various levels of complexity and performance as they relate to detecting JSW loss (ie, joint space narrowing). Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area and JSW at fixed locations.

Automated measurement of joint space width in small joints of patients with rheumatoid arthritis.

OBJECTIVE: Comparison of performances of 5 (semi)automated methods in measuring joint space width (JSW) in rheumatoid arthritis. METHODS: Change in JSW was determined by 5 measurement methods on 4 radiographs per patient from 107 patients included in the COBRA trial (comparing sulfasalazine alone or in combination with methotrexate and corticosteroids). For each method the number of patients with sufficient available results was assessed (efficiency). An independent repeated measurement was carried out on a random sample of 30 patients' baseline and 1-year radiographs, to evaluate within-method reliability of change scores. Discriminatory ability (DA) of the measurement methods (between the 2 treatment arms) was compared with the DA of the Sharp-van der Heijde score (SHS) and its 2 components (erosion and JSW scores). RESULTS: The overall success rate varied widely between methods. Applying the chosen threshold of a minimum of 50% available joints with a change score per patient resulted in a success rate > 92% in 4/5 methods. Repeatability of measurements was good for most methods (intraclass correlation coefficient > or = 0.80 in 4/5 methods). Almost all measurement methods in 3 followup periods (12/14) showed a lower mean loss of JSW in patients from the intensive treatment group, although this was rarely statistically significant, confirming the known difference in structural damage. JSW as measured by the (semi)automated systems often showed higher DA than the JSW score of the SHS, but was lower than the total SHS and erosion scores. CONCLUSION: Although efficiency of the methods should be improved further, results already show good reliability and encouraging DA of most methods. Optimal information may be obtained with a combination of scoring of erosions and (semi)automated measurement of JSW.

Longitudinal performance evaluation and validation of fixed-flexion radiography of the knee for detection of joint space loss.

OBJECTIVE: The ability of nonfluoroscopically guided radiography of the knee to assess joint space loss is an important issue in studies of progression and treatment of knee osteoarthritis (OA), given the practical limitations of protocols involving fluoroscopically guided radiography of the knee. We evaluated the ability of the nonfluoroscopically guided fixed-flexion radiography protocol to detect knee joint space loss over 3 years. METHODS: We assessed the same-day test-retest precision for measuring minimum joint space width (JSW), the sensitivity for detection of joint space loss using serial films obtained a median of 37 months (range 23-47 months) apart, and the relationship of joint space loss to radiographic and magnetic resonance imaging (MRI) measures of knee OA. Participants were men and women (ages 70-79 years) with knee pain who were participating in the Health, Aging, and Body Composition Study. We assessed baseline radiographic OA and measured JSW using a computerized algorithm. Serial knee MRIs obtained over the same interval were evaluated for cartilage lesions. RESULTS: A total of 153 knees were studied, 35% of which had radiographic OA at baseline. The mean +/- SD joint space loss for all knees over 3 years was 0.24 +/- 0.59 mm (P < 0.001 for change). In knees with OA at baseline, the mean +/- SD joint space loss over 3 years was 0.43 +/- 0.66 mm (P < 0.001), and in knees with joint space narrowing at baseline, joint space loss was 0.50 +/- 0.67 mm (P < 0.001). Joint space loss and its standardized response mean increased with the severity of baseline joint space narrowing and with the presence of cartilage lesions at baseline and worsening during followup. CONCLUSION: Radiography of the knee in the fixed-flexion view provides a sensitive and valid measure of joint space loss in multiyear longitudinal studies of knee OA, without the use of fluoroscopy to aid knee positioning.

Computer based methods for measurement of joint space width: update of an ongoing OMERACT project.

Computer-based methods of measuring joint space width (JSW) could potentially have advantages over scoring joint space narrowing, with regard to increased standardization, sensitivity, and reproducibility. In an early exercise, 4 different methods showed good agreement on measured change in JSW over time in the small joints of the hands and feet. Despite differences in measurement values between methods, measurement of within-joint change over time showed no systematic differences. The within-method variation was small, with intra-operator variation being smaller than inter-operator variation. Although this initial study was limited in terms of the number of patients and timepoints (total 10), the number of joints was relatively high (340 joints), so the results were considered strong evidence supporting the validity of computer-based JSW measurements to continue the study of the potential value of JSW by comparison of measurements to manual scoring of joint space narrowing using the COBRA trial images.

Measurement of joint space width and erosion size.

Measurement of radiographic abnormalities in metric units has been reported by several investigators during the last 15 years. Measurement of joint space in large joints has been employed in a few trials to evaluate therapy in osteoarthritis. Measurement of joint space width in small joints has been reported by several investigators but has not yet found a place in clinical trials in rheumatoid arthritis or osteoarthritis. We review methods for measuring joint space width in finger, toe, and wrist joints; special attention is given to how the joint edges are found, the method used to measure distance between joint margins, size of an area of the sampled joint, and reproducibility of measurements. Methods for measurement of erosion size, which have had less attention, are briefly discussed.