Roy D. Altman

Classification of disease: Osteoarthritis

Criteria for the classification of osteoarthritis (OA) have been developed to establish uniformity in the reporting of this disease. Different criteria sets were developed for OA of the knee, hand, and hip that can serve different investigative purposes. The use of checklists facilitates the use of the criteria sets.

Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees

OBJECTIVE The aim of this study was to evaluate the reliability of a software tool that assesses knee cartilage volumes using magnetic resonance (MR) images. The objectives were to assess measurement reliability by: (1) determining the differences between readings of the same image made by the same reader 2 weeks apart (test-retest reliability), (2) determining the differences between the readings of the same image made by different readers (between-reader agreement), and (3) determining the differences between the cartilage volume readings obtained from two MR images of the same knee image acquired a few hours apart (patient positioning reliability). METHODS Forty-eight MR examinations of the knee from normal subjects, patients with different stages of symptomatic knee osteoarthritis (OA), and a subset of duplicate images were independently and blindly quantified by three readers using the imaging system. The following cartilage areas were analyzed to compute volumes: global cartilage, medial and lateral compartments, and medial and lateral femoral condyles. RESULTS Between-reader agreement of measurements was excellent, as shown by intra-class correlation (ICC) coefficients ranging from 0.958 to 0.997 for global cartilage (P<0.0001), 0.974 to 0.998 for the compartments (P<0.0001), and 0.943 to 0.999 for the condyles(P<0.0001). Test-retest reliability of within-reader data was also excellent, with Pearson correlation coefficients ranging from 0.978 to 0.999 (P<0.0001). Patient positioning reliability was also excellent, with Pearson correlation coefficients ranging from 0.978 to 0.999 (P<0.0001). CONCLUSIONS The results of this study establish the reliability of this MR imaging system. Test-retest reliability, between-reader agreement, and patient positioning reliability were all extremely high. This study represents a first step in the overall validation of an imaging system designed to follow progression of human knee OA.

Risedronate in the Treatment of Paget's Disease of Bone: An Open Label, Multicenter Study

An open‐label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Pagets disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196‐day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by ≥25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Pagets disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Prevalence of Pelvic Paget's Disease of Bone in the United States

The objective of this article was to estimate the prevalence of Pagets disease of bone in the United States from a statistically derived sample of the general population. Pelvic radiographs obtained in the First National Health and Nutrition Examination Survey (NHANES‐I) were reviewed for the presence of Pagets disease. Age, sex, and geographic distribution of Pagets disease of the pelvic region were determined. The overall prevalence of Pagets disease in the United States was estimated. Pelvic Pagets disease is estimated to be present in 0.71 + 0.18% of the radiographs of the general population. The disease was higher in frequency in people who were in the older decades of life with the highest prevalence of 2.32 + 0.54% in the 65‐ to 74‐year‐old people. There is a slight male predominance in the 45‐ to 74‐year age group. The regional distribution suggests the highest prevalence in the Northeast (1.48 + 0.52%) with the lowest prevalence in the South (0.26 + 0.25%). The prevalence was equal in white people and black people. An estimate of the overall prevalence of Pagets disease in the United States was at least 1% and perhaps as much as 2% of the general population with near equal sex distribution and the highest prevalence in the northeastern United States.

Treatment of canine osteoarthritis with insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate.

The potential therapeutic effects of insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate (PPS) were evaluated in an anterior cruciate ligament-deficient canine model of osteoarthritis (OA). A control group of animals received no treatment or surgery (N). The remaining four groups of animals received anterior cruciate transection and either no treatment (OA), intra-articular IGF-1 (IGF-1), intra-muscular PPS (PPS), or a combination of intra-articular IGF-1 and intra-muscular PPS (IGF-1/PPS). All therapy was begun 3 weeks after surgery and continued for 3 weeks. At 6 weeks, articular cartilage from the femoral condyle was evaluated for anatomy, histology (Mankin grade) and biochemistry. Anatomically, only cartilage from dogs in the IGF-1/PPS group approximated that found in N. Mankin scores indicated less severe disease in both PPS and IGF-1/PPS groups compared with the OA group. Consistent with histology, the level of active neutral metalloproteinase was lower in cartilage from the PPS group compared with the OA group. Active and total neutral metalloproteinase, tissue inhibitor of metalloproteinases (TIMP), total collagenase, uronate and hydroxyproline contents were all near normal in the IGF-1/PPS group. In a model of mild OA, therapeutic intervention with IGF-1 and PPS appeared to successfully maintain cartilage structure and biochemistry. From these data, it is hypothesized that proteinase activity was successfully blocked by PPS, and that this allowed the observed growth factor induced effects. As we unravel the various factors that regulate cartilage metabolism, it is becoming apparent that combinations of agents will be needed to effectively control cartilage repair in OA. The addition of PPS to IGF-1 shows promise as a therapeutic intervention and introduces a new rational approach to therapy of OA.

Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions.

OBJECTIVE To relate the rate of bone resorption to serum levels of both hyaluronan (HA) and antigenic keratan sulfate (KS) in canine experimental osteoarthritis (OA) and to evaluate the effects of calcitonin on these parameters and the OA lesions of the unstable knee. METHODS Twenty-two dogs underwent anterior cruciate ligament transection (ACLT) and 6 dogs underwent sham operation. Urinary pyridinium crosslinks were quantified by high-performance liquid chromatography. Immunoassays quantified hyaluronan (HA) and antigenic KS. Macroscopic and histologic OA lesions were scored. Calcitonin treatment was started on day 14 postsurgery and stopped on either day 49 or day 104 postsurgery. Control dogs and all treated dogs were killed on day 105. RESULTS All ACLT joints developed OA. In contrast to sham-operated animals, all operated dogs exhibited an early and sustained rise in the levels of their urinary and serum markers. Calcitonin markedly reduced the levels of these markers and the severity of OA lesions. Furthermore, the longer the period of calcitonin therapy, the lower the score of the OA lesions. CONCLUSION Bone, synovium, and articular cartilage all appear to be involved in the state of hypermetabolism that develops in unstable joints. Furthermore, the rate of bone resorption increases markedly in the early stages of this OA model and is likely to contribute to cartilage breakdown. Since calcitonin reduced the severity of OA changes, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury.

Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).

Previous studies in Caucasians with progressive systemic sclerosis (PSS) have suggested associations of antitopoisomerase I (antitopo I) autoantibodies with either serologically defined HLA-DR2 or DR5. To better define class II HLA associations with the antitopo I response, 161 PSS patients (132 Caucasians and 29 American blacks) were studied for antitopo I autoantibodies by immunodiffusion and immunoblotting, and their HLA-DRB1, DRB3, DQA1, and DQB1 alleles were determined by restriction fragment length polymorphic analysis and DNA oligotyping. Among Caucasians with antitopo I, HLA-DR5(DRB1*1101-*1104), DRB3*0202 and DQw3 (DQw7,8,9) were significantly increased in frequency. In American blacks, however, only HLA-DQB1*0301(DQw7) was significantly increased. The presence of HLA-DQB1*0301(DQw7) and other HLA-DQB1 alleles bearing the uncharged polar amino acid residue tyrosine at position 30 of the outermost domain was found in all antitopo I-positive Caucasian PSS patients compared with 66% of antitopo I-negative PSS patients (pc = 0.007) and 70% of normal controls (pc = 0.008), as well as all antitopo I-positive black patients. The association with HLA-DQB1 was independent of HLA-DR5(DRB1*1101-*1104) or any other HLA-DRB1, DRB3, or DQA1 alleles. Alternative or additional candidate epitopes for this autoimmune response include alanine at position 38 and threonine at position 77 of these same DQB1 alleles. These data suggest that genetic predisposition to the antitopo I response in PSS is associated most closely with the HLA-DQB1 locus.

Biomechanical and biochemical properties of dog cartilage in experimentally induced osteoarthritis.

The finding of other investigators that increased water content is often associated with signs of a torn collagen network in human osteoarthritic (OA) cartilage led to this study. In the Pond-Nuki model of post-traumatic OA experimental but not control femoral condylar cartilage showed evidence of breakdown and stiffening of collagen network as assessed by measurement of swelling properties and indentation behaviour respectively. These changes in the unstable knees occurred despite lack of erosion of that surface cartilage ascertained from carbon black mapping and history. The stiffening rather than softening change was therefore attributed to cartilage oedema of the middle and deep certilagenous zones, wherein breakdown of collagen network has been postulated to occur. Because of insignificant reduction of total hexuronate in these cartilages, a proteoglycan (PG) profile of sedimentation coefficients for aggregate (PGA) and subunit species (PGS) was analysed to see if collagen network changes in the dog preceded PG alteration. Despite minimal histological changes our results confirmed previous findings in the tibial plateau cartilage in this model, that PGA was reduced in size and PGS increased in amount. Slight enzymatic breakdown of PGs, or altered synthesis due to cellular responses to either the injury directly or to synovial inflammation, seems necessary to explain such changes in the absence of cartilage erosion.

Capsaicin cream 0.025% as Monotherapy for Osteoarthritis: A double-blind study

The efficacy and safety of 0.025% capsaicin cream were evaluated when it was used as the only symptomatic therapy in patients with osteoarthritis (OA) pain. Patients (113) received either topical capsaicin or vehicle four times daily in this 12-week, double-blind, randomized, vehicle-controlled, multicenter study. Capsaicin was superior to vehicle in providing pain relief. At the end of the study, more patients on capsaicin (81 %) than vehicle (54%) were improved by physicians global evaluation ( P = .03). Similar results were obtained by patients global evaluation. Capsaicin-treated patients reported greater reduction of pain on the visual analog scale (VAS) at week 4 ( P = .01), week 8 ( P = .01), and week 12 ( P = .02). Capsaicin -treated patients also had greater reduction in pain on passive range of motion by week 8 ( P = .03) that was sustained through week 12 ( P = .03). Joint tenderness evaluated by palpation declined in capsaicin-treated patients at week 4 ( P = .03), week 8 ( P = .01 ), and week 12 ( P = .01 ). Adverse effects attributable to capsaicin were mild to moderate burning and stinging at the application site (46% of patients). The burning resolved in most patients; only 3 (7%) patients experienced burning at week 12. These results support the beneficial effects of 0.025% capsaicin cream as a first-line therapy for OA pain.

Preliminary observations of chondral abrasion in a canine model.

Articular cartilage repair was followed for one year in skeletally mature dogs after destabilisation by anterior cruciate ligament transection of the stifle joint (CT), abrasion of the inferior medial condyle (ABR) to bleeding bone, or anterior cruciate transection followed by chondral abrasion (CT/ABR). ABR animals formed repair cartilage at the abrasion site (ABR and CT/ABR) at six months as determined by arthroscopy and at necropsy. CT and CT/ABR animals had an additional cartilage ulcer on the superior aspect of the medial condyle. The abraded site extended in CT/ABR condyles. Repair cartilage (ABR and CT/ABR) contained reduced amounts of proteoglycan as seen by histological loss of safranin O staining and reduced uronic acid content. Fibrocartilage was suggested by histological appearance, hypocellularity, and a higher hydroxyproline content. In contrast with ABR animals, the repair cartilage in the CT/ABR animals contained near normal amounts of hydroxyproline. Collagen profiles of abrasion site repair cartilage in ABR animals had more types I and V collagens, similar amounts of type VI collagen, and decreased amounts of types II, IX, and XI collagens than CT/ABR animals. The results of this study are consistent with abrasion chondroplasty leading to a repair cartilage. Despite extended ulcers, repair cartilage from the destabilised joint (CT/ABR) animals was more hyaline-like in its hydroxyproline content and collagen composition than repair cartilage from the stable joint (ABR animals). In these models additional measures appear to be needed as the defects induced by abrasion chondroplasty did not form a functional hyaline cartilage.