How should worsening in osteoarthritis be defined? Development and initial validation of preliminary criteria for clinical worsening in knee and hip osteoarthritis.

OBJECTIVES: There is a need to define and validate measures of clinical worsening in knee and hip osteoarthritis (OA). The objectives of this exploratory project were: (i) to characterize worsening criteria in knee and hip OA using psychometric methods; (ii) to estimate their sensitivity and specificity; and (iii) to validate and compare these criteria with worsening criteria previously described in the literature. METHOD: An Expert Group reached consensus on 10 sets of worsening criteria to be tested in observational data sets of patients with knee or hip OA who received multimodal conservative treatment. These sets included 219 patients (derivation cohort) and 296 patients (validation cohort). We estimated minimal clinically important worsening (MCIW) values for pain, function, stiffness, and patient global assessment, and tested candidate worsening criteria in the derivation cohort. Finally, using patient judgement, we examined the sensitivity and specificity of literature-based as well as candidate worsening criteria in the validation cohort. RESULTS: Literature-based worsening criteria were found to have high specificity (range 60-92%) but low sensitivity (range 22-59%). Two out of 10 candidate worsening criteria constructed by the Expert Group showed an acceptable combination of sensitivity and specificity in the derivation cohort, which was confirmed in the validation cohort (ranging from 54% to 65% and 67% to 74%, respectively). CONCLUSIONS: This is the first study to describe symptomatic worsening criteria based on expert consensus after examining the performance of candidate criteria derived from the literature applied to data in an observational study. The newly proposed worsening criteria show an acceptable combination of sensitivity and specificity.

Adherence with bisphosphonate therapy and change in bone mineral density among women with osteoporosis or osteopenia in clinical practice.

UNLABELLED: In clinical practice, adherence with bisphosphonate therapy varies greatly among women with osteoporosis or osteopenia. Our study suggests that better adherence with bisphosphonates confers tangible benefits in terms of graded increases in bone mineral density. Interventions to improve drug adherence should be an important component of disease management. INTRODUCTION: In clinical trials, bisphosphonates have been found to increase bone mineral density (BMD) in women with osteoporosis or osteopenia. In clinical practice, where drug adherence is more variable, change in BMD with bisphosphonate therapy-overall and by level of adherence-is largely unknown. METHODS: A retrospective cohort study was conducted at Henry Ford Health System (Detroit, MI, USA). Study subjects were women who had low BMD at the left total hip (T-score<-1.0), began oral bisphosphonate therapy, and had ≥1 BMD measurements at the left total hip≥6 months following treatment initiation. Change in BMD was calculated between the most recent pretreatment scan and the first follow-up scan. Adherence (i.e., medication possession ratio (MPR)) was measured from therapy initiation to the first follow-up scan. RESULTS: Among 644 subjects, mean age was 66 years, pretreatment BMD was 0.73 g/cm2, and pretreatment T-score was -1.8. Over a mean follow-up of 27.1 months, mean MPR was 0.57 (95% CI, 0.54 and 0.59), and mean percentage change in BMD was 1.5% (1.1 and 1.9%). Within the MPR strata (five consecutive equi-intervals, from low (0-0.19) to high (0.80-1.0)), mean change in BMD was -0.8% (-1.6 and 0.1%), 0.7% (-0.3 and 1.7%), 2.1% (1.1 and 3.0%), 2.1% (1.4 and 2.9%), and 2.9% (2.3 and 3.5%), respectively. In adjusted analyses, percentage change in BMD was higher (by 1.4-3.4%, p<0.05 for all) in the highest four MPR intervals, respectively, versus MPR 0-0.19. CONCLUSIONS: Among women with osteoporosis or osteopenia in clinical practice, better adherence with bisphosphonates appears to confer tangible benefits in terms of increases in BMD.

Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.

Psoriasis is a hyperproliferative and inflammatory skin disorder of unknown aetiology. A fusion protein composed of human interleukin-2 and fragments of diphtheria toxin (DAB389IL-2), which selectively blocks the growth of activated lymphocytes but not keratinocytes, was administered systemically to ten patients to gauge the contribution of activated T cells to the disease. Four patients showed striking clinical improvement and four moderate improvement, after two cycle of low dose IL-2-toxin. The reversal of several molecular markers of epidermal dysfunction was associated with a marked reduction in intraepidermal CD3+ and CD8+ T cells, suggesting a primary immunological basis for this widespread disorder.

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study.

BACKGROUND: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. OBJECTIVE: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. METHODS: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. RESULTS: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively. CONCLUSION: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

The American English version of the validated French Flare Assessment in RA Questionnaire (FLARE-RA).

OBJECTIVE: To evaluate use of a British English version of the validated French FLARE-RA questionnaire among American English speaking patients. In addition, to create a culturally adapted American English (AmE) FLARE-RA questionnaire and to examine its attributes of patient-reported RA flare status. METHODS: Using standardized cultural adaptation guidelines, we cognitively debriefed 25 American English speaking rheumatoid arthritis (RA) outpatients and created AmE-FLARE-RA with their input. One hundred three additional RA patients were recruited. Patients completed the Routine Assessment of Patient Index Data 3 (RAPID3), patient global visual analogue scale (VAS), AmE-FLARE-RA, and self-reports of flare. Physician global VAS, physician-assessed flare, swollen and tender joint count (TJC), and clinical disease activity index (CDAI) were documented. AmE-FLARE-RA and disease activity measures were compared between patient-reported and physician-reported flare categories. RESULTS: Patients were female (89%), with mean (SD) age 51.1 (± 15.3) years and mean disease duration (SD) 11.9 (± 10.1) years, with 26% in remission/low disease activity. Total AmE-FLARE-RA scores, RAPID3, CDAI, and patient global VAS were significantly higher for both patient-reported flares and physician-reported flares compared with non-flaring patients by self- or physician report (p < 0.05). Total AmE-FLARE-RA scores correlated significantly with RAPID3 (corr = 0.50, p < 0.0001) and with CDAI (corr = 0.45, p < 0.0001). Across "no flares," "one flare," and "several flare" groups, there was a non-significant increase in AmE-FLARE-RA scores (p = 0.07). CONCLUSION: The British English FLARE-RA was successfully adapted for AmE-speaking RA patients. AmE-FLARE-RA significantly correlated with RAPID3 and CDAI and distinguished between patient-reported and physician-reported flares, making it useful to detect flares in American RA patients.Key Points• The American English FLARE-RA (AmE-FLARE-RA) questionnaire is the result of cognitive debriefing with American RA patients using the British English version of the validated French FLARE-RA and incorporates patient-recommended language modifications..• Patients self-reporting flares had significantly higher AmE-FLARE-RA scores, compared with those without flares at the time of visit. AmE-FLARE-RA scores correlate with RAPID3 and CDAI.• There was a non-statistically significant trend using the AmE-FLARE-RA scores when examining patients with no flare, one flare, or several flares.• AmE-FLARE-RA total scores are uniformly elevated (~ 6.0 on a 0-10 scale), regardless of discordance between patient and MD assessment of flare at time of visit (~ 30%).

Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers.

DAB486IL-2, a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with interleukin-2 (IL-2), has displayed significant activity in patients with chemotherapy refractory hematological cancers. To further investigate the safety and antitumor effect of this agent, we conducted a single arm, dose escalation study of a 90-min infusion of DAB486IL-2 daily for 5 days. Patients with cancers of a histology previously reported to express the p55 component of the IL-2 receptor and who could not receive potentially more effective therapy were eligible for enrollment. Fifteen men and 8 women with a median age of 49 years were given a total of 51 courses of DAB486IL-2. The maximum tolerated dose was 0.3 mg/kg/day defined by renal insufficiency associated with hemolysis and thrombocytopenia. The clearance of DAB486IL-2 from serum fit a one-compartment model with a half-life of 11.5 +/- 4.3 (SD) min at the 0.2-mg/kg dose. Two patients sustained a partial response and 4 patients had tumor reduction not qualifying for an objective response. No tumors that were negative for expression of the p55 subunit of the receptor responded to DAB486IL-2 treatment. Reduction in size occurred in 2 tumors in which p55 expression was unknown and 4 patients with tumors that were known to be p55 positive. Dosing determined by specific activity rather than mass also appeared to be an important determinant of response. This study suggests that the presence of p55 expression on tumor cells is necessary, but alone may not be sufficient to achieve a tumor response. The correlation of additional variables such as specific activity of DAB486IL-2 and tumor expression of the p75 subunit of the IL-2 receptor and receptor function will also require further study.

Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug-Adverse Event Association.

The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment.

Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma.

PURPOSE: A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. PATIENTS AND METHODS: Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. RESULTS: Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. CONCLUSION: The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.

Severe glomerulonephritis with late emergence of classic Wegener's granulomatosis. Report of 4 cases and review of the literature.

We have analyzed an unusual group of 19 patients (15 previously reported) with Wegener's granulomatosis, who presented with severe glomerulonephritis and developed diagnostic respiratory lesions only after 4 to 78 months. Necrotizing glomerulonephritis, often with crescents, and rarely with vasculitis, was the predominant renal lesion. Wegener's granulomatosis was unsuspected initially, since systemic manifestations, such as fever, arthralgias, malaise, and even pulmonary hemorrhage, were nonspecific or transient, and because renal biopsy findings resembled those seen in microscopic polyarteritis or idiopathic crescentic nephritis. Despite therapy, usually with corticosteroids, only 4 patients maintained adequate renal function. Most patients were receiving chronic dialysis when respiratory involvement developed. Cavitary nodular pulmonary infiltrates were seen in 12 of the 17 patients with lung involvement, and otorhinological disease occurred in 10 patients. Arthralgias, fever, and cough, with or without hemoptysis, were common. Wegener's granulomatosis was diagnosed by lung biopsy in 15 cases and by nasal biopsy in 4. Specific treatment was required for the respiratory disease and was delayed in many patients, because of lack of awareness that Wegener's granulomatosis may present with primary glomerulonephritis and become active during chronic renal failure or dialysis. Nevertheless, all but 1 patient eventually responded to treatment, although 3 additional patients died of late complications.

Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis.

Immunocytochemical analyses of human plaques and experimental arterial lesions have implicated activated lymphocytes and monocytes in the pathogenesis of atherosclerosis, as demonstrated by the expression of interleukin-2 (IL-2) membrane receptors and major histocompatibility complex class II epitopes. The objective is to determine if targeting these cells with an IL-2 receptor-specific chimeric toxin, DAB486-IL-2, can inhibit experimental post-angioplasty vascular neointimal thickening. Twenty-two atherogenically modeled rabbits were treated in vivo with DAB486-IL-2 (0.1 mg/kg per day i.v.; n = 11) or placebo (n = 11) for 10 days following aortic balloon angioplasty (4 atm x 30 s each x 2 dilatations). In vitro 3H-leucine incorporation studies of mononuclear leukocyte and vascular smooth muscle cell protein synthesis inhibition by DAB486-IL-2 were also performed. Angioplasty sites were examined for evidence of hyperproliferative atherosclerotic narrowing by quantitative angiography and histomorphometry of neointimal cross-sectional area at baseline and 6 weeks after injury. In vitro Concanavalin-A stimulated rabbit mononuclear leukocyte protein synthesis was 50% inhibited by DAB486-IL-2 at a concentration (IC50) of 6 x 10(-11) M. Rabbit vascular smooth muscle cells were approximately 150-fold less sensitive to DAB486-IL-2 (IC50 = 10(-8) M). In vivo studies showed no change in angioplasty site angiographic minimum luminal diameter at 6 weeks in DAB486-IL-2 treated animals (from 2.96 +/- 0.52 to 2.96 +/- 0.48 mm; percent cross-sectional area reduction = 1 +/- 10%; P = N.S.). In control animals, luminal diameter decreased from 2.79 +/- 0.4 to 2.32 +/- 0.52 mm at 6 weeks, and percent cross-sectional area was reduced by 34 +/- 14% (P < 0.01 vs. placebo). Quantitative histomorphometric angioplasty segmental intimal cross-sectional area reduction of treated and placebo vessels also differed significantly (19 +/- 16% vs. 31 +/- 21%; P < 0.05). DAB486-IL-2 caused no adverse effects on animal survival, weight or hepatic transaminase levels. We conclude that post-angioplasty administration of the chimeric toxin DAB486-IL-2 inhibits angiographic narrowing and neointimal thickening in the atherogenic rabbit model. Although this IL-2 receptor-specific molecule was cytotoxic in vitro for activated mononuclear leukocytes and vascular smooth muscle cells, systemic toxicity did not occur in vivo at a dose comparable to that evaluated in clinical trials of this agent. Potential anti-proliferative effects of this chimeric toxin may be mediated by direct local inhibition of leukocyte-mediated inflammation, or through the indirect modification of vascular cell mitogenesis and cytokine release.

Phase I trial of the diphtheria toxin/interleukin-2 fusion protein DAB486IL-2: efficacy in mycosis fungoides and other non-Hodgkin's lymphomas.

The purpose of this study was to investigate the biologic activity of DAB486IL-2 when administered three times daily, in terms of toxicity, pharmacokinetics, and anti-tumor effects in patients with IL-2R expressing hematologic malignancies, especially mycosis fungoides. 20 patients were enrolled in this dose escalation phase I trial. Patient cohorts were treated at levels of 0.03 mg/kg, 0.05 mg/kg, 0.07 mg/kg and 0.09 mg/kg every 8 hours for a total of 12 doses, every 21 days as toxicity and response warranted. Eight patients experienced transient fevers associated with DAB486IL-2 administration. One patient experienced grade 3 hypotension, and a second developed fluid retention manifested as weight gain/pedal edema. Dose limiting toxicity consisted of one episode of transient grade 4 hepatic transaminase elevation, and 8 episodes of transient asymptomatic grade 3 hepatic transaminase elevation. At the maximum tolerated dose DAB486IL-2 exhibited biphasic clearance kinetics; transient receptor saturation may be one mechanism for this observation. Initial serum concentration and apparent steady state level (plateau) directly correlated with the dose administered, but no difference in area under the concentration curve with greater dose was observed. Biologic activity was noted in patients with mycosis fungoides with skin lesion clearing and relief of pruritus. One patient with mycosis fungoides, and one patient with a relapsed intermediate grade non-Hodgkin's lymphoma achieved partial responses. The novel mechanism of action, toxicity profile, and evidence of biologic activity in refractory cancer patients, support development of more active constructs of this agent; such trials are underway.

Phase I trial of a genetically engineered interleukin-2 fusion toxin (DAB486IL-2) as a 6 hour intravenous infusion in patients with hematologic malignancies.

DAB486IL-2 is a recombinant fusion toxin, created by replacement of the receptor binding domain sequences of the diphtheria toxin gene with the sequences for human interleukin-2 (IL-2). It selectively binds to and intoxicates cells expressing the high-affinity IL-2 receptor. A total of 17 patients with refractory hematologic malignancies were entered in a phase I study of DAB486IL-2, administered as a 6 hour continuous intravenous infusion on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle. Cohorts of 3 to 6 patients were treated with escalating doses. The starting dose was 0.1 mg/kg/day with increments of 0.1 mg/kg/day per dose level up to 0.3 mg/kg/day. Significant adverse effects included transient asymptomatic elevation of liver transaminases, hypersensitivity, anemia, thrombocytopenia, fever, and creatinine elevation. A partial response of approximately nine months duration was observed in a patient with small cell lymphocytic non-Hodgkin's lymphoma, previously refractory to high-dose chemotherapy and autologous bone marrow transplantation. The observance of antitumor activity in a patient highly refractory to chemotherapy suggests that DAB486IL-2 may have efficacy in selected patients whose malignant cells express the IL-2 receptor.

Health status response of rheumatoid arthritis to treatment with DAB486IL-2.

OBJECTIVE: To examine and compare health status and disease activity changes in patients with rheumatoid arthritis (RA) in a clinical trial of the biologic agent DAB486IL-2. METHODS: Data on 45 patients with RA who were enrolled in a multicourse, double-blind trial, consisting of a first, placebo-controlled, course followed by open-label treatment with the active agent to a total of 3 active courses, were examined for evidence of improvement in health status (measured using the 5 components of the Arthritis Impact Measurement Scales 2 [AIMS2]) and disease activity (measured using standard clinical measures and erythrocyte sedimentation rate). RESULTS: Over a single course of treatment, DAB486IL-2-treated patients showed significant improvement relative to placebo-treated patients on the symptom and social components of AIMS2 and in patient's assessment of disease activity. With subsequent open-label courses of treatment with DAB486IL-2, all 5 AIMS2 health status components and the disease activity measures of tender and swollen joint counts, grip strength, and the observer and patient assessments showed steady and generally parallel improvement. CONCLUSION: Short-term health status effects of this biologic agent were detected using the AIMS2.

Recombinant fusion toxins--a new class of targeted biologic therapeutics.

The design and construction of a new class of recombinant therapeutic agents, receptor-specific cytotoxins, has occurred within the last 5 years. Development of a number of receptor-targeted fusion toxins has been based on a detailed understanding of the structure-function relationships of both diphtheria toxin and Pseudomonas exotoxin A, and availability of the nucleic acid sequences of each structural gene. A variety of fusion toxins in which the native receptor-binding domain of either diphtheria toxin or Pseudomonas exotoxin A has been genetically replaced with either a polypeptide hormone or growth factor have been constructed. These fusion toxins selectively intoxicate receptor-bearing cells in vitro and are active in a variety of animal model systems. DAB486IL-2, and IL-2 receptor targeted cytotoxin, is the first fusion toxin to be evaluated in patients. Phase I/II clinical trials have been performed in refractory leukemia/lymphoma, severe rheumatoid arthritis, and Type 1 diabetes. DAB486IL-2 has been administered to more than 200 patients, has been well tolerated, and has shown encouraging signs of potential efficacy in all three clinical indications. Thus, DAB486IL-2 represents a new class of targeted biological therapeutic response modifiers whose mode of action is based on selective elimination of target cells.

Early clinical studies of IL-2 fusion toxin in patients with severe rheumatoid arthritis and recent onset insulin-dependent diabetes mellitus.

DAB486IL-2 is the first of a new class of targeted biologicals called fusion toxins. This agent is an interleukin-2 receptor (IL-2R)-targeted cytotoxin which kills activated IL-2R-expressing lymphocytes at 10(-10) M concentrations. Since activated lymphocytes are thought to play a role in many autoimmune conditions, DAB486IL-2 has been evaluated in patients with severe rheumatoid arthritis and recent onset autoimmune insulin-dependent diabetes mellitus. Initial safety, pharmacokinetics and evidence of IL-2R specific cytotoxicity were obtained in patients with IL-2 receptor expressing malignancies; these studies served as a basis for the initiation of an open label phase I/II evaluation of DAB486IL-2 in patients with severe, methotrexate refractory rheumatoid arthritis. This pilot study provided preliminary evidence of acceptable safety at doses which induced meaningful (> 25%) or substantial (> 50%) improvement in 9 of 18 patients who received a mid (130 kU/kg/d) or a high (260 kU/kg/d) dose daily for 5 to 7 days. The most frequent adverse effects were transient hepatic transminase elevation and fever. Although some patients noted a transient increase in joint pain, onset of improvement occurred within 7 to 14 days of initiation of DAB486IL-2. Because of these results, a two-center, double-blind, placebo-controlled trial was conducted from December 1991 to December 1992. Forty-five patients with active severe RA unresponsive to at least 2 DMARDS were randomized to placebo or DAB486IL-2 following a 3 to 4 week washout/run-in period to establish a stable baseline (< 40% fluctuation in swollen and painful, tender joint counts).(ABSTRACT TRUNCATED AT 250 WORDS)

Responsiveness, effect size, and smallest detectable difference of Magnetic Resonance Imaging in knee osteoarthritis.

OBJECTIVE: The aim of this study was to determine the responsiveness, effect size (ES) and smallest detectable difference (SDD) of two Magnetic Resonance Imaging (MRI) measures for osteoarthritis (OA) of the knee: a whole-organ semiquantitative evaluation and cartilage volume. DESIGN: This analysis was performed on a dataset from a randomized, double-blind trial (Roche NI-15713) conducted in 1998 of a novel therapy in subjects with mild-moderate knee OA, with MRI at baseline and 6-month follow-up. The trial measurements included (1) cartilage volume measured using a proprietary software method; and (2) semiquantitative scoring of other parameters important for "whole organ" evaluation of OA knee joint pathology, using the Whole-Organ MRI Score (WORMS). The analysis initially examined the distributional characteristics of WORMS items, such as cartilage morphology. Standardized response mean (SRM), ES, and SDD between baseline and 6-month follow-up were then calculated in the whole group and the placebo group alone. RESULTS: In general, the differences were small and this was reflected in the small ESs and SRMs. There was also a suggestion of a treatment effect with reduction in differences between baseline and follow-up in the treatment group. CONCLUSION: Of the MRI semiquantitative measures, cartilage morphology, synovitis and osteophytes appeared to be responsive to change and the focus of repeat measures should highlight these articular features. In general, the ESs and SRMs were small.

Assessment of the radioanatomic positioning of the osteoarthritic knee in serial radiographs: comparison of three acquisition techniques.

OBJECTIVE: Recent studies using various standardized radiographic acquisition techniques have demonstrated the necessity of reproducible radioanatomic alignment of the knee to assure precise measurements of medial tibiofemoral joint space width (JSW). The objective of the present study was to characterize the longitudinal performance of several acquisition techniques with respect to long-term reproducibility of positioning of the knee, and the impact of changes in positioning on the rate and variability of joint space narrowing (JSN). METHODS: Eighty subjects were randomly selected from each of three cohorts followed in recent studies of the radiographic progression of knee osteoarthritis (OA): the Health ABC study (paired fixed-flexion [FF] radiographs taken at a 36-month interval); the Glucosamine Arthritis Intervention Trial (GAIT) (paired metatarsophalangeal [MTP] radiographs obtained at a 12-month interval), and a randomized clinical trial of doxycycline (fluoroscopically assisted semiflexed anteroposterior (AP) radiographs taken at a 16-month interval). Manual measurements were obtained from each radiograph to represent markers of radioanatomic positioning of the knee (alignment of the medial tibial plateau and X-ray beam, knee rotation, femorotibial angle) and to evaluate minimum JSW (mJSW) in the medial tibiofemoral compartment. The effects on the mean annualized rate of JSN and on the variability of that rate of highly reproduced vs variable positioning of the knee in serial radiographs were evaluated. RESULTS: Parallel or near-parallel alignment was achieved significantly more frequently with the fluoroscopically guided positioning used in the semiflexed AP protocol than with either the non-fluoroscopic FF or MTP protocol (68% vs 14% for both FF and MTP protocols when measured at the midpoint of the medial compartment; 75% vs 26% and 34% for the FF and MTP protocols, respectively, when measured at the site of mJSW; P<0.001 for each). Knee rotation was reproduced more frequently in semiflexed AP radiographs than in FF radiographs (66% vs 45%, P<0.01). In contrast, the FF technique yielded a greater proportion of paired radiographs in which the femorotibial angle was accurately reproduced than the semiflexed AP or MTP protocol (78% vs 59% and 56%, respectively, P<0.01 for each). Notably, only paired radiographs with parallel or near-parallel alignment exhibited a mean rate of JSN (+/-SD) in the OA knee that was more rapid and less variable than that measured in all knees (0.186+/-0.274 mm/year, standardized response to mean [SRM]=0.68 vs 0.128+/-0.291 mm/year, SRM=0.44). CONCLUSION: This study confirms the importance of parallel radioanatomic alignment of the anterior and posterior margins of the medial tibial plateau in detecting JSN in subjects with knee OA. The use of radiographic methods that assure parallel alignment during serial X-ray examinations will permit the design of more efficient studies of biomarkers of OA progression and of structure modification in knee OA.

Examining a whole-organ magnetic resonance imaging scoring system for osteoarthritis of the knee using Rasch analysis.

OBJECTIVE: The ability to reliably quantify all the structural abnormalities in osteoarthritis (OA) of the knee is a long-standing goal of OA research. On December 5 and 6, 2002, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society, International held a Workshop for Consensus on Osteoarthritis Imaging in Bethesda, MD, with the aim of providing a state-of-the-art review of imaging outcome measures for OA of the knee. As part of the Workshop, data from previous clinical trials and epidemiological studies of OA were analysed with respect to the metrological properties of the measurement methods used. The following report outlines the results of analyses aimed at evaluating the internal construct validity of a whole-organ, ordinal (semi-quantitative) magnetic resonance imaging score (WORMS) using Rasch analysis. The fit of data to the Rasch model offers a measure of the validity of summing different items into a subscale score and the degree to which this score behaves as a unidimensional, interval level measurement tool. METHODS: The Rasch model was applied in two OA studies. The first was a clinical cohort comprising OA knee subjects entering a clinical trial; study entry criteria included patients with at least moderate pain, radiographic osteophytes and a minimum of 1.5mm tibiofemoral joint-space width. The second cohort was from the Boston Osteoarthritis Knee Study, an observational cohort of subjects with symptomatic knee OA with pain on most days and a definite osteophyte in either the tibiofemoral or patellofemoral joints. Baseline WORMS scores from both studies were used for the Rasch analysis, performed with RUMM 2020 software. RESULTS: There was a substantial proportion of subjects in both study populations with zero scores in several of the subscales of WORMS. Few of the subscales met the requirements of the Rasch measurement model when summated across all sites, and summations of some postulated compartmentally based sites also failed to fit the Rasch model. The existing scoring categories also required rescoring at many sites. CONCLUSION: There remain important issues in constructing outcome measurements that summate different features across multiple anatomical sites. The whole-organ scoring system evaluated here is no exception. Resolving these issues will improve the ability of imaging studies to assess complex pathological structural change.

Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of a 1 year longitudinal arthroscopic study in 422 patients.

OBJECTIVE: To evaluate the prevalence of synovitis in painful medial tibiofemoral knee osteoarthritis (OA) and to evaluate correlation between synovitis and the structural severity and progression of tibiofemoral cartilage damage. STUDY: Multicenter, longitudinal, 1-year duration. PATIENTS: Primary painful knee OA (ACR criteria) of the medial tibiofemoral compartment, with pain of the signal knee on at least 30 days in the past 2 months, medial joint space width > or = 2mm, at least 10% of one cartilage surface of the medial compartment affected by superficial fibrillation or worse at baseline arthroscopy. ARTHROSCOPIC PARAMETERS: Knee arthroscopy under local anesthesia was performed and videorecorded at entry and after 1 year. Medial chondropathy was scored by using Societe Francaise d'Arthroscopie (SFA) score (0-100) and reader's overall assessment (VAS score, 100 mm). Progression of medial chondropathy was defined by a change in SFA and VAS scores over 4.5 and 8.0 mm after 1 year, respectively. Medial perimeniscal synovium was scored as normal (few translucent and slender villi, fine vascular network), reactive (proliferation of opaque villi), or inflammatory (hypervascularization and/or proliferation of hypertrophic and hyperemic villi). Medial chondropathy and synovitis were scored by a single reader blind to chronology of paired videotapes. RESULTS: Four hundred and twenty-two patients were enrolled (mean age: 61 years, females: 59%, body mass index: 31, mean disease duration: 4 years) and completed the 1-year study. Synovial abnormalities were present in 50% of the patients with reactive and inflammatory aspects in 29% and 21% of the patients, respectively. Patients with a reactive or inflammatory medial synovium had a more severe medial chondropathy. The worsening in medial chondropathy after 1 year was statistically more severe in the group of patients with an inflammatory perimeniscal synovial membrane at baseline compared to patients with normal and reactive aspects, with no difference between these two latter groups. The odds ratio for progression in VAS score after 1 year was 3.11 (95% CI [1.07, 5.69]) for patients with inflammatory synovium at baseline compared to patients with normal synovium. CONCLUSIONS: This study suggests that abnormalities of the medial perimeniscal synovium are a common feature of painful medial knee OA, associated with more severe medial chondropathy. It also suggests that an inflammatory aspect of the medial perimeniscal synovium could be considered as a predictive factor of subsequent increased degradation of medial chondropathy.

Biological factors affecting enflagellation of Naegleria fowleri.

Naegleria fowleri is a pathogenic amoeboflagellate that can be evoked to transform from amoebae to flagellates by subculture to nonnutrient buffer. More than half of the amoebae of strains KUL, nN68, and Lovell became enflagellated 300 min after subculture to amoeba-saline, whereas no amoebae of strains NF66, NF69, and HB4 did. N. fowleri nN68 enflagellated best when grown at 32 or 37 degrees C and subcultured to amoeba-saline at 37 or 42 degrees C. Amoebae from the stationary phase of growth enflagellated more readily than did actively growing amoebae. Incubation in expended culture medium from stationary-phase cultures enhanced the capability of growing amoebae to enflagellate after subculture to amoebasaline. Enflagellation was more extensive when the population density in amoebasaline did not exceed 2 x 10(5) amoebae per ml. Cycloheximide at 1 microgram/ml and actinomycin D at 25 micrograms/ml inhibited growth of N. fowleri nN68. Cycloheximide at 0.5 microgram/ml and actinomycin D at 25 micrograms/ml completely prevented enflagellation when added at time zero. Cycloheximide at 0.5 microgram/ml, added 120 to 300 min after initiation of enflagellation, prevented further differentiation and caused existing flagellates to revert to amoeboid cells. Similarly, actinomycin D at 25 micrograms/ml, added 90 to 300 min after initiation of enflagellation, retarded differentiation and caused flagellates to revert. Radiolabeled precursors were incorporated into macromolecules during differentiation in nonnutrient buffer. Enflagellation of N. fowleri is a suitable model for studying regulation of a eucaryotic protist.