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PubMed2026

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING: Summit Therapeutics.

Humans↗

PubMed2003

Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis.

This paper extends on previous data on prognosis in multiple sclerosis (MS), to encompass the entire course of the disease. The first episode suggestive of MS [the clinically isolated syndrome (CIS)] was included as a starting point, and the speed of secondary progression as an end point. Primary progressive MS was not included. Unique preconditions, with one neurological service covering the Göteborg district, allowed for establishing a strictly population-based, essentially untreated 15-year incidence cohort of 308 MS patients who were followed for 25 years. Survival analysis was performed as Kaplan-Meyer graphs, and independent predictors were ascertained by Cox regression analysis. A matrix of several predictors and end points was created. From CIS, a higher risk of developing clinically definite MS (CDMS), secondary progressive course and Disability Status Scale 7 (DSS7) was predicted by efferent tract lesions. However, less than 25% had reached DSS7 25 years after CIS with pure afferent lesions or other favorable predictors. During the first five years, higher relapse frequency, as well as incomplete remission of early bouts, predicted higher risks of secondary progressive course and DSS7 during follow-up to 25 years. However, these early predictors were unable to predict the rate of progression, which seems to contain an element of the disease process unassociated with its early events. Only late predictors, such as a shorter time from onset to secondary progression (1-10 years) and a higher number of functional systems involved at onset of progression predicted a faster progression rate. Predictors from this study could be used to refine historically controlled trials.

Adult↗

PubMed2004

Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials.

BACKGROUND: A European (EU) and a North American (NA) placebo-controlled study with interferon beta-1b (IFNB-1b) in secondary progressive multiple sclerosis (SPMS) showed divergent results with regard to their primary outcome of sustained Expanded Disability Status Scale (EDSS) progression, while effects were similar on relapse and MRI-related endpoints. Reasons for this discrepancy were explored in the combined dataset. METHODS: Baseline characteristics and variability in EDSS assessments were compared. Retrospective combined analyses for time to confirmed progression were performed to assess treatment effects overall and in subgroups defined by pre-study disease activity criteria and other key baseline variables. RESULTS: The variance of EDSS measurements was 6.5% higher in the NA-SPMS study. The EU study included patients in an earlier phase of SPMS and with more active disease both pre-study (relapses, MRI) as well as on study (EDSS, relapses, and MRI variables as assessed in the placebo groups). The pooled analysis showed an overall risk reduction by about 20% in patients treated with 8 MIU (250 mcg) IFNB-1b for EDSS progression confirmed at 6 months (p = 0.008). Risk reduction by 30% to 40% was found for patients with at least one relapse or change in EDSS by >1 in the 2 years prior to study entry. No other consistent across-studies relation of clinical and MRI variables at baseline to potential treatment response was found. CONCLUSIONS: Although post hoc, this combined analysis of the two large studies with IFNB-1b in secondary progressive multiple sclerosis suggests that both pronounced disability progression and continuing relapse activity might help in identifying those patients in the secondary progressive phase of the disease who are more likely to benefit from treatment.

Adult↗

PubMed2006

Can selection of rapidly progressing patients shorten clinical trials in amyotrophic lateral sclerosis?

BACKGROUND: The marked variability in progression of amyotrophic lateral sclerosis (ALS) requires large numbers of patients to detect a significant effect in current clinical trial designs. OBJECTIVE: To test the utility of a lead-in period to assess rate of progression so that patients with rapidly progressive ALS can be selected for subsequent clinical trials. DESIGN: Prospective study. SETTING: The ALS Center, University of Lisbon, Lisbon, Portugal. PATIENTS: Fifty-seven consecutively recruited patients assessed at diagnosis and 3 months later (end of lead-in period). INTERVENTIONS: Change in ALS Functional Rating Scale (ALS-FRS) score was analyzed to establish a statistically significant cutoff point to define patients with rapid (group 1) or slow (group 2) progression. Patients from both groups were reexamined 1 and 3 months after the lead-in period. MAIN OUTCOME MEASURES: Changes in ALS-FRS score, motor unit number estimation, and neurophysiologic index, and resultant grouping of patients according to rate of progression at 1 and 3 months. RESULTS: Both the 80th percentile and 2 SDs above the mean of the change in ALS-FRS score identified the same patients. Twelve patients showed rapid progression (group 1) and 45 showed slow progression (group 2). One month after the lead-in period there was a significant reduction in ALS-FRS score, motor unit number estimation, and neurophysiologic index in group 1, and after 3 months all these measurements changed significantly in both groups. CONCLUSIONS: This strategy of selecting patients with rapidly progressing ALS for inclusion in exploratory, short phase II clinical trials offers substantial savings in costs and time, and could accelerate the process of testing potentially useful drugs for the treatment of ALS.

Adult↗

PubMed2001

How many steps of progression of diabetic retinopathy are meaningful? The Wisconsin epidemiologic study of diabetic retinopathy.

OBJECTIVE: To determine whether a 1-step or more or 2-step or more progression on the Early Treatment Diabetic Retinopathy Study retinopathy severity scale over a 4-year period is meaningful in predicting the subsequent incidence of proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME) over the following 6 years. DESIGN: Population-based study of diabetic persons with 10 years of follow-up. SETTING AND PATIENTS: Eleven-county area in southern Wisconsin. There were 1025 persons with diabetes who had fundus photographs at baseline and at 4- and 10-year follow-up examinations. MAIN OUTCOME MEASURES: Incidence of PDR or CSME between the 4- and 10-year follow-up examinations as determined by masked grading of color stereoscopic fundus photographs of 7 standard fields. RESULTS: In a univariate analysis, those with 1 or more steps of progression (n = 551) over the first 4 years of the study were significantly (P<.0001) more likely to develop PDR over the next 6 years than those with no progression (n = 474) (26% vs 4%) (relative risk, 5.85; 95% confidence interval, 4.05-8.47). Similarly, those with 2 or more (n = 364) (33%) or 3 or more (n = 231) (41%) steps of progression over the first 4 years of the study were significantly (P<.0001) more likely to develop PDR over the next 6 years than those with lesser progression (n = 661 [7%] and n = 794 [9%], respectively) (relative risk, 5.10; 95% confidence interval, 3.83-6.80; and relative risk, 4.61; 95% confidence interval, 3.57-5.99, respectively). Similar associations were apparent at every level of retinopathy, duration of diabetes, and glycosylated hemoglobin, and by type of diabetes at baseline. There were also associations between retinopathy progression and incidence of CSME. CONCLUSIONS: It seems that 1 or more or 2 or more steps of progression of retinopathy over a 4-year period strongly predict the development of PDR over the next 6 years. Therefore, using these end points of progression would result in the need for fewer subjects or shorter follow-up in some clinical trials.

Adult↗

PubMed2002

Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.

OBJECTIVE: To provide the results of the Early Manifest Glaucoma Trial, which compared the effect of immediately lowering the intraocular pressure (IOP), vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma. DESIGN: Randomized clinical trial. PARTICIPANTS: Two hundred fifty-five patients aged 50 to 80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, -4 dB), and a median IOP of 20 mm Hg, mainly identified through a population screening. Patients with an IOP greater than 30 mm Hg or advanced visual field loss were ineligible. INTERVENTIONS: Patients were randomized to either laser trabeculoplasty plus topical betaxolol hydrochloride (n = 129) or no initial treatment (n = 126). Study visits included Humphrey Full Threshold 30-2 visual field tests and tonometry every 3 months, and optic disc photography every 6 months. Decisions regarding treatment were made jointly with the patient when progression occurred and thereafter. MAIN OUTCOME MEASURES: Glaucoma progression was defined by specific visual field and optic disc outcomes. Criteria for perimetric progression were computer based and defined as the same 3 or more test point locations showing significant deterioration from baseline in glaucoma change probability maps from 3 consecutive tests. Optic disc progression was determined by masked graders using flicker chronoscopy plus side-by-side photogradings. RESULTS: After a median follow-up period of 6 years (range, 51-102 months), retention was excellent, with only 6 patients lost to follow-up for reasons other than death. On average, treatment reduced the IOP by 5.1 mm Hg or 25%, a reduction maintained throughout follow-up. Progression was less frequent in the treatment group (58/129; 45%) than in controls (78/126; 62%) (P =.007) and occurred significantly later in treated patients. Treatment effects were also evident when stratifying patients by median IOP, mean deviation, and age as well as exfoliation status. Although patients reported few systemic or ocular conditions, increases in clinical nuclear lens opacity gradings were associated with treatment (P =.002). CONCLUSIONS: The Early Manifest Glaucoma Trial is the first adequately powered randomized trial with an untreated control arm to evaluate the effects of IOP reduction in patients with open-angle glaucoma who have elevated and normal IOP. Its intent-to-treat analysis showed considerable beneficial effects of treatment that significantly delayed progression. Whereas progression varied across patient categories, treatment effects were present in both older and younger patients, high- and normal-tension glaucoma, and eyes with less and greater visual field loss.

Adrenergic beta-Antagonists↗

PubMed2003

Using the arteriolar Pressure Attenuation Index to predict ocular hypertension progression to open-angle glaucoma.

BACKGROUND: Vascular phenomena are considered important to optic nerve and visual field progression in open-angle glaucoma (OAG). A recently described formulation, the Pressure Attenuation Index (PAI), links arteriolar caliber variations to pressure loss along the retinal arteriolar system. OBJECTIVE: To examine whether the PAI could predict ocular hypertension (OHT) progression to OAG. METHODS: The PAI was calculated for 27 eyes of 14 patients with OHT using initial and final digitized optic disc photographs taken during a follow-up interval of 5 to 18 years. Serial stereo color disc photographs and visual fields were analyzed to determine progression. RESULTS: At baseline, the arteriolar tree of 8 subjects with OHT that progressed to OAG (n = 8 eyes) demonstrated a 45.8% greater mean PAI value than that of 7 subjects who did not progress (n = 7 eyes) (mean +/- SEM, 5.31 +/- 0.93 vs 3.64 +/- 0.34; r = 0.83). Progression was independent of baseline cup-disc ratio. The PAI values of subjects with stable OHT remained stable after a median follow-up interval of 12.0 years. The PAI values of subjects with OHT that progressed demonstrated a further increase of 19.97% +/- 11.24% during a median follow-up period of 6.0 years. CONCLUSIONS: The results support the hypothesis that low end-arteriolar pressure predicts the progression from OHT to OAG. The PAI provides a new, early, reproducible, and physiological method to study vascular phenomena in glaucoma.

Adult↗

PubMed2003

Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio.

BACKGROUND: Individuals with early or intermediate stages of age-related macular degeneration (AMD) make up a large and growing segment of our elderly population. To advise these high-risk patients regarding preventive measures, we evaluated anthropomorphic, behavioral, and medical factors associated with progression to the advanced stages of AMD associated with visual loss. METHODS: The design was a prospective cohort study in a hospital-based retinal practice. The 261 participants were 60 years or older, with some sign of nonadvanced AMD and visual acuity of 20/200 or better in at least 1 eye. The average follow-up time was 4.6 years, and the total person-years of follow-up was 1198. Factors associated with rates of progression to advanced AMD were assessed by the Cox proportional hazards model. OUTCOME MEASURES: Progression to geographic atrophy and neovascular disease. RESULTS: Higher body mass index (calculated as weight in kilograms divided by the square of height in meters) increased the risk for progression to the advanced forms of AMD. Relative risk (RR) was 2.35 (95% confidence interval [CI], 1.27-4.34) for a body mass index of at least 30, and 2.32 (95% CI, 1.32-4.07) for a body mass index of 25 to 29, relative to the lowest category (<25) after controlling for other factors (P =.007 for trend). Higher waist circumference was associated with a 2-fold increased risk for progression (RR for the highest tertile compared with the lowest, 2.04; 95% CI, 1.12-3.72), with a significant trend for increasing risk with a greater waist circumference (P =.02). Higher waist-hip ratio also increased the risk for progression (RR, 1.84; 95% CI, 1.07-3.15) for the highest tertile compared with lowest (P =.02 for trend). More physical activity tended to be associated with a reduced rate of progression (25% reduction for 3 times per week vigorous activity vs none, P =.05 to P =.07). Relative risks for smoking ranged from 1.48 to 1.99, but were not statistically significant. CONCLUSIONS: Results provide new information regarding modifiable factors for individuals with the early or intermediate stages of this disease. Overall and abdominal obesity increased the risk for progression to advanced AMD, and more physical activity tended to decrease risk. These preventive measures deserve additional research and greater emphasis.

Adipose Tissue↗

PubMed2004

Factors associated with long-term progression or stability in exfoliation glaucoma.

OBJECTIVE: To evaluate the effect of intraocular pressure (IOP) reduction on long-term progression or stability in patients with exfoliation glaucoma. DESIGN: Multicenter (Greece, Spain, Russia, and Hungary), retrospective analysis. METHODS: Medical record analysis of 167 patients with at least 5 years of follow-up, who were stable (n = 85) or whose condition had progressed (n = 82) after the beginning of the follow-up period. RESULTS: The mean +/- SD IOP was 18.1 +/- 2.6 mm Hg in the stable group and 20.1 +/- 4.3 mm Hg in the progressed group (P<.001). The mean +/- SD follow-up time was 6.1 +/- 2.3 years for the stable group and 3.4 +/- 1.7 years for the progressed group. The mean SD for each patient's average IOP was 2.9 mm Hg for the stable group and 4.6 mm Hg for the progressed group (P<.001). Twenty-eight percent of patients who had a mean IOP of 17 mm Hg or lower, 43% of those with an IOP of 18 to 19 mm Hg, and 70% of those with an IOP of 20 mm Hg or higher progressed. Progressed patients had statistically greater optic disc damage at baseline and more medication changes and trabeculectomies during follow-up than stable patients (P<.05). CONCLUSION: This study suggests that IOP reduction helps to prevent glaucoma progression in patients with exfoliation glaucoma, although it does not guarantee the prevention or worsening of the disease.

Aged↗

PubMed1997

Automatic detection of glaucomatous visual field progression with neural networks.

OBJECTIVE: To evaluate computerized neural networks to determine visual field progression in patients with glaucoma. METHODS: Two hundred thirty-three series of Octopus G1 visual fields of 181 patients with glaucoma were collected. Each series was composed of 4 or more reliable visual fields from patients who had previously undergone automated perimetry. The visual fields were independently evaluated in a masked fashion by 3 experienced observers (K.N.-M, M.W., and J.C.) and were judged to show progression based on the agreement of 2 observers. The stable and progressed series were matched for mean defect at baseline. The threshold data were submitted to a back propagation neural network that was trained to classify each series as stable or progressed. Two thirds of the data were used for the training and the remaining one third to test the performance of the network. This was repeated 3 times to classify all of the series (changing the training and test series). RESULTS: Fifty-nine series of visual fields showed progression and 151 were judged stable. Neural network sensitivity was 73% and specificity was 88% (threshold for progression = 0.5). The concordance of the neural network with the observers was good (0.50 < or = kappa > or = 0.64). CONCLUSIONS: A neural network can be trained to recognize visual field progression in good concordance with experienced observers. Neural networks may be used to aid the physician in the evaluation of glaucomatous visual field progression.

Aged↗

PubMed2001

The role of knee alignment in disease progression and functional decline in knee osteoarthritis.

CONTEXT: Knee osteoarthritis (OA) is a leading cause of disability in older persons. Few risk factors for disease progression or functional decline have been identified. Hip-knee-ankle alignment influences load distribution at the knee; varus and valgus alignment increase medial and lateral load, respectively. OBJECTIVE: To test the hypotheses that (1) varus alignment increases risk of medial knee OA progression during the subsequent 18 months, (2) valgus alignment increases risk of subsequent lateral knee OA progression, (3) greater severity of malalignment is associated with greater subsequent loss of joint space, and (4) greater burden of malalignment is associated with greater subsequent decline in physical function. DESIGN AND SETTING: Prospective longitudinal cohort study conducted March 1997 to March 2000 at an academic medical center in Chicago, Ill. PARTICIPANTS: A total of 237 persons recruited from the community with primary knee OA, defined by presence of definite tibiofemoral osteophytes and at least some difficulty with knee-requiring activity; 230 (97%) completed the study. MAIN OUTCOME MEASURES: Progression of OA, defined as a 1-grade increase in severity of joint space narrowing on semiflexed, fluoroscopically confirmed knee radiographs; change in narrowest joint space width; and change in physical function between baseline and 18 months, compared by knee alignment at baseline. RESULTS: Varus alignment at baseline was associated with a 4-fold increase in the odds of medial progression, adjusting for age, sex, and body mass index (adjusted odds ratio [OR], 4.09; 95% confidence interval [CI], 2.20-7.62). Valgus alignment at baseline was associated with a nearly 5-fold increase in the odds of lateral progression (adjusted OR, 4.89; 95% CI, 2.13-11.20). Severity of varus correlated with greater medial joint space loss during the subsequent 18 months (R = 0.52; 95% CI, 0.40-0.62 in dominant knees), and severity of valgus correlated with greater subsequent lateral joint space loss (R = 0.35; 95% CI, 0.21-0.47 in dominant knees). Having alignment of more than 5 degrees (in either direction) in both knees at baseline was associated with significantly greater functional deterioration during the 18 months than having alignment of 5 degrees or less in both knees, after adjusting for age, sex, body mass index, and pain. CONCLUSION: This is, to our knowledge, the first demonstration that in primary knee OA varus alignment increases risk of medial OA progression, that valgus alignment increases risk of lateral OA progression, that burden of malalignment predicts decline in physical function, and that these effects can be detected after as little as 18 months of observation.

Aged↗

PubMed2002

The influence of alignment on risk of knee osteoarthritis progression according to baseline stage of disease.

OBJECTIVE: Varus and valgus malalignment increase the risk of medial and lateral osteoarthritis (OA) progression, respectively. The impact of a mechanical factor such as alignment depends not only on the factor itself, but also on the state of the joint. The less-damaged joint of mild OA may be less vulnerable to malalignment effects than the more-damaged joint of moderate OA. Our goal was to explore the impact of alignment on subsequent progression of knee OA according to the baseline stage of disease. METHODS: Two hundred thirty patients with knee OA (defined by the presence of osteophytes and symptoms) recruited from the community underwent assessment of both lower limbs at baseline and at an 18-month followup. Alignment was measured on a full-limb radiograph as the angle made by the intersection of the femoral and tibial mechanical axes. Compartment-specific progression was defined as an increase between baseline and 18 months in the grade of severity of joint space narrowing on radiographs of semiflexed knees taken after fluoroscopic confirmation of position. Knees were grouped according to their baseline stage of OA as Kellgren/Lawrence (K/L) grades 0-1, 2, or 3. Progression odds ratios were estimated from logistic regression using generalized estimating equations. RESULTS: There were 377 K/L grade 0-3 knees in 230 subjects (173 women and 57 men, mean age 64.0 years, mean body mass index 30.4 kg/m(2)) in this longitudinal study. In knees with mild OA (K/L grade 2), the odds of 18-month progression in the medial compartment were significantly increased 4-fold by varus alignment at baseline. In K/L grade 2 knees, the odds of lateral progression were increased 2-fold by valgus alignment (approaching significance). In knees with moderate OA (K/L grade 3), the risk of progression was comparably increased by varus or valgus alignment (10-fold). CONCLUSION: While some effect of malalignment was suggested at almost all stages of knee OA examined, the impact of varus or valgus malalignment on the odds of OA progression over the ensuing 18 months was greater in knees with moderate (K/L grade 3) OA at baseline, possibly due to greater joint vulnerability with some contribution from slightly more severe malalignment.

Aged↗

PubMed2002

Risk factors for progressive cartilage loss in the knee: a longitudinal magnetic resonance imaging study in forty-three patients.

OBJECTIVE: To evaluate the rate of progression of cartilage loss in the knee joint using magnetic resonance imaging (MRI) and to evaluate potential risk factors for more rapid cartilage loss. METHODS: We evaluated baseline and followup MRIs of the knees in 43 patients (minimum time interval of 1 year, mean 1.8 years, range 52-285 weeks). Cartilage loss was graded in the anterior, central, and posterior regions of the medial and lateral knee compartments. Knee joints were also evaluated for other pathology. Data were analyzed using analysis of variance models. RESULTS: Patients who had sustained meniscal tears showed a higher average rate of progression of cartilage loss (22%) than that seen in those who had intact menisci (14.9%) (P <or= 0.018). Anterior cruciate ligament (ACL) tears had a borderline significant influence (P <or= 0.06) on the progression of cartilage pathology. Lesions located in the central region of the medial compartment were more likely to progress to more advanced cartilage pathology (progression rate 28%; P <or= 0.003) than lesions in the anterior (19%; P <or= 0.564) and posterior (17%; P <or= 0.957) regions or lesions located in the lateral compartment (average progression rate 15%; P <or= 0.707). Lesions located in the anterior region of the lateral compartment showed less progression of cartilage degradation (6%; P <or= 0.001). No specific grade of lesion identified at baseline had a predilection for more rapid cartilage loss (P <or= 0.93). CONCLUSION: MRI can detect interval cartilage loss in patients over a short period (<2 years). The presence of meniscal and ACL tears was associated with more rapid cartilage loss. Cartilage lesions located in the central region of the medial compartment showed more rapid progression of cartilage loss than cartilage lesions in the anterior and posterior portions of the medial compartment. The findings in this study suggest that patients entering clinical trials investigating antiarthritis regimens may need to be randomized based on location of the lesion.

Adolescent↗

PubMed2002

Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study.

OBJECTIVE: Several studies have suggested that increased subchondral bone turnover is a determinant of progression of osteoarthritis (OA). To test this hypothesis, the level of urinary N-terminal type I collagen telopeptides (NTx) and C-terminal type I collagen telopeptides (CTx), which are validated markers of bone resorption, was measured at 3 different time points in a subset of patients from the Chingford study. METHODS: The original Chingford study population comprised 1,003 women. From this group, postmenopausal women not receiving any bone-modifying medication who had a baseline knee radiograph and a repeat radiograph 4 years later, and for whom a baseline lumbar spine bone mineral density (BMD) measurement was available, were identified and separated into 4 groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples collected at baseline, year 1, and year 2. RESULTS: Patient age and years since menopause were similar among groups at baseline. As expected, both body mass index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption marker levels over the 3 time points were 31-87% higher in patients with either progressive OA or osteoporosis than in controls and patients with nonprogressive OA (P < 0.01, except for levels of CTx in patients with progressive OA versus nonprogressive OA). Levels of NTx and CTx did not differ significantly between women with progressive OA (defined either by the presence of osteophytes or by joint space narrowing) and those with osteoporosis or between controls and women with nonprogressive OA. Results were essentially unchanged after adjustment for age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx values at each time point were analyzed separately. CONCLUSION: Our data demonstrate that bone resorption is increased in patients with progressive knee OA and is not increased in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA is similar to that observed in patients with osteoporosis. Altered bone turnover may be a diagnostic or therapeutic target in patients with progressive OA.

Biomarkers↗

PubMed2003

Risk factors for progression of lumbar spine disc degeneration: the Chingford Study.

OBJECTIVE: Few data exist concerning the natural history of lumbar spine disc degeneration and associated risk factors. We therefore undertook this study to examine the radiographic progression of lumbar spine disc degeneration over the course of 9 years in a population-based inception cohort of women from the Chingford Study. METHODS: Seven hundred ninety-six paired lumbar spine radiographs were read by a single reader for anterior osteophytes (AO) and disc space narrowing (DSN) using the Lane atlas at each lumbar disc space (L1-5). Disc degeneration was defined using thresholds of AO and DSN grade 1+ in one or more vertebrae (L1-5) within a subject. Progression was defined as an increase in grade in an affected year-1 vertebra. Potential risk factors were assessed using odds ratios and 95% confidence intervals adjusted for age, body mass index (BMI), and other potential confounders in logistic regression models using the STATA statistical package. RESULTS: The mean +/- SD age at baseline was 53.8 +/- 6.0 years, and mean +/- SD BMI was 25.4 +/- 4.1 kg/m(2). Progression rates for AO and DSN were 4% per annum and 3% per annum, respectively. Progression of DSN was predicted by age, back pain, and radiographic hip and knee osteoarthritis (OA). Progression of AO was predicted by age and radiographic hip OA, with borderline significance for BMI >30 kg/m(2). No significant effects were seen for smoking, physical activity, hormone replacement therapy use, multiparity, or hand OA. CONCLUSION: This is the first population-based longitudinal study to assess progression of the individual radiographic features of AO and DSN in lumbar spine disc degeneration. We demonstrated progression rates of 3-4% per annum, with important risk factors for progression, including age, back pain, and radiographic OA at the hip and knee.

Disease Progression↗

PubMed2006

Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.

OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups.

Adult↗

PubMed2004

Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis.

Hepatic fibrosis and cirrhosis are possible consequences of corticosteroid-treated autoimmune hepatitis. Our aims were to determine the frequency of progressive fibrosis and the factors associated with this progression. Two hundred seventy-seven liver tissue specimens that had been obtained from 73 patients were interpreted in batch under code by a single pathologist. Fibrosis scores and histological activity indices were determined using the Ishak scoring system, and worsening fibrosis scores were correlated with clinical features, laboratory findings, and treatment responses. Fibrosis scores increased (2.3 +/- 0.4 points to 4.2 +/- 0.4 points; P <.0001) in 18 patients (25%) during 79 +/- 13 months. Only five patients (7%) developed cirrhosis, and 55 patients (75%) had stable (16 patients) or decreased (39 patients) fibrosis scores. Human leukocyte antigen (HLA) DR3/DR4 occurred more frequently in patients with progressive fibrosis than others (23% vs. 2%; P =.03). Patients with progressive fibrosis had higher histological activity indices at last follow-up than patients with stable or reduced fibrosis (3.2 +/- 0.7 vs. 1.7 +/- 0.2; P =.01), and these indices worsened more commonly during therapy (17% vs. 2%, P =.04). Relapse, treatment failure, and incomplete response did not affect progression of fibrosis. In conclusion, fibrosis progresses in only a minority of patients during corticosteroid therapy. Progression is associated with HLA DR3/DR4 and worsening histological activity. Exacerbations or persistence of disease activity does not increase disease progression after treatment has been instituted.

Disease Progression↗

PubMed2007

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis.

UNLABELLED: The predictive role of antinuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end-point, positive anti-gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti-centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. CONCLUSION: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive-anti-gp210 and positive-anticentromere antibodies, respectively.

Adult↗