The Prognostic Potential of End-Stage Knee Osteoarthritis and Its Components to Predict Knee Replacement: Data From the Osteoarthritis Initiative.

OBJECTIVE: We aimed to determine how 2 definitions of end-stage knee osteoarthritis (esKOA) and each component (knee symptoms, persistent knee pain, radiographic severity, and presence of limited mobility or instability) related to future knee replacement (KR). METHODS: We performed knee-based analyses of Osteoarthritis Initiative data from baseline to the first 4 annual follow-up visits, and data on KR from baseline until the fifth yearly contact. We calculated a base model using common risk factors for KR in logistic regression models with generalized estimating equations. We assessed model performance with area under the receiver-operating characteristic curve (AUC) and Hosmer-Lemeshow test. We then added esKOA or each component from the visit (< 12 months) before a KR and change in the year before a KR. We calculated the net reclassification improvement (NRI) index and the integrated discrimination improvement (IDI) index. RESULTS: Our sample was mostly female (58%), ≥ 65 years old, White (82%), and without radiographic knee osteoarthritis (50%). At the visit before a KR, Kellgren-Lawrence (KL) grades (ordinal scale; AUC 0.88, NRI 1.12, IDI 0.11), the alternate definition of esKOA (AUC 0.84, NRI 1.16, IDI 0.12), and a model with every component of esKOA (AUC 0.91, NRI 1.30, IDI 0.17) had the best performances. During the year before a KR, change in esKOA status (alternate definition) had the best performance (AUC 0.86, NRI 1.24, IDI 0.12). CONCLUSION: Radiographic severity may be a screening tool to find a knee that will likely receive a KR. However, esKOA may be an ideal outcome in clinical trials because a change in esKOA state predicts future KR.

The natural history of end-stage knee osteoarthritis: Data from the osteoarthritis initiative.

OBJECTIVE: We aimed to describe the natural history leading to end-stage knee osteoarthritis (esKOA), focusing on knee symptoms, radiographic severity, and the presence of limited mobility or instability. METHODS: We performed knee-based analyses of Osteoarthritis Initiative data from 7691 knees (4165 participants). We used a validated definition of esKOA that relied on meeting one of two criteria: (1) severe radiographic knee osteoarthritis (Kellgren-Lawrence [KL] grade=4) with moderate-to-intense pain (Likert WOMAC pain+function>11/88) or (2) KL grade<4 with intense or severe pain (WOMAC pain+function>22) and limited mobility (flexion contracture≥5°) or instability (based on a varus and valgus stress test). We also introduced an alternate definition of esKOA that relied on meeting one of two criteria that omitted physical exam findings:(1) severe radiographic knee osteoarthritis (KL grade=4) with at least moderate symptoms or (2) KL grade=2 or 3 with intense or severe symptoms and persistent knee pain (frequent knee pain during three or more months in the past year). We used descriptive statistics to explore the frequency of components of esKOA at the index visit when they had incident esKOA, at the annual visit before developing esKOA, and the interval change between those visits. RESULTS: Our analytic sample was mostly female (58%), without radiographic knee osteoarthritis (KL grade=0 or 1; 60%), without stability or mobility concerns (91%), and without persistent knee pain (77%). At the visit before incident esKOA, most knees already had moderate-to-severe radiographic osteoarthritis using the original (62%) or alternate (50%) definition (versus <15% for either definition of no esKOA). Over 80% of knees that reached the criteria for esKOA achieved this based on increased knee symptom severity - typically without worsening radiographic severity (80%). CONCLUSION: Radiographic severity predisposed a knee to esKOA. However, worsening knee symptoms led to the development of incident esKOA. If investigators want to increase the chance of identifying incident esKOA as an outcome, they should enrich their study samples with people with moderate-to-severe radiographic osteoarthritis. Our findings also highlight the potential reversibility of esKOA (a knee that is classified with esKOA but later is not classified with esKOA). Reversibility is not a flaw of an outcome defining esKOA but rather a desirable clinical outcome to demonstrate a therapeutic intervention can help people with esKOA improve their knee symptoms and delay a knee replacement.

Translational drug discovery and development with the use of tissue-relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy.

Due to the clinical development of drugs such as secukinumab, ustekinumab and dupilumab, major changes have been achieved in the treatment of patients diagnosed with psoriasis and atopic dermatitis. In academia and the pharmaceutical industry, research is increasingly moving towards the development of bispecific antibodies and multi-specific nanobodies, as there is a compelling need for new treatment modalities for patients suffering from autoimmune or malignant disease. The purpose of this review is to discuss aspects of translational drug development with a particular emphasis on indications such as psoriasis and atopic dermatitis. The identification of biomarkers, the assessment of target organ pharmacokinetic and pharmacodynamics interactions and a wide range of in vitro, ex vivo and in vivo models should contribute to an appropriate prediction of a biological effect in the clinical setting. As human biology may not be perfectly reflected by approaches such as skin equivalents or animal models, novel approaches such as the use of human skin and dermal microperfusion assays in healthy volunteers and patients appear both reasonable and mandatory. These models may indeed generate highly translationally relevant data that have the potential to reduce the failure rate of drugs currently undergoing clinical development.

Sample size calculations for detecting disease-modifying osteoarthritis drug effects on the incidence of end-stage knee osteoarthritis in clinical trials: Data from the Osteoarthritis Initiative.

OBJECTIVE: We previously published data representing calculations for sample sizes assuming that the reduction of the incidence of knee joint replacement (KJR) would be an endpoint to prove efficacy of a disease-modifying drug in osteoarthritis (DMOAD). The sample sizes required for such hypothetical studies appeared to be high, rendering those studies unrealistic in the clinical research setting for practical reasons. The purpose of this work is to calculate sample sizes for hypothetical trials for DMOAD efficacy using a proxy for reaching end-stage knee osteoarthritis (esKOA) as an endpoint. METHODS: Based on a sub-population of the Osteoarthritis Initiative, the cumulative incidence for both esKOA and KJR were calculated for a period of four years. The sample sizes of hypothetical DMOAD trials were then calculated for particular sub-cohorts of the OAI subpopulation, subdividing the groups according to age, Kellgren-Lawrence (KL) grades and gender. RESULTS: Both the incidence for esKOA and for KJR over the four year period increase along with rising age, severity of OA and being female. The sample sizes to detect DMOAD efficacy are considerably smaller if reduction of the incidence of esKOA is chosen as an endpoint instead of reduction of the incidence of KJR. CONCLUSION: In the future, generating health-economic data may become increasingly important to gain reimbursement. By choosing esKOA as an endpoint in DMOAD trials, we are able to show in our work that clinical trials in the field of OA are feasible, merely including a few hundred study participants per study arm.

Determination of serum biomarkers in osteoarthritis patients: a previous interventional imaging study revisited.

To evaluate in an interventional trial on knee osteoarthritis (OA) the level and change of two serum biomarkers and their correlation with imaging parameters. The previously reported interventional OA study (ClinicalTrials.gov: NCT00536302) identified a positive effect of collagen hydrolysate (CH) on cartilage morphology in patients with knee OA using delayed gadolinium enhanced magnetic resonance imaging (dGEMRIC). It was the objective in this research project to evaluate in an interventional clinical trial on knee OA the level and change of two serum biomarkers and their correlation with imaging parameters. In blood samples of study participants, we determined the concentration of procollagen type II N-terminal propeptide (PIIANP) and aggrecan chondroitin sulfate 846 epitope (CS846) at baseline (BL) and at the follow-up (FU) visits at 24 and 48 weeks. We measured the level and change of biomarker concentrations in both study groups, and the correlation of those changes with changes in dGEMRIC. For the biomarker PIIANP, we observed a significantly greater increase in the CH group (29.9% vs. 1.2% at week 24, P= 0.001). For CS846, the mean concentration was lower among the CH treated participants at 24 weeks (78% vs. 96%, P= 0.045). Consistent correlations of changes in biomarkers PIIANP and CS846 with changes of the dGEMRIC score could not be observed. In this study, different changes per treatment group, CH and placebo were seen for dGEMRIC and PIIANP BL to 24 weeks FU, but only weak correlations between changes in dGEMRIC and biochemical markers.

Sample Size Calculations for Detecting Disease-Modifying Osteoarthritis Drug Effects on Knee Replacement Incidence in Clinical Trials: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate the extent to which the current designs of clinical trials in knee osteoarthritis (OA) permit detection of a therapeutic effect of disease-modifying OA drugs (DMOADs) on the incidence of knee replacement, and to provide estimates of the required sample sizes. METHODS: We selected distinct subcohorts of the Osteoarthritis Initiative (OAI), based on available information on eligibility criteria for clinical knee OA trials (ClinicalTrials.gov) and additional subcohorts stratified for age, sex, and the severity of radiographic OA. The observed incidence of knee replacement in these OAI subcohorts was used to estimate the expected incidence of knee replacement in the control group of a clinical trial. Based on this estimate, the sample sizes required to detect hypothetical treatment effects on the incidence of knee replacement were calculated, assuming observation periods of 2, 5, or 7 years. RESULTS: The cumulative knee replacement incidence rates in the OAI subcohorts ranged from 0.9% to 12.9%. The corresponding sample sizes required to detect 50% improvement by the DMOAD, with a power of 80% and 95% confidence, were 5,459 and 362, respectively. Including only women with advanced age and radiographic OA increased the incidence of knee replacement and decreased the required sample size. CONCLUSION: The sample sizes that are commonly used in clinical trials do not enable the effects of a DMOAD on incident knee replacement to be detected with sufficient power and confidence. The estimated incidence rates of knee replacement and the corresponding sample sizes are important for informing the design of trials for disease course-modifying effects as well as for socioeconomic evaluation of a DMOAD in terms of preventing knee replacement.

A novel gelatin sponge for accelerated hemostasis.

To more effectively manage the substantial bleeding encountered during surgical procedures in oto-rhino-laryngology, we developed a novel hemostatic sponge made of pharmaceutical grade, chemically cross-linked gelatin. The sponge is characterized by a high pore density, reduced ligaments, and a high nanoscale roughness of lamella surfaces in the matrix. In vitro blood uptake assays revealed a very rapid absorption of human blood, which was two to three times faster than that measured with comparative hemostyptic devices. In an in vitro hemorrhage model using human veins, the novel gelatin sponge matrix induced hemostasis less than a minute after bleeding was induced. The sponge was shown to bring about rapid hemostasis when it was administered in a young patient suffering from acute bleeding of a pharyngeal angiofibroma, even though the patient had been treated with an anticoagulant because of a transient ischemic attack. As the gelatin matrix of the sponge is biocompatible and resorbable, the hemostyptic device could be left in place and was shown to be resorbed within 2 weeks. We hypothesize that the excellent hemostatic performance of the sponge might be linked to enhanced capillary effects in conjunction with optimized anchoring of fibrinogen on the nano-rough material surface, as suggested by scanning electron microscopy. The novel gelatin sponge appears to be a promising hemostatic matrix, which could be of great benefit for patients suffering from epistaxis and other acute injuries resulting in severe bleeding.

24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain.

BACKGROUND: Collagen hydrolysate is a nutritional supplement that has been shown to exert an anabolic effect on cartilage tissue. Its administration appears beneficial in patients with osteoarthritis. OBJECTIVE: To investigate the effect of collagen hydrolysate on activity-related joint pain in athletes who are physically active and have no evidence of joint disease. DESIGN AND SETTING: A prospective, randomized, placebo-controlled, double-blind study was conducted at Penn State University in University Park, Pennsylvania. Parameters including joint pain, mobility, and inflammation were evaluated with the use of a visual analogue scale during a 24-week study phase. STUDY PARTICIPANTS: Between September 2005 and June 2006, 147 subjects who competed on a varsity team or a club sport were recruited. Data from 97 of 147 subjects could be statistically evaluated. INTERVENTION: One hundred and forty-seven subjects (72 male, 75 female) were randomly assigned to two groups: a group (n = 73) receiving 25 mL of a liquid formulation that contained 10 g of collagen hydrolysate (CH-Alpha) and a group (n = 74) receiving a placebo, which consisted of 25 mL of liquid that contained xanthan. MAIN OUTCOME MEASURES: The primary efficacy parameter was the change in the visual analogue scales from baseline during the study phase in relation to the parameters referring to pain, mobility, and inflammation. RESULTS: When data from all subjects (n = 97) were evaluated, six parameters showed statistically significant changes with the dietary supplement collagen hydrolysate (CH) compared with placebo: joint pain at rest, assessed by the physician (CH vs. placebo (-1.37 +/- 1.78 vs. -0.90 +/- 1.74 (p = 0.025)) and five parameters assessed by study participants: joint pain when walking (-1.11 +/- 1.98 vs. -0.46 +/- 1.63, p = 0.007), joint pain when standing (-0.97 +/- 1.92 vs. -0.43 +/- 1.74, p = 0.011), joint pain at rest (-0.81 +/- 1.77 vs. -0.39 +/- 1.56, p = 0.039), joint pain when carrying objects (-1.45 +/- 2.11 vs. -0.83 +/- 1.71, p = 0.014) and joint pain when lifting (-1.79 +/- 2.11 vs. -1.26 +/- 2.09, p = 0.018). When a subgroup analysis of subjects with knee arthralgia (n = 63) was performed, the difference between the effect of collagen hydrolysate vs. placebo was more pronounced. The parameter joint pain at rest, assessed by the physician, had a statistical significance level of p = 0.001 (-1.67 +/- 1.89 vs. -0.86 +/- 1.77), while the other five parameters based on the participants' assessments were also statistically significant: joint pain when walking (p = 0.003 (-1.38 +/- 2.12 vs. -0.54 +/- 1.65)), joint pain when standing (p = 0.015 (-1.17 +/- 2.06 vs. -0.50 +/- 1.68)), joint pain at rest with (p = 0.021 (-1.01 +/-1.92 vs. -0.47 +/- 1.63)), joint pain when running a straight line (p = 0.027 (-1.50 +/- 1.97 vs. -0.80 +/- 1.66)) and joint pain when changing direction (p = 0.026 (-1.87 +/- 2.18 vs. -1.20 +/- 2.10)). CONCLUSION: This was the first clinical trial of 24-weeks duration to show improvement of joint pain in athletes who were treated with the dietary supplement collagen hydrolysate. The results of this study have implications for the use of collagen hydrolysate to support joint health and possibly reduce the risk of joint deterioration in a high-risk group. Despite the study's size and limitations, the results suggest that athletes consuming collagen hydrolysate can reduce parameters (such as pain) that have a negative impact on athletic performance. Future studies are needed to support these findings.