Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design.

OBJECTIVE: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. METHOD: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. RESULTS: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. CONCLUSIONS: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

Test-retest precision and longitudinal cartilage thickness loss in the IMI-APPROACH cohort.

OBJECTIVE: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine-learning-estimated structural progression score (s-score) for cartilage thickness loss in the IMI-APPROACH cohort - an exploratory, 5-center, 2-year prospective follow-up cohort. DESIGN: Quantitative cartilage morphology at baseline and at least one follow-up visit was available for 270 of the 297 IMI-APPROACH participants (78% females, age: 66.4 ± 7.1 years, body mass index (BMI): 28.1 ± 5.3 kg/m2, 55% with radiographic knee osteoarthritis (OA)) from 1.5T or 3T MRI. Test-retest precision (root mean square coefficient of variation) was assessed from 34 participants. To define progressor knees, smallest detectable change (SDC) thresholds were computed from 11 participants with longitudinal test-retest scans. Binary logistic regression was used to evaluate the odds of progression in femorotibial cartilage thickness (threshold: -211 µm) for the quartile with the highest vs the quartile with the lowest s-scores. RESULTS: The test-retest precision was 69 µm for the entire femorotibial joint. Over 24 months, mean cartilage thickness loss in the entire femorotibial joint reached -174 µm (95% CI: [-207, -141] µm, 32.7% with progression). The s-score was not associated with 24-month progression rates by MRI (OR: 1.30, 95% CI: [0.52, 3.28]). CONCLUSION: IMI-APPROACH successfully enrolled participants with substantial cartilage thickness loss, although the machine-learning-estimated s-score was not observed to be predictive of cartilage thickness loss. IMI-APPROACH data will be used in subsequent analyses to evaluate the impact of clinical, imaging, biomechanical and biochemical biomarkers on cartilage thickness loss and to refine the machine-learning-based s-score. GOV IDENTIFICATION: NCT03883568.

Reflections from the 2021 OARSI clinical trial symposium: Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

Objective: Osteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients. Design: To facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients. Results: OARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution. Conclusions: The main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of "illness vs disease". There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient.

Low levels of type II collagen formation (PRO-C2) are associated with response to sprifermin: a pre-defined, exploratory biomarker analysis from the FORWARD study.

OBJECTIVE: Osteoarthritis (OA) is characterized by the gradual loss of cartilage. Sprifermin, a recombinant FGF18, is being developed as a cartilage anabolic drug. PRO-C2 is a serum marker of type II collagen formation and low levels have been shown to be prognostic of radiographic progression. The aim of the study was to investigate whether the patient groups with either high or low PRO-C2 levels responded differently to sprifermin. DESIGN: PRO-C2 was measured in synovial fluid (SF) (n = 59) and serum samples (n = 225) from participants of the FORWARD study, a 2-year phase IIb clinical trial testing the efficacy of intra-articular (IA) sprifermin over placebo. The difference between sprifermin and placebo in respect to in change cartilage thickness (measured by quantitative (q) MRI) was analyzed in groups with either high or low (3rd vs 1st-2nd tertiles) baseline serum PRO-C2 levels. RESULTS: SF levels of PRO-C2 increased over time in response to sprifermin, but not to placebo. In the placebo arm, significantly (p = 0.005) more cartilage was lost in the low vs high PRO-C2 group over the 2-year period. The contrast between sprifermin and placebo was significant (p < 0.001), ranging from 0.104 mm at week 26 to 0.229 mm at week 104 in the low PRO-C2 group. This result was not significant in the high PRO-C2 group ranging from -0.034 to 0.142. CONCLUSIONS: Patients with low serum PRO-C2 levels lost more cartilage thickness over time and grew more cartilage in response to sprifermin vs a placebo when compared to patients with high PRO-C2 levels.

Automated MRI assessment confirms cartilage thickness modification in patients with knee osteoarthritis: post-hoc analysis from a phase II sprifermin study.

BACKGROUND: Sprifermin is under investigation as a potential disease-modifying osteoarthritis drug. Previously, 2-year results from the FORWARD study showed significant dose-dependent modification of cartilage thickness in the total femorotibial joint (TFTJ), medial and lateral femorotibial compartments (MFTC, LFTC), and central medial and lateral TFTJ subregions, by quantitative magnetic resonance imaging (qMRI) using manual segmentation. OBJECTIVE: To determine whether qMRI findings from FORWARD could be reproduced by an independent method of automated segmentation using an identical dataset and similar anatomical regions in a post-hoc analysis. METHOD: Cartilage thickness was assessed at baseline and 6, 12, 18 and 24 months, using automated cartilage segmentation with active appearance models, a supervised machine learning method. Images were blinded for treatment and timepoint. Treatment effect was assessed by observed and adjusted changes using a linear mixed model for repeated measures. RESULTS: Based on automated segmentation, statistically significant, dose-dependent structural modification of cartilage thickness was observed over 2 years with sprifermin vs placebo for TFTJ (overall treatment effect and dose response, both P < 0.001), MFTC (P = 0.004 and P = 0.044), and LFTC (both P < 0.001) regions. For highest dose, in the central medial tibial (P = 0.008), central lateral tibial (P < 0.001) and central lateral femoral (P < 0.001) regions. CONCLUSIONS: Cartilage thickness assessed by automated segmentation provided a consistent dose response in structural modification compared with manual segmentation. This is the first time that two independent quantification methods of image analysis have reached the same conclusions in an interventional trial, strengthening the conclusions that sprifermin modifies structural progression in knee osteoarthritis.

Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo.

Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characterize the temporal ECM remodeling of human knee OA articular cartilage in response to sprifermin treatment. Articular cartilage explants from patients with knee OA (npatients = 14) were cultured for 70 days, with permanent exposure to sprifermin (900, 450, 225 ng/mL), FGF18 (450 ng/mL), insulin-like growth factor-1 (100 ng/mL, positive control) or vehicle (nreplicates/treatment/patient = 2). Metabolic activity (AlamarBlue) and biomarkers of type IIB collagen (PIIBNP) formation (Pro-C2 enzyme-linked immunosorbent assay [ELISA]) and aggrecanase-mediated aggrecan neo-epitope NITEGE (AGNx1 ELISA) were quantified once a week. At end of culture (day 70), gene expression (quantitative reverse transcription polymerase chain reaction) and proteoglycan content (Safranin O/Fast green staining) were quantified. The cartilage had continuously increased metabolic activity, when treated with sprifermin/FGF18 compared to vehicle. During days 7-28 PIIBNP was decreased and NITEGE was increased, and during days 35-70 PIIBNP was increased. At end of culture, the cartilage had sustained proteoglycan content and relative expression of ACAN < COL2A1 < SOX9 < COL1A1, indicating that functional chondrocytes remained in the explants. Sprifermin induces a temporal biphasic cartilage remodeling in human knee OA articular cartilage explants, with early-phase increased aggrecanase activity and late-phase increased type II collagen formation.

A consensus-based framework for conducting and reporting osteoarthritis phenotype research.

BACKGROUND: The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. METHODS: A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. RESULTS: Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. CONCLUSIONS: This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients.

Tissue distribution of sprifermin (recombinant human fibroblast growth factor 18) in the rat following intravenous and intra-articular injection.

Objective: Fibroblast growth factor 18 (FGF18) is involved in chondrogenesis and articular cartilage repair. We investigated tissue distribution and pharmacokinetics of radioactive [3H]sprifermin, a recombinant human FGF18, in rats after a single intravenous (i.v.) or intra-articular (i.a.) injection. Design: In two studies (48-96-h [n = 23] and 28-day [n = 12]), 35 male albino (Sprague Dawley) rats received single i.v. or i.a. dose [3H]sprifermin (0.24 mg/kg). Radioactivity was measured in blood, serum, and (in animals receiving i.a. administration) in the knee joint by liquid scintillation counting. Radioactivity in organs, tissues, and distribution in the whole body were measured with whole-body autoradiography. Results: After i.v. injection, radioactivity peaked in serum and whole blood after 4 and 24 h, respectively, with greater total radioactivity in serum. After i.a. injection, radioactivity peaked in serum and whole blood after 24 and 48 h, respectively; intact [3H]sprifermin was not detected in vena caval serum and systemic exposure was low, approximately 20% of that with i.v. injection. Following i.v. injection, radioactivity was mainly found in the liver, adrenal glands, kidney, and spleen; following i.a. injection, radioactivity was preferentially concentrated in articular cartilage after initial distribution in the joint capsule, and still evident in the joint after 28 days. Conclusions: After i.a. injection of [3H]sprifermin in rats, radioactivity was concentrated in the knee joint, particularly articular cartilage, with low levels in other investigated tissues. Systemic exposure to sprifermin was greater with i.v. than i.a. injection. Subsequent clinical investigation in patients with osteoarthritis has reported consistent results.

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors.

OBJECTIVE: Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction. METHODS: Synovial membrane explants (SMEs) were prepared from OA patients' synovial biopsies. SMEs were cultured for 10 days under following conditions: culture medium alone, OSM + TNFα, TLR2 agonist - Pam2CSK4, Pam3CSK4 or synthetic aggrecan 32-mer, TLR4 agonist - Lipid A. Release of pro-inflammatory and degradation biomarkers (acMMP3 and C3M) were measured by ELISA in conditioned media along with IL-6. Additionally, human cartilage was digested with ADAMTS-5, with or without the ADAMTS-5 inhibiting nanobody - M6495. Digested cartilage solution (DCS) and synthetic 32-mer were tested for TLR activation in SEAP based TLR reporter assay. RESULTS: Western blotting confirmed TLR2 and TLR4 in untreated OA synovial biopsies. TLR agonists showed an increase in release of biomarkers - acMMP3 and C3M in SME. Synthetic 32-mer showed no activation in the TLR reporter assay. ADAMTS-5 degraded cartilage fragments activated TLR2 in vitro. Adding M6495 - an anti-ADAMTS-5 inhibiting nanobody®, blocked ADAMTS-5-mediated DCS TLR2 activation. CONCLUSION: TLR2 is expressed in synovium of OA patients and their activation by synthetic ligands causes increased tissue turnover. ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments which activates the TLR2 receptor in vitro. M6495 suppressed cartilage degradation by ADAMTS-5, limiting the activation of TLR2. In conclusion, pain and joint destruction may be linked to generation of ADAMTS-5 cartilage metabolites.

Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix.

OBJECTIVE: Fibroblast growth factor (FGF) 18 has been shown to increase cartilage volume when injected intra-articularly in animal models of osteoarthritis (OA) and in patients with knee OA (during clinical development of the recombinant human FGF18, sprifermin). However, the exact nature of this effect is still unknown. In this study, we aimed to investigate the effects of sprifermin at the cellular level. DESIGN: A combination of different chondrocyte culture systems was used and the effects of sprifermin on proliferation, the phenotype and matrix production were evaluated. The involvement of MAPKs in sprifermin signalling was also studied. RESULTS: In monolayer, we observed that sprifermin promoted a round cell morphology and stimulated both cellular proliferation and Sox9 expression while strongly decreasing type I collagen expression. In 3D culture, sprifermin increased the number of matrix-producing chondrocytes, improved the type II:I collagen ratio and enabled human OA chondrocytes to produce a hyaline extracellular matrix (ECM). Furthermore, we found that sprifermin displayed a 'hit and run' mode of action, with intermittent exposure required for the compound to fully exert its anabolic effect. Finally, sprifermin appeared to signal through activation of ERK. CONCLUSIONS: Our results indicate that intermittent exposure to sprifermin leads to expansion of hyaline cartilage-producing chondrocytes. These in vitro findings are consistent with the increased cartilage volume observed in the knees of OA patients after intra-articular injection with sprifermin in clinical studies.

Predictive and concurrent validity of cartilage thickness change as a marker of knee osteoarthritis progression: data from the Osteoarthritis Initiative.

OBJECTIVE: To investigate the predictive and concurrent validity of magnetic resonance imaging (MRI)-based cartilage thickness change between baseline (BL) and year-two (Y2) follow-up (predictive validity) and between Y2 and Y4 follow-up (concurrent validity) for symptomatic and radiographic knee osteoarthritis (OA) progression during Y2→Y4. METHODS: 777 knees from 777 Osteoarthritis Initiative (OAI) participants (age: 61.3 ± 9.0 years, BMI: 30.1 ± 4.8 kg/m2) with Kellgren Lawrence (KL) grade 1-3 at Y2 (visit before progression interval) had cartilage thickness measurements from 3T MRI at BL, Y2 (n = 777), and Y4 (n = 708). Analysis of covariance and logistic regression were used to assess the association of pain progression (≥9 WOMAC units [scale 0-100], n = 205/572 with/without progression) and radiographic progression (≥0.7 mm minimum joint space width (mJSW) loss, n = 166/611 with/without progression) between Y2 and Y4 with preceding (BL→Y2) and concurrent (Y2→Y4) change in central medial femorotibial (cMFTC) compartment cartilage thickness. RESULTS: Symptomatic progression was associated with concurrent (Y2→Y4: -305 ± 470 µm vs -155 ± 346 µm, Odds ratios (OR) = 1.5 [1.2, 1.7]) but not with preceding cartilage thickness loss in cMFTC (-150 ± 276 µm vs -151 ± 299 µm, OR = 0.9 95% CI: [0.8, 1.1]). Radiographic progression, in contrast, was significantly associated with both concurrent (-542 ± 550 µm vs -98 ± 255 µm, OR = 3.4 [2.6, 4.3]) and preceding cMFTC thickness loss (-229 ± 355 µm vs -130 ± 270 µm, OR = 1.3 [1.1, 1.5]). CONCLUSIONS: These results extend previous reports that did not discern predictive vs concurrent associations of cartilage thickness loss with OA progression. The observed predictive and concurrent validity of cartilage thickness loss for radiographic progression and observed concurrent validity for symptomatic progression provide an important step in qualifying cartilage thickness loss as a biomarker of knee OA progression. CLINICALTRIALS. GOV IDENTIFICATION: NCT00080171.

Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future.

Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes.

Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria.

OBJECTIVE: To review and summarize biomarker data published from April 2014 to May 2015 to provide insight to the ongoing work in the field of osteoarthritis (OA). Furthermore, to summarize the BIPED criteria and set it in context of the medical needs of 2015. METHODS: PubMed was used as searching machine: Time period 2014/04/01-2015/05/01, MeSH term [Biomarker] AND [Osteoarthritis], Language; English, Full text available. Reviews were excluded. Only papers describing protein based biomarkers measured in human body fluids from OA patients were included. RESULTS: Biomarkers of joint tissue turnover, cytokines, chemokines and peptide arrays were measured in different cohorts and studies. Amongst those were previously tested biomarkers such as osteocalcin, Carboxy-terminal cross-linked fragment of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP). A majority of the biomarker were classified as I, B or B biomarkers according to the BIPED criteria. Work is continuing on testing biomarkers in OA. There is still a huge, unmet medical need to identify, test, validate and qualify novel and well-known biomarkers. A pre-requisite for this is better characterization and classification of biomarkers to their needs, which may not be reached before higher understanding of OA phenotypes has been gained. In addition, we provide some references to some recent guidelines from Food and Drug Administration (FDA) and European Medicines Agency (EMA) on qualification and usage of biomarkers for drug development and personalized medicine, which may provide value to the field.

OA phenotypes, rather than disease stage, drive structural progression--identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA.

BACKGROUND/PURPOSE: The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI. METHODS: Data from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA). RESULTS: There was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner. CONCLUSION: These data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression.

Rates and sensitivity of knee cartilage thickness loss in specific central reading radiographic strata from the osteoarthritis initiative.

OBJECTIVE: To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. METHODS: One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). RESULTS: The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 µm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 ± 159 vs -31 ± 126 µm; P = 0.02). For comparison, the loss in grade3 knees was -72 ± 122 µm. CONCLUSIONS: In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs).

Trajectory of cartilage loss within 4 years of knee replacement--a nested case-control study from the osteoarthritis initiative.

OBJECTIVE: Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior to KR vs non-replaced controls. METHODS: A nested case-control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence (T0), and at 1-4 years prior to T0 (T-1 to T-4). Cartilage loss between cases and controls was compared using paired t-tests and conditional logistic regression. RESULTS: One hundred and eighty-nine knees of 164 OAI participants [55% women; age 64 ± 8.7; body mass index (BMI) 29 ± 4.5] had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls [94 ± 137 vs 55 ± 104 µm; P = 0.0017 (paired t); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08-1.70)]. The discrimination was stronger for T-2 → T0 [OR 1.61 (1.33-1.95), n = 127] than for T-1 → T0, and was not statistically significant for intervals prior to T-2 [i.e., T-4 → T-2, OR 0.97 (0.67-1.41), n = 60]. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI. CONCLUSIONS: In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined.

Osteoarthritis--a case for personalized health care?

For both economic and ethical reasons, identification of the optimal treatment for each individual patient is a pressing concern, not only for the patients and their physician, but also health care payers and the pharmaceutical industry. In the field of osteoarthritis (OA) this is of particular relevance, due to the heterogeneity of the disease and the very large number of affected individuals. There is a need to pair the right patients with the right therapeutic modes of action. At present, the clinical trial failures in OA may be a consequence of both bona fide treatment failures and trial failures due to clinical design deficiencies. Tools are needed for characterization and segregation of patients with OA. Key lessons may be learned from advances with another form of arthritis, namely rheumatoid arthritis (RA). Personalized health care (PHC) may be more advantageous for a number of specific indications which are characterized by costly therapy, low response rates and significant problems associated with trial and error prescription, including the risk of serious side effects. We discuss the use of diagnostic practices guiding RA treatment, which may serve as a source of key insights for diagnostic practices in OA. We discuss the emerging concept of PHC, and outline the opportunities and current successes and failures across the RA field, as the OA field collects further data to support the hypothesis. We attempt to outline a possible path forward to assist patients, physicians, payers and the pharmaceutical industry in assuring the 'right' patients are treated with the 'right drug' in OA. Finally we highlight methods for possible segregation of OA patients that would allow identification of patient subtypes, such as OA driven by inflammation that may be ideally suited for PHC and for targeted therapies.

FGF18 augments osseointegration of intra-medullary implants in osteopenic FGFR3(-/-) mice.

Enhancement of endogenous bone regeneration is a priority for integration of joint replacement hardware with host bone for stable fixation of the prosthesis. Fibroblast Growth Factor (FGF) 18 regulates skeletal development and could therefore have applications for bone regeneration and skeletal repair. This study was designed to determine if treatment with FGF 18 would promote bone regeneration and integration of orthopedic hardware in FGF receptor 3 deficient (FGFR3(-/-)) mice, previously characterized with impaired bone formation. Rigid nylon rods coated with 200 nm of titanium were implanted bilaterally in the femora of adult FGFR3(-/-) and FGFR3(+/+) mice to mimic human orthopedic hardware. At the time of surgery, LEFT femora received an intramedullary injection of 0.5 µg FGF18 (Merck Serono) and RIGHT femora received PBS as a control. Treatment with FGF18 resulted in a significant increase in peri-implant bone formation in both FGFR3(+/+) and FGFR3(-/-) mice, with the peri-implant fibrous tissue frequently seen in FGFR3(-/-) mice being largely replaced by bone. The results of this pre-clinical study support the conjecture that FGF18 could be used in the clinical setting to promote integration of orthopedic hardware in poor quality bone.

Protection against murine tuberculosis by an attenuated recombinant Salmonella typhimurium vaccine strain that secretes the 30-kDa antigen of Mycobacterium bovis BCG.

A recombinant (r-) Salmonella typhimurium aroA vaccine that secretes the naturally secreted protein of Mycobacterium bovis strain BCG, Ag85B, by means of the HlyB/HlyD/TolC export machinery (termed p30 in the following) was constructed. In contrast to r-S. typhimurium control, oral vaccination of mice with the r-S. typhimurium p30 construct induced partial protection against an intravenous challenge with the intracellular pathogen Mycobacterium tuberculosis, resulting in similar vaccine efficacy comparable to that of the systemically administered attenuated M. bovis BCG strain. The immune response induced by r-S. typhimurium p30 was accompanied by augmented interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) levels produced by restimulated splenocytes. These data suggest that the HlyB/HlyD/TolC-based antigen delivery system with attenuated r-S. typhimurium as carrier is capable of inducing an immune response against mycobacterial antigens.

Participation of group 2 CD1 molecules in the control of murine tuberculosis.

Besides the classical major histocompatibility complex (MHC) class I and MHC class II molecules, human CD1 molecules have been shown to present mycobacterial antigens in vitro. In this study, in vivo treatment of mice with anti-CD1 monoclonal antibodies resulted in exacerbated tuberculosis at very early time points. In CD1-modulated mice, Mycobacterium tuberculosis-specific production of the type 1 cytokines, IL-12, TNF, and IFN-gamma as well as of TGF beta was reduced. These findings suggest an antigen-presenting role of CD1 molecules in tuberculosis.