Long-term cost-effectiveness of matrix-associated chondrocyte implantation in the German health care system: a discrete event simulation.

INTRODUCTION: Cartilage defects in the knee can be caused by injury, various types of arthritis, or degeneration. As a long-term consequence of cartilage defects, osteoarthritis can develop over time, often leading to the need for a total knee replacement (TKR). The treatment alternatives of chondral defects include, among others, microfracture, and matrix-associated autologous chondrocyte implantation (M-ACI). The purpose of this study was to determine cost-effectiveness of M-ACI in Germany with available mid- and long-term outcome data, with special focus on the avoidance of TKR. MATERIALS AND METHODS: We developed a discrete-event simulation (DES) that follows up individuals with cartilage defects of the knee over their lifetimes. The DES was conducted with a status-quo scenario in which M-ACI is available and a comparison scenario with no M-ACI available. The model included 10,000 patients with articular cartilage defects. We assumed Weibull distributions for short- and long-term effects for implant failures. Model outcomes were costs, number of TKRs, and quality-adjusted life years (QALYs). All analyses were performed from the perspective of the German statutory health insurance. RESULTS: The majority of patients was under 45 years old, with defect sizes between 2 and 7 cm2 (mean: 4.5 cm2); average modeled lifetime was 48 years. In the scenario without M-ACI, 26.4% of patients required a TKR over their lifetime. In the M-ACI scenario, this was the case in only 5.5% of cases. Thus, in the modeled cohort of 10,000 patients, 2700 TKRs, including revisions, could be avoided. Patients treated with M-ACI experienced improved quality of life (22.53 vs. 21.21 QALYs) at higher treatment-related costs (18,589 vs. 14,134 € /patient) compared to those treated without M-ACI, yielding an incremental cost-effectiveness ratio (ICER) of 3376 € /QALY. CONCLUSION: M-ACI is projected to be a highly cost-effective treatment for chondral defects of the knee in the German healthcare setting.

Treatment Costs of Matrix-Associated Autologous Chondrocyte Implantation Compared With Microfracture: Results of a Matched-Pair Claims Data Analysis on the Treatment of Cartilage Knee Defects in Germany.

BACKGROUND: Articular cartilage damage is caused by traumatic sport accidents or age-related degeneration and might lead to osteoarthritis, which represents a socioeconomic burden to society. Cartilage damage in the knee is commonly treated surgically with microfracture (MFX) or matrix-associated autologous chondrocyte implantation (MACI). PURPOSE: To quantify the initial and follow-up costs associated with MFX and MACI treatments from the viewpoint of statutory health insurance in Germany. STUDY DESIGN: Economic decision analysis; Level of evidence, 2. METHODS: This comparative study was based on an anonymized representative claims data set of 4 million patients covered by statutory health insurance in Germany. Patients undergoing outpatient or inpatient treatment with MACI or MFX for cartilage damage in the knee between January 1, 2012, and December 31, 2013, were included and evaluated over 5 years. Groups (MACI and MFX) were adjusted via propensity score matching before initial treatment. The matched groups were compared regarding their outpatient, inpatient, pharmaceutical, and other costs during the 5-year period. RESULTS: In total, 127 patients per group were analyzed (59.1% male, 40.9% female; mean age, 37 years). In the year of the initial surgical procedure, costs were €14,804.13 in the MACI group and €5458.59 in the MFX group. In years 2 and 3 after initial surgery, treatment costs were comparable between patients treated with MACI (€2897.97 and €2114.87, respectively) and MFX (€2842.66 and €1967.42, respectively), with slightly higher treatment costs for those treated with MACI. In years 4 and 5 after surgery, costs were less in patients treated with MACI (€2154.79 and €1478.08, respectively) than in those treated with MFX (€2232.57 and €2061.63, respectively). Costs related to revision surgery were, on average, €3732 for MACI and €3765 for MFX. Thus, additional costs in years with revision surgery were €1672 for MACI and €1915 for MFX. CONCLUSION: This was the first study to analyze a large representative population claims database with propensity score matching, and results indicated that follow-up costs of patients treated with MACI and MFX began to converge over time. We found that total costs for MACI were higher than for MFX but that additional costs for MACI were lower than previously reported. Perceived morbidity may have little to do with cost.

Matrix-Associated Chondrocyte Implantation Is Associated With Fewer Reoperations Than Microfracture: Results of a Population-Representative, Matched-Pair Claims Data Analysis for Cartilage Defects of the Knee.

BACKGROUND: Symptomatic cartilage defects of the knee are commonly surgically treated by microfracture (MFX) or matrix-associated chondrocyte implantation (M-ACI). Several randomized controlled trials have compared MFX and M-ACI, showing a tendency to lower reoperation rates for M-ACI, but results vary widely between studies. PURPOSE: To compare reoperation rates after MFX and M-ACI in cartilage defects of the knee outside clinical trials in a representative sample of the population. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study was based on anonymized, population-representative claims data of 4 million insured persons in Germany. Patients who underwent MFX or M-ACI for cartilage defects of the knee with a follow-up of 2 years were compared. The primary endpoint was the need for a reoperation, defined as a claim for a second surgical procedure from the same patient at the knee joint (27 procedure codes), meniscus and cartilage (35 procedure codes), or patella (102 procedure codes) or the need for knee replacement (11 procedure codes). Group comparisons were performed using log-rank tests, with a 2-sided P value of <.05 to indicate significance. For adjusted analysis, propensity score matching was applied. Age, sex, comedications, and comorbidities were used as matching parameters. RESULTS: A total of 6425 patients fulfilled the inclusion criteria: 6273 treated with MFX and 152 treated with M-ACI (mean age, 53 and 36 years, respectively). In the 2 years after treatment, 1271 patients in the MFX group needed a reoperation compared with 19 in the M-ACI group (20.3% vs 12.5%, respectively; P = .0199). For adjusted analysis after propensity score matching, 127 patients per group were analyzed. Their mean age was 37 years. At the end of the second follow-up year, 28 and 16 patients needed reoperations in the MFX and M-ACI groups, respectively (22.0% vs 12.6%, respectively; P = .0498). CONCLUSION: This study used a representative sample of the population and a broad definition of a reoperation, thus expanding evidence from clinical trials. We found a significant advantage of M-ACI in reoperation rates 2 years after treatment. After adjusting for age, sex, comedications, and comorbidities, M-ACI still showed significantly lower reoperation rates after 2 years.

The prevalence of diagnosed α1-antitrypsin deficiency and its comorbidities: results from a large population-based database.

α1-Antitrypsin deficiency (AATD) is a genetically determined disorder that is associated with different clinical manifestations. We aimed to assess the prevalence of diagnosed AATD and its comorbidities using a large healthcare database.In this retrospective longitudinal observational study, we analysed data from 4 million insurants. Using International Classification of Diseases revision 10 (ICD-10) codes, we assessed the prevalence, comorbidities and healthcare utilisation of AATD patients (E88.0 repeatedly coded) relative to non-AATD patients with chronic obstructive pulmonary disease (COPD), emphysema or asthma.In our study population, we identified 673 AATD patients (590 aged ≥30 years), corresponding to a prevalence of 23.73 per 100 000 in all age groups and 29.36 per 100 000 in those ≥30 years. Based on the number of AATD cases detected in the sample size (673 out of 2 836 585), we extrapolated that there were 19 162 AATD cases in Germany during the years studied. AATD patients had a higher prevalence of arterial hypertension, chronic kidney disease and diabetes relative to non-AATD asthma or emphysema patients. When compared to non-AATD COPD patients, AATD patients had significantly more consultations and more frequent and longer hospitalisations.Our data strengthen the assumption that AATD is associated with a variety of other diseases. Healthcare utilisation appears to be higher among AATD patients as compared to patients with non-AATD-related obstructive lung diseases.

Dynamic of ligand binding to Drosophila melanogaster ecdysteroid receptor.

Ligand binding to ecdysone receptor (EcR) is an autonomous function of the ligand binding domain (LBD) and is not modified by other receptor domains or tags fused to the LBD. Association and dissociation velocity of hormone to EcR was studied in the absence and presence of its main dimerization partner Ultraspiracle (USP). Mutational analysis of the EcR(LBD) revealed that ligand entry and exit is affected differently by the same point mutation, indicating that different pathways are used for association and dissociation of the ligand. Heterodimerization with wild type USP(LBD) increases ligand association to EcR(LBD) about fivefold and reduces dissociation 18-fold. Opposite effects of the same mutation (N626K) on dissociation velocity of ligand in EcR and EcR/USP indicate that not only hormone binding itself, but also the kinetic behaviour of ligand binding is modified by the dimerization partner. A general effect of the point mutations on the 3D architecture seems unlikely due to the highly selective effects on the kinetics of hormone binding.

Functional studies on the ligand-binding domain of Ultraspiracle from Drosophila melanogaster.

The functional insect ecdysteroid receptor is comprised of the ecdysone receptor (EcR) and Ultraspiracle (USP). The ligand-binding domain (LBD) of USP was fused to the GAL4 DNA-binding domain (GAL4-DBD) and characterized by analyzing the effect of site-directed mutations in the LBD. Normal and mutant proteins were tested for ligand and DNA binding, dimerization, and their ability to induce gene expression. The presence of helix 12 proved to be essential for DNA binding and was necessary to confer efficient ecdysteroid binding to the heterodimer with the EcR (LBD), but did not influence dimerization. The antagonistic position of helix 12 is indispensible for interaction between the fusion protein and DNA, whereas hormone binding to the EcR (LBD) was only partially reduced if fixation of helix 12 was disturbed. The mutation of amino acids, which presumably bind to a fatty acid evoked a profound negative influence on transactivation ability, although enhanced transactivation potency and ligand binding to the ecdysteroid receptor was impaired to varying degrees by mutation of these residues. Mutations of one fatty acid-binding residue within the ligand-binding pocket, 1323, however, evoked enhanced transactivation. The results confirmed that the LBD of Ultraspiracle modifies ecdysteroid receptor function through intermolecular interactions and demonstrated that the ligand-binding pocket of USP modifies the DNA-binding and transactivation abilities of the fusion protein.

Characterization of the ligand-binding domain of the ecdysteroid receptor from Drosophila melanogaster.

Mutants created by site-directed mutagenesis were used to elucidate the function of amino acids involved in ligand binding to ecdysteroid receptor (EcR) and heterodimer formation with ultraspiracle (USP). The results demonstrate the importance of the C-terminal part of the D-domain and helix 12 of EcR for hormone binding. Some amino acids are involved either in ligand binding to EcR (E476, M504, D572, I617, N626) or ligand-dependent heterodimerization as determined by gel mobility shift assays (A612, L615, T619), while others are involved in both functions (K497, E648). Some amino acids are suboptimal for ligand binding (L615, T619), but mediate ligand-dependent dimerization. We conclude that the enhanced regulatory potential by ligand-dependent modulation of dimerization in the wild type is achieved at the expense of optimal ligand binding. Mutation of amino acids (K497, E648) involved in the salt bridge between helix 4 and 12 impair ligand binding to EcR more severely than hormone binding to the heterodimer, indicating that to some extent heterodimerization compensates for the deleterious effect of certain mutations. Different effects of the same point mutations on ligand binding to EcR and EcR/USP (R511, A612, L615, I617, T619, N626) indicate that the ligand-binding pocket is modified by heterodimerization.

Ligand-induced heterodimerization between the ligand binding domains of the Drosophila ecdysteroid receptor and ultraspiracle.

The insect ecdysteroid receptor consists of a heterodimer between EcR and the RXR-orthologue, USP. We addressed the question of whether this heterodimer, like all other RXR heterodimers, may be formed in the absence of ligand and whether ligand promotes dimerization. We found that C-terminal protein fragments that comprised the ligand binding, but not the DNA binding domain of EcR and USP and which were equipped with the activation or DNA binding region of GAL4, respectively, exhibit a weak ability to interact spontaneously with each other. Moreover, the heterodimer formation is greatly enhanced upon administration of active ecdysteroids in a dose-dependent manner. This was shown in vivo by a yeast two-hybrid system and in vitro by a modified electromobility shift assay. Furthermore, the EcR fragment expressed in yeast was functional and bound radioactively labelled ecdysteroid specifically. Ligand binding was greatly enhanced by the presence of a USP ligand binding domain. Therefore, ecdysteroids are capable of inducing heterodimer formation between EcR and USP, even when the binding of these receptor proteins to cognate DNA response elements does not occur. This capability may be a regulated aspect of ecdysteroid action during insect development.

Expression of ecdysteroid receptor and ultraspiracle from Chironomus tentans (Insecta, Diptera) in E. coli and purification in a functional state.

Full length clones of ecdysteroid receptor (EcR) and Ultraspiracle (USP) from Chironomus tentans were expressed as GST fusion proteins in E. coli and purified by affinity chromatography. The absence of detergents during the purification procedure is essential for retaining receptor function, especially ligand binding. Presence of USP is mandatory for ligand binding to EcR, but no other cofactors or posttranslational modifications seem to be important, since Scatchard plots revealed the same characteristics (two high affinity binding sites for Ponasterone A with K(D1)=0.24+/-0.1nM and K(D2)=3.9+/-1.3.nM) as found in 0.4 M NaCl extracts of Chironomus cells. Gel mobility shift assays showed binding of the heterodimer to PAL and DR5 even after removal of the GST-tag, whereas EcR binding to PAL1 is GST-dependent. USP binds preferentially to DR5. Addition of unprogrammed reticulocyte lysate improves ligand binding only slightly. Removal of GST has no effect on (3)H-ponasterone A binding, but alters DNA binding characteristics. Calculation of specific binding (5.3+3.0 nmol/mg GST EcR) revealed that 47+/-26% of purified receptor protein was able to bind ligand. The addition of purified EcR to cell extracts of hormone resistant subclones of the epithelial cell line from C. tentans, which have lost their ability to bind ligand, restores specific binding of (3)H-ponasterone A.