Network meta-analysis of biologic treatments for psoriasis using absolute Psoriasis Area and Severity Index values ≤1, 2, 3 or 5 derived from a statistical conversion method.

BACKGROUND: In practice, the goal of treatment for patients with psoriasis is to achieve almost clear or clear skin and maintain disease control, regardless of baseline disease severity. However, identifying absolute Psoriasis Area and Severity Index (PASI) values for new treatment goals is challenging, as most clinical trials report relative PASI 50, 75, 90 or 100 improvements but rarely absolute PASI values achieved. OBJECTIVE: Our objective was to illustrate a statistical conversion method that was developed to derive absolute PASI values from available clinical trial data on relative PASI improvements. The results of network meta-analyses (NMAs) based on these derived data were then compared with those of NMAs based on the corresponding relative PASI improvement data for selected biologics for moderate-to-severe psoriasis. METHODS: The PASI statistical conversion method was applied to relative PASI improvement data for 11 biologic treatment regimens and placebo at 12 weeks using data from 50 published studies. The respective proportions of patients reaching absolute PASI values ≤1, 2, 3 or 5 were then calculated. Frequentist NMAs (Rücker method) were subsequently used to compare efficacy results across relative and absolute PASI data. RESULTS: The ranking of included treatment regimens for patients achieving absolute PASI 0 to 8 was aligned with results for relative PASI scores (from 100 to 60) at end of induction therapy. Across the range of PASI scores considered, the most effective treatment regimens based on both absolute and relative PASI NMAs were brodalumab 210 mg every 2 weeks and ixekizumab 80 mg every 2 weeks, followed by guselkumab 100 mg every 8 weeks and risankizumab 150 mg every 12 weeks. CONCLUSION: Data generated using this mathematical model will be useful to inform ongoing scientific discussions on treatment goals in the absence of primary absolute PASI data for all available treatments for moderate-to-severe plaque psoriasis.

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

BACKGROUND: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). METHODS: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. RESULTS: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. CONCLUSIONS: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.

Bone quality of the newest bone formed after two years of teriparatide therapy in patients who were previously treatment-naïve or on long-term alendronate therapy.

UNLABELLED: The results of the present study, involving analysis of biopsies from patients who received teriparatide for 2 years and were previously either treatment-naïve or on long-term alendronate therapy, suggest that prior alendronate use does not blunt the favorable effects of teriparatide on bone quality. INTRODUCTION: Examine the effect of 2 years of teriparatide (TPTD) treatment on mineral and organic matrix properties of the newest formed bone in patients who were previously treatment-naïve (TN) or on long-term alendronate (ALN) therapy. METHODS: Raman and Fourier transform infrared microspectroscopic analyses were used to determine the mineral/matrix (M/M) ratio, the relative proteoglycan (PG) content, and the mineral maturity/crystallinity (MMC; determined by three methods: carbonate content, full width at half height of the v 1 PO4 band [FWHH], and wavelength at maxima of the v 1 PO4 band), as well as collagen maturity (ratio of pyridinoline/divalent cross-links), in paired iliac crest biopsies at trabecular, endosteal, and osteonal surfaces of newly formed bone in postmenopausal osteoporotic women who were previously either TN (n = 16) or receiving long-term ALN treatment (n = 24). RESULTS: Trabecular M/M ratio increased and matrix content decreased significantly in the ALN pretreated group. Collagen maturity decreased in both patient groups. Endosteal M/M ratio increased significantly in the TN group. Trabecular M/M ratio was higher at endpoint in the ALN pretreated group than in the TN group. Overall, no changes from baseline were observed in PG content, except that PG content was higher in the ALN pretreated group than in the TN group at endosteal surfaces at endpoint. The ability of TPTD treatment to reduce MMC in both patient groups and at the different bone surfaces depended on the measurement tool (relative carbonate content or wavelength at maxima of the v 1 PO4 band). None of the changes in MMC were different between the two patient groups. CONCLUSIONS: The results suggest some favorable impact of TPTD on bone mineral and organic matrix properties of in situ forming bone in terms of increased initial mineralization and decreased MMC and collagen maturity. Moreover, prior long-term ALN administration may have only limited influence on these properties in bone newly formed after 2 years of TPTD treatment.

Study description and baseline characteristics of the population enrolled in a multinational observational study of extended teriparatide use (ExFOS).

OBJECTIVE: To better characterize patients who are currently being prescribed teriparatide in Europe, this article describes the study design and baseline characteristics of participants of the Extended Forsteo * Observational Study (ExFOS). RESEARCH DESIGN AND METHODS: ExFOS is a noninterventional, multicenter, prospective, observational study in men and women with osteoporosis treated with teriparatide during the course of normal clinical practice for up to 24 months and with a post-treatment follow-up of at least 18 months. MAIN OUTCOME MEASURES: Baseline characteristics, including history of fracture and back pain, and health-related quality of life (HRQoL, assessed using the EuroQol-5 Dimension [EQ-5D]). RESULTS: Of 1607 patients enrolled, 90.9% were women. At baseline, mean (standard deviation [SD]) age was 70.3 (9.8) years, and 85.8% of patients had a history of fracture (64.7% with ≥2 fragility fractures). Of those with historic fractures, 90.8% had vertebral fractures (67.8% had thoracic fractures). The mean (SD) of reported bone mineral density T-scores were -3.0 (1.2), -2.4 (1.0), and -2.5 (0.9) for lumbar spine, total hip (left), and femoral neck (left), respectively. Overall, 39.3% of patients had experienced ≥1 fall during the 12 months before enrollment. At baseline, 11.4% of patients were osteoporosis-treatment naïve and 15% were currently using glucocorticoids. The mean (SD) visual analog scale score for back pain during the last month was 50.7 (26.9), and 62.1% of patients experienced daily or almost daily back pain. The median EQ-5D health state value at baseline was 0.62 (first and third quartiles: 0.19, 0.74). CONCLUSIONS: Baseline characteristics of the ExFOS study cohort indicate that patients prescribed teriparatide in Europe have severe osteoporosis with highly prevalent vertebral fractures, frequent and disabling back pain, and a poor HRQoL, despite previous pharmacotherapy for osteoporosis. Limitations include non-randomization, lack of a comparator group, and patient self-report for data on prior medication and fracture history.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis.

UNLABELLED: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. INTRODUCTION: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. METHODS: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 µg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. RESULTS: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. CONCLUSIONS: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis.

SUMMARY: The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1-34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone turnover initially due to previous alendronate (ALN) therapy. INTRODUCTION: Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment. METHODS: Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5 ± 16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end. RESULTS: Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11-0.34 cycles per year, 3.96-9.8% in the ALN-pretreated group and 0.19-0.33 cycles per year, 6.2-11.3% (p < 0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r = 0.57, p < 0.001 and r = 0.48, p < 0.01) and OS (r = 0.51, p < 0.01 and r = 0.56, p < 0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r = 0.52, p < 0.01) and OS (r = 0.54, p < 0.01) after 24 months. CONCLUSIONS: The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.

Patient compliance with alendronate, risedronate and raloxifene for the treatment of osteoporosis in postmenopausal women.

OBJECTIVES: The aim was to investigate patient compliance with different osteoporosis medications commonly prescribed in clinical practice, to determine risk factors associated with discontinuation and to evaluate quality of life changes. RESEARCH DESIGN AND METHODS: We conducted a 1-year observational study of patients of age > or = 60 years in a clinical setting at 917 sites in 10 European countries (Germany, Greece, UK, Sweden, Netherlands, Romania, Norway, Finland, Denmark, Estonia), Lebanon and South Africa. Demographic data, concomitant diseases, the reasons for intervention, educational, socio-economical status and disease knowledge were captured at baseline. Self-reported compliance, discontinuation data and health status were collected. MAIN OUTCOME MEASURES: Out of 5198 patients, 3490 (67.1%) patients received 60 mg daily raloxifene (RAL), 452 (8.7%) 10 mg daily alendronate (AQD), 769 (14.8%) 70 mg once weekly alendronate (AQW) and 487 (9.4%) 5 mg daily risedronate (RIS). Among patients completing the study (4231, 81%), the percentage of patients with high compliance was 80% (RAL), 79% (AQD), 65% (AQW) and 76% (RIS). The discontinuation due to side effects was highest on AQW (7.0%), followed by AQD (6.4%), RAL (3.8%) and RIS (3.4%). The discontinuation-rate was higher for patients with a history of surgical menopause, increased age, lack of knowledge about medical prevention of osteoporosis and thin frame as a reason for intervention. The EQ-5D weighted index showed the highest improvement for RIS (0.13), followed by RAL (0.11), AQD (0.08) and AQW (0.07). CONCLUSIONS: Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.