Sub-setting systemic lupus erythematosus by combined molecular phenotypes defines divergent populations in two phase III randomized trials.

OBJECTIVES: Heterogeneity of SLE patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity. METHODS: Combinations of IFN (high/low), anti-dsDNA (+/-) and C3 and C4 (low/normal) were used to subset n = 1747 patients from two randomized phase III trials. A dichotomous classification scheme defined SLE (+) as: IFN (high), anti-dsDNA (+), C3 (low) and/or C4 (low). SLE (-) required all of the following: IFN (low), anti-dsDNA (-), C3 (normal) and C4 (normal). Additional analyses subset the data further by IFN, anti-dsDNA and complement. RESULTS: The trials enrolled n = 2262 patients of which n = 1747 patients had data for IFN, anti-dsDNA, C3 and C4 at baseline. There were n = 247 patients in the SLE (-) population and n = 1500 patients in the SLE (+) population. The SLE (-) population had more mucocutaneous and musculoskeletal disease at baseline, while SLE (+) had more haematological, renal and vascular involvement. There was lower concomitant medication use in the SLE (-) population for corticosteroids and immunosuppressants, except for MTX. Time to severe flare was significantly longer in SLE (-) vs SLE (+) (P < 0.0001) and SRI-4 response rate was significantly lower in SLE (-) vs SLE (+) (P = 0.00016). The USA had more SLE (-) patients (22%) than Mexico/Central America/South America (10%), Europe (7%) and the rest of the world (5%). CONCLUSION: Combinatorial analysis of four molecular biomarkers revealed subsets of SLE patients that discriminated by disease manifestations, concomitant medication use, geography, time to severe flare and SRI-4 response. These data may be useful for designing clinical trials and identifying subsets of patients for analysis. Rheumatology key messages SLE patients from a P3 trial were categorized by IFN, anti-dsDNA, C3 and C4 status. Patients lacking molecular markers of SLE distinguished from biomarker positive patients on multiple clinical parameters. Biomarker negative patients have distinct disease characteristics that may impact clinical trial outcomes.

Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies.

OBJECTIVES: To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED). To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction. PATIENTS AND METHODS: Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated. EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively. Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5. Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10. RESULTS: A total of 3581 randomized subjects were studied. Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata. In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001). Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement. Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction. Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD. CONCLUSIONS: Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction. Proportions of subjects reporting improved ejaculatory or orgasmic function were ≈ twofold higher with tadalafil than with placebo. These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).

Factors associated with ejaculatory and orgasmic dysfunction in men with erectile dysfunction: analysis of clinical trials involving the phosphodiesterase type 5 inhibitor tadalafil.

OBJECTIVE: To determine frequencies of, and risk factors for, ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) in men with different degrees of erectile dysfunction (ED). PATIENTS AND METHODS: Baseline data from 28 ED trials were integrated and analysed. The International Index of Erectile Function Question 9 (IIEF-Q9; 'When you had sexual stimulation or intercourse, how often did you ejaculate?') and IIEF-Q10 ('How often did you have the feeling of orgasm with or without ejaculation?') were used to evaluate ejaculatory and orgasmic functions. Responses of 'almost never or never' or 'a few times (much less than half the time)' were taken as evidence of EjD or OD, respectively, whereas responses of 'almost always or always' or 'most times (much more than half the time)' were taken as evidence of normal function. Estimates of the relative risks (RRs) of EjD or OD were determined for multiple patient characteristics. RESULTS: Among 12,130 study participants with available data, only 5117 (42.2%) reported normal ejaculatory function, and 4321 (35.6%) normal orgasm, regardless of ED severity. Among subjects with poor ejaculatory function, 16.7% had mild ED, and among subjects with poor sensation of orgasm, 21.9% had mild ED. Frequencies of EjD and OD increased with increasing ED severity. Of the 5117 individuals with normal ejaculatory function, 796 (15.6%) had poor sensation of orgasm. Of the 4321 subjects with normal orgasm, 226 (5.2%) had poor ejaculatory function. Men with (vs without) EjD or OD tended to be younger: 53.7 vs 56.9 years and 54.2 vs 56.2 years, respectively. Factors associated with increased RRs of EjD and OD included cardiomyopathy (RR for EjD 1.74; RR for OD 1.59); cardiac failure (RR 1.40; 1.22); and baseline use (or history of use) of antipsychotics (RR 1.45; 1.30), selective serotonin reuptake inhibitors (RR 1.31; 1.27), and tricyclic antidepressants (RR 1.34; 1.28). CONCLUSIONS: EjD and OD occurred at baseline in more than one in three men enrolled in tadalafil trials. Even men with mild ED reported EjD or OD. Further studies are warranted to better understand the impacts of EjD and OD on male sexuality and quality of life.

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years.

OBJECTIVE: Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN: The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS: Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS: Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.

Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction.

OBJECTIVES: To compare the safety and efficacy of the daily erectogenic therapy, tadalafil, on lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS) in men with or without comorbid erectile dysfunction (ED). METHODS: Following a 4-week placebo run-in period, men with moderate-to-severe BPH-LUTS were randomized to placebo or tadalafil 2.5, 5, 10, or 20 mg once daily for 12 weeks. International Prostate Symptom Scores (IPSS), IPSS quality of life, and BPH Impact Index were measured every 4 weeks. Safety was mainly assessed via spontaneous reports of adverse events. Data from men with (n=716) or without (n=340) ED at baseline were compared in posthoc analyses. RESULTS: Men with ED were older and had more frequent hypertension, hyperlipidemia, coronary artery disease, and diabetes at baseline compared with men without ED. After 12 weeks, changes in IPSS in men with ED (least squares mean change from baseline, placebo: -2.4; tadalafil 2.5, 5, 10, 20 mg: -4.3, -4.8, -5.3, -5.6) and without ED (-2.4, -3.2, -5.3, -5.1, -4.5) were not significantly different (subgroup/interaction P values: .352/.644). Similar effects were observed for IPSS quality of life (with ED: -0.6, -0.9, -0.9, -1.0, -1.1; without ED: -0.6, -0.7, -0.9, -0.8, -0.8; 0.090/0.773) and BPH Impact Index (with ED: -0.7, -0.9, -1.3, -1.3, -1.4; without ED: -1.0, -0.7, -1.3, -1.3, -1.2; 0.753/0.852). Tadalafil was generally well tolerated, and men with or without ED had similar tolerability profiles. CONCLUSIONS: Changes in BPH-LUTS after 12 weeks of treatment with placebo or various doses of once daily tadalafil were similar in men with or without comorbid ED.