Real-life effectiveness of once-daily calcipotriol and betamethasone dipropionate gel vs. ointment formulations in psoriasis vulgaris: final analysis of the 52-week PRO-long study.

BACKGROUND: Topical therapies are the mainstay of treatment for psoriasis vulgaris. The fixed combination of calcipotriol (Cal) 50 µg/g plus betamethasone 0.5 mg/g (as dipropionate; BD) is a first-line topical treatment and available as a gel or ointment. The use of these fixed combination products was compared in PRO-long, a long-term noninterventional study, for which interim results (4 and 12 weeks) have previously been reported. OBJECTIVE: To describe and compare patients' perspectives on the fixed combination gel and ointment formulations; to include efficacy, adherence behaviour, treatment satisfaction and health-related quality of life (HRQoL) aspects during long-term real-life psoriasis management. METHODS: PRO-long was a multicentre, prospective, observational, 52-week study of patients prescribed fixed combination Cal/BD gel or ointment in clinical practice. For final analysis the following were assessed at weeks 24, 36 and 52: differences in the proportion of patients with 'mild'/'very mild' disease according to patient's global assessment of disease severity, adherence behaviour, treatment satisfaction (nine-item treatment satisfaction questionnaire for medication) and HRQoL (Skindex-29). RESULTS: Patients (n = 328) were prescribed once-daily Cal/BD gel (n = 152) or ointment (n = 176). At week 52, a higher proportion of patients reported that the severity of their psoriasis was 'mild'/'very mild' vs. baseline (gel: 60.2 vs. 47.1%; ointment: 58.8 vs. 42.4%), with greater treatment satisfaction reported in patients using gel vs. those using ointment. A higher proportion of patients found the gel 'easy' to use compared with the ointment (66.7 vs. 45.2%). Daily application of treatment took ≤ 5 min for 86.1% of patients using gel and 71.0% of patients using ointment. CONCLUSION: This real-life study has demonstrated similar effectiveness between the Cal/BD formulations. However, over a 52-week treatment period, patients reported greater treatment satisfaction with the gel, which was considered easier to use, faster to apply and overall a more convenient product.

Real-life effectiveness of once-daily calcipotriol and betamethasone dipropionate gel vs. ointment formulations in psoriasis vulgaris: 4- and 12-week interim results from the PRO-long study.

BACKGROUND: Psoriasis is most often treated using topical therapies such as the once-daily fixed combination of calcipotriol and betamethasone dipropionate, which is available as a gel and an ointment. To date, there have been no direct comparisons of patient perspectives on the two formulations. OBJECTIVE: To describe and compare patients' perspectives on calcipotriol and betamethasone gel and ointment formulations, including real-life effectiveness, adherence behaviour, treatment satisfaction and health-related quality of life (QoL), during long-term psoriasis vulgaris management, according to interim findings from the PRO-long study. METHODS: PRO-long is a multicentre, prospective, observational, 52-week cohort study in patients prescribed fixed-combination calcipotriol (50 µg/g) and betamethasone (0.5 mg/g; as dipropionate) gel or ointment for long-term psoriasis management. Difference in effectiveness at 4 and 12 weeks was assessed by comparing the proportion of patients with controlled (mild or very mild) disease, according to the Patient's Global Assessment. Additional patient questionnaires were used to assess adherence behaviour, treatment satisfaction (nine-item Treatment Satisfaction Questionnaire for Medication) and health-related QoL (Skindex-29). RESULTS: A total of 156 patients were included in the analysis. In single items of the adherence behaviour and treatment satisfaction questionnaires, patients preferred the gel over the ointment as convenient, easy to use and fast to apply. Post hoc analysis demonstrated significant differences between gel and ointment for convenience and application time. More patients had controlled disease at week 12 with gel (71.9%) vs. ointment (65.7%); however, the difference was not statistically significant (primary end point; P = 0.40). CONCLUSION: This interim analysis supports fixed-combination calcipotriol and betamethasone gel as more convenient, easier to use and faster to apply than the ointment formulation in real-life conditions according to patients with psoriasis vulgaris. Furthermore, a numerical difference in patient-reported real-life effectiveness was seen in favour of the gel, although this was not statistically significant.

A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: quality-of-life outcomes of a randomized controlled trial of supervised treatment of psoriasis in a day-care setting.

BACKGROUND: Calcipotriol ointment and short-contact dithranol cream therapy are well-established topical treatments for psoriasis. Quality of life, i.e. the physical, psychological, and social functioning and well-being of the patient, has become an essential outcome measure in chronic skin disease. OBJECTIVES: To compare the quality-of-life outcomes of calcipotriol ointment with that of short-contact dithranol cream in a supervised treatment regimen, and to determine the degree of improvement in quality of life these topical treatments can accomplish. METHODS: In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily in a 12-week intensive treatment programme. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. Quality of life was assessed with the Skindex-29 and the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). RESULTS: At the end of treatment, no statistically significant differences were found between the calcipotriol and the dithranol group in any of the quality-of-life domains or scales of the Skindex-29 and the SF-36. Over time, a significant improvement of quality of life was found on all three scales of the dermatology-specific Skindex-29, predominantly of a moderate magnitude. In the calcipotriol group, a significant change of a small magnitude was found in the Physical Component Summary of the SF-36. No significant changes were found in the Mental Component Summary (or on any of the eight scales composing the questionnaire) of the SF-36. CONCLUSIONS: The hypothesis was confirmed, that no statistically significant differences in improvement of quality of life could be found between calcipotriol ointment and dithranol short-contact cream in a day-care setting. Given this result, both calcipotriol and dithranol can be welcome alternatives for the patient. Calcipotriol, being more practical and patient friendly, can be considered as a first-line approach in clinical practice. However, in patients recalcitrant to calcipotriol and/or other topical treatments, preference should be given to the dithranol regimen. Topical treatment in combination with interventions explicitly focusing on improvement of coping behaviour and psychosocial functioning may further increase the degree of improvement in the psychosocial domains of quality of life. The results of this study are likely to give further evidence to the notion that the generic SF-36 is little or not responsive to small to moderate changes in quality of life in mild to moderate psoriasis.

A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: a randomized controlled trial of supervised treatment of psoriasis vulgaris in a day-care setting.

BACKGROUND: Calcipotriol has become a first-line treatment for psoriasis. Its efficacy and safety have been shown in many comparative clinical trials carried out in outpatients. In a comparative study in patients visiting the outpatient department once every 14 days, it was shown that calcipotriol was more effective and better tolerated compared with dithranol. OBJECTIVES: To compare the clinical efficacy of calcipotriol ointment with that of dithranol cream in a supervised treatment regimen. METHODS: In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks. RESULTS: This study failed to prove that calcipotriol is as efficacious as dithranol when used in a day-care setting (noninferiority test). The mean percentage reduction in Psoriasis Area and Severity Index from baseline to end of treatment was 57.0% in the calcipotriol group vs. 63.6% in the dithranol group. However, the two-sided test for superiority indicated no statistically significant difference between the treatment groups (P = 0.39). At the end of treatment, 15% of the patients treated with calcipotriol ointment and 25% of those treated with dithranol cream did not require any further treatment. Although calcipotriol ointment appeared to be more effective during the first 8 weeks, a difference was no longer apparent at 12 weeks. In comparison with the high number of drop-outs due to cutaneous side-effects in the calcipotriol group, the frequency of a tolerable degree of irritation appeared to be higher in patients treated with dithranol. However, concomitant corticosteroid treatment of dithranol irritation in seven patients may have contributed to this difference between both treatments. Moreover, patients receiving therapy with calcipotriol ointment experienced fewer application-related skin and subcutaneous tissue disorders than patients treated with dithranol cream: 21 of 53 (40%) and 37 of 52 (71%), respectively. This difference is statistically significant (P = 0.001). CONCLUSIONS: The hypothesis that calcipotriol ointment might be at least as effective as dithranol cream in the day-care setting could not be proven in the present study. Whereas calcipotriol has become a mainstay in the routine outpatient treatment of psoriasis not requiring a day-care setting, dithranol treatment, being difficult as a routine outpatient therapy, has increased efficacy and improved tolerability if the treatment is carried out in a day-care setting.

The risk of Strongyloides stercoralis transmission from patients with disseminated strongyloidiasis to the medical staff.

To assess the risk of Strongyloides stercoralis transmission from two patients with disseminated strongyloidiasis to medical staff who had been in close contact with the patients, blood and stool specimens were obtained from medical staff two to three months after close contact with the patients. Antibodies to S. stercoralis were determined in blood. Stool specimens were tested for parasites with three different procedures.Forty-one medical staff were included. Culture and stool examination were negative in all subjects. Serology was negative in all subjects but one who had a borderline titer without signs or symptoms of strongyloidiasis. No evidence of transmission of S. stercoralis from patients with disseminated strongyloidiasis to medical staff was found.

Resistance of staphylococci in The Netherlands: surveillance by an electronic network during 1989-1995.

An electronic surveillance network for monitoring antibiotic resistance in The Netherlands has been in operation since 1989. Seven public health laboratories participate and the system covers about 25% of all bacteriological determinations in The Netherlands. This paper reports the results of staphylococci isolated in the period 1989-1995. About 0.3% of the Staphylococcus aureus isolates in the study period were resistant to methicillin. This low percentage may be due to the restrictive use of antibiotics and to strict isolation measures aimed at eradicating methicillin-resistant S. aureus. Low frequencies of resistance among methicillin-resistant S. aureus were found for vancomycin (0%), chloramphenicol (11%), cotrimoxazole (11%), mupirocin (3% low-level resistance) and fusidic acid (7%). Twenty-one percent of the coagulase-negative staphylococci were resistant to methicillin. Low frequencies of resistance among these methicillin-resistant coagulase-negative staphylococci were those to vancomycin (0.4%), nitrofurantoin (2%), doxycycline (20%) and amikacin (20%). Coagulase-negative staphylococci from cerebrospinal fluid, blood and skin were less often resistant to quinolones than isolates from respiratory tract, faeces and urine. A significant increase in resistance of coagulase-negative staphylococci to methicillin, erythromycin, gentamicin and ciprofloxacin was observed in the investigated period but the resistance to doxycycline and co-trimoxazole decreased in the last few years. To confirm the determination of methicillin resistance and coagulase production, a PCR method was developed which detects both the mecA and the coagulase gene. The results of the PCR method correlated well with the methicillin MIC as determined by an agar-dilution method.

Moraxella catarrhalis in acute laryngitis: infection or colonization?

The complement phenotypes of Moraxella catarrhalis isolates obtained from adult patients with acute laryngitis were investigated using a microliter serum bactericidal assay and compared with those of other donor groups. Laryngitis isolates had a higher proportion (57%) of complement-resistant strains than did carrier strains from healthy 8- to 13-year-old schoolchildren (16%). The difference between these groups was statistically significant (chi2 [3 x 2 table] = 21.55; P < .001). The relatively frequent occurrence of the complement-resistant (virulence-associated) phenotype in adults with acute laryngitis supports the theory of an active role of M. catarrhalis in the pathogenesis of acute laryngitis.

Complement resistance is a virulence factor of Branhamella (Moraxella) catarrhalis.

The purpose of this study was to investigate complement resistance in Branhamella (Moraxella) catarrhalis isolated from healthy schoolchildren or sputum-producing adult patients. Two techniques were used: a serum bactericidal assay as the gold standard and an easier 'culture and spot' test. Children (age 4-13; n = 303) and patients (n = 1047) showed high colonization/infection rates with B. catarrhalis (31% and 19%, respectively). Complement resistance or intermediate sensitivity occurred frequently in patient isolates (62% and 27%, respectively) and less often in children (33% and 8.5%, respectively; P << 0.0001). In young children (age 4-5 years), the proportion of complement-resistant strains was around 50%. Complement resistance in B. catarrhalis is associated with illness and may hence be considered a virulence factor.

Assessment of complement-mediated killing of Moraxella (Branhamella) catarrhalis isolates by a simple method.

Recently, we showed that complement resistance is an important virulence factor of Moraxella (Branhamella) catarrhalis. Our study used a serum bactericidal assay to determine complement resistance in M. catarrhalis. Although the serum bactericidal assay is considered the "gold standard" for determining complement resistance, it is laborious and time-consuming and therefore not well suited for large-scale studies. Using a large number (n = 324) of M. catarrhalis isolates obtained from the sputa of patients with lower respiratory tract infections (n = 200) and young carriers (n = 124), we assessed the value of a simple "culture-and-spot" test as an alternative to the serum bactericidal assay. For both groups of isolates, the degree of concordance between the two tests used was very significant (P < 0.0001). The agreement between the two assays was estimated to be "excellent beyond chance" (as determined by Cohen's kappa test). The culture-and-spot assay is a valuable alternative to the serum bactericidal assay, not only for screening purposes as shown here but also for studying the mechanism of complement resistance in M. catarrhalis at the molecular level.

Experimental evidence for Moraxella-induced penicillin neutralization in pneumococcal pneumonia.

Resistance of microorganisms to antimicrobial agents is an increasing problem in the treatment of infectious diseases. In mixed infections, an interesting development can arise when one organism protects another from being killed by an antibiotic. Unfortunately, in the case of respiratory tract infections, experimental evidence of this development is poor. In this study, mice intranasally infected with a lethal number of pneumococci and treated with a curative dose of penicillin or amoxicillin died from pneumococcal pneumonia when they were coinoculated with beta-lactamase-producing Moraxella catarrhalis. beta-lactamase-negative M. catarrhalis did not show a similar indirect pathogenic effect. Treatment with a combination of amoxicillin and the beta-lactamase inhibitor clavulanic acid was not affected by beta-lactamase-producing M. catarrhalis. These findings help explain antibiotic failure in respiratory tract infections, even though the causative microorganism is sensitive to the antibiotic in vitro.

Differences in complement activation between complement-resistant and complement-sensitive Moraxella (Branhamella) catarrhalis strains occur at the level of membrane attack complex formation.

The mechanism of resistance to human complement-mediated killing in Moraxella catarrhalis was studied by comparing different complement-sensitive and complement-resistant M. catarrhalis strains in a functional bystander hemolysis assay and an enzyme-linked immunosorbent assay (ELISA) for soluble terminal complement complexes. Complement-resistant stains appeared to activate complement to the same extent as, or even slightly better than, complement-sensitive strains. This indicates that complement-resistant strains do not inhibit classical or alternative pathway activation but interfere with complement at the level of membrane attack complex formation. A clear difference in dose-response curves for resistant and sensitive strains was observed both in the bystander hemolysis assay and in the ELISA. Complement-resistant strains showed optimum curves, whereas complement-sensitive strains gave almost linear curves. We conclude that resistant strains bind and/or inactivate one of the terminal complement components or intermediates involved in membrane attack complex formation. Trypsin, known to abolish complement resistance, changed the optimum dose-response curve of a resistant strain to a linear one, which strongly suggests that complement resistance is mediated by an M. catarrhalis-associated protein. This protein acts directly or through the binding of a terminal complement inhibitor present in serum.

Protective effects of orally administered, Klebsiella-containing bacterial lysates in mice.

The efficacy, as oral vaccines, of hepta- and mono-valent, Klebsiella-containing bacterial lysates and a number of control preparations was tested in mice. The preparations were administered during two periods of four days each, interrupted by an interval of 3 days. Fourteen days after the first dose, the animals were challenged either intraperitoneally (i.p.; peritonitis/sepsis model) or intranasally (i.n.; pneumonia model). Animals treated with low doses of Klebsiella lysate, in the form of either a 7-valent lysate or a Klebsiella monolysate, showed enhanced survival in both the peritonitis/sepsis and the pneumonia models. Hexa- and tetra-valent preparations without Klebsiella were not protective in the models tested. Furthermore, it was found that the protection is accompanied by priming for Klebsiella-specific IgG responsiveness (probably at the T cell level) and by significant IgA anti-Klebsiella serum antibody levels in about one third of the animals. The oral efficacy of Klebsiella-containing lysates suggests the presence of an adjacent component that directs Klebsiella antigen(s) to follow a selective intestinal pathway which renders them immunogenic. The identity of this component is under investigation.

Bacterium-induced autoimmune reactivity.

Evidence is growing that autoimmune reactivity results from a combination of endogenous (e.g. MHC type) and environmental factors. Our experimental study focuses on the induction of autoimmune reactivity by microbial factors. Splenic formation and serum levels of anti-erythrocyte antibodies and circulating immune complexes were taken as parameters. It was found that experimental infection of mice with Escherichia coli and Salmonella typhimurium was accompanied by clear signs of autoimmune reactivity, smooth bacteria being almost ten times as potent as rough mutant strains. An attempt was made to correlate the data obtained with live bacteria to their corresponding endotoxins. It was concluded that the induction of more prominent autoimmune reactivity by smooth bacteria must be ascribed to a longer survival time in vivo. Our data support the view that bacterium-derived factors are involved in the etiology (and possibly also the course) of autoimmune diseases.