Randomised clinical trial: a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis.

BACKGROUND: Tumour necrosis factor alpha (TNFα)-antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα-antagonist-naïve patients with moderate-to-severe active UC despite conventional treatment. AIM: To evaluate dose-response relationship, select IV golimumab induction doses for continued development, and evaluate the safety and efficacy of selected doses. METHODS: Adults with Mayo scores of 6-12 and endoscopic subscores ≥2 were enrolled into this multicentre, randomised, double-blind, placebo-controlled, integrated Phase 2/3 dose-finding/dose-confirming study. In Phase 2, 176 patients were randomised (1:1:1:1) to a single IV infusion of placebo, 1-, 2- or 4-mg/kg golimumab. While Phase 2 data were analysed to select doses for continued development, 71 additional patients were randomised. Phase 3 enrolment stopped after 44 additional patients were randomised (1:1:1) to placebo, 2- or 4-mg/kg golimumab. Due to insufficient power for the Phase 3 primary endpoint analysis (clinical response at week 6), efficacy analyses are considered exploratory and include all randomised patients. RESULTS: No dose-response was observed in Phase 2; however, higher serum golimumab exposure was associated with greater proportions of patients achieving more favourable clinical outcomes, clinical response and greater improvement in Mayo scores compared with placebo-treated patients and those with lower serum concentrations. Among all randomised patients, numerically greater proportions were in clinical response at week 6 in the 2- and 4-mg/kg golimumab groups compared with placebo [44.0% (33/75) and 41.6% (32/77) vs. 30.1% (22/73)]. CONCLUSIONS: Efficacy with single-dose golimumab IV induction was lower than expected and less than observed in the SC induction study. No new safety findings were observed. ClinicalTrials.gov Number, NCT00488774.

Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years.

BACKGROUND: An unmet need remains for safe and effective long-term treatments of psoriasis. OBJECTIVES: To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial. METHODS: Patients (n = 766) with moderate-to-severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re-randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50-74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician's Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures. RESULTS: Overall, 79·8% of the ustekinumab-treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity. CONCLUSIONS; Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.

Cardiovascular safety of ustekinumab in patients with moderate to severe psoriasis: results of integrated analyses of data from phase II and III clinical studies.

BACKGROUND: Patients with psoriasis are believed to be at an increased risk of cardiovascular (CV) morbidity, and the effect of biological agents on CV safety is not fully understood. OBJECTIVES: To evaluate the effect of ustekinumab on CV events using detailed analyses of pooled data from the phase II/III clinical studies of its use in moderate to severe psoriasis. METHODS: The incidence of major adverse CV events [MACE: myocardial infarction (MI), stroke or CV death] is reported. Meta-analyses using risk difference and odds ratio estimates are presented based on data collected during the placebo-controlled period of ustekinumab trials. The cumulative numbers of events and rates of MIs and strokes over time were compared with those expected in the psoriasis and/or general populations. RESULTS: During the placebo-controlled period (12/20 weeks), five MACE were reported in 1582 ustekinumab-treated patients [0·3%; 95% confidence interval (CI) 0·1-0·7%] compared with no events in 732 placebo-treated patients (0·0%; 95% CI 0·0-0·5%). MACE rates were stable over time during both the controlled and uncontrolled study periods, with 19 of 3117 ustekinumab-treated patients (0·6%) experiencing 21 events for a combined event rate per 100 patient-years of follow-up of 0·44 (95% CI 0·27-0·67) through up to 3 years. Standardized incidence ratios for comparison of ustekinumab clinical data with external data sources ranged from 0·34 to 0·52, suggesting no increased risk of MI or stroke in ustekinumab-treated patients compared with the general U.S. and psoriasis populations. CONCLUSIONS: The totality of available clinical data suggests neither a detrimental nor a beneficial effect of ustekinumab on serious CV events. Additional data are needed to define the net effect of ustekinumab on CV events.

Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.

BACKGROUND: Psoriasis affects patients both physically and psychologically. OBJECTIVES: To investigate the effect of comorbidities on health-related quality of life (HRQoL) and to determine whether infliximab improved HRQoL in the presence of these conditions. METHODS: In this multicentre, double-blind study, 835 patients with moderate-to-severe plaque psoriasis were randomized to receive infliximab 3 or 5 mg kg(-1) or placebo at weeks 0, 2 and 6. Infliximab-treated patients were re-randomized at week 14 to receive the same treatment every 8 weeks or as needed through week 46; placebo patients crossed over to infliximab 5 mg kg(-1) at week 16. Disease severity (Psoriasis Area and Severity Index, PASI) and HRQoL (Dermatology Life Quality Index, DLQI; 36-item Short-Form Health Survey, SF-36) were measured at various time points. The effect of patient comorbidities on baseline HRQoL was assessed using multiple regression models. The impact of key comorbidities on infliximab treatment effect was also assessed. RESULTS: Disease severity (PASI), depression and psoriatic arthritis (PsA) were predictors of poor baseline HRQoL. At week 10, infliximab 3 and 5 mg kg(-1) significantly improved physical and mental health dimensions of the SF-36 and the DLQI (all P < 0.001). Consistent improvement in HRQoL with infliximab treatment was observed regardless of baseline patient characteristics or comorbidities. Through week 50, HRQoL and PASI scores were most improved with infliximab 5 mg kg(-1) administered every 8 weeks. CONCLUSIONS: Disease severity, depression and PsA were significant predictors of poor HRQoL. Infliximab significantly improved HRQoL, regardless of these characteristics.

Cardiovascular disease and risk factors among psoriasis patients in two US healthcare databases, 2001-2002.

BACKGROUND: Cardiovascular diseases or risk factors (CVDR) seem to be more common in psoriasis patients than in the general population. OBJECTIVE: We assessed the relationship of psoriasis with CVDR by analysis of healthcare claims data using a cross-sectional, prevalence-based study design. PATIENTS AND METHODS: The IMS Health and MarketScan claims databases were used to identify adults with psoriasis diagnostic codes. Non-psoriasis controls were matched 3:1 based on age, gender, census region and previous medical insurance coverage. Odds ratios evaluated the relative prevalence of CVDR, and Mantel-Haenszel confidence intervals were estimated. RESULTS: CVDR prevalence was generally higher in psoriasis patients than controls in both datasets. Odds ratios for atherosclerosis, congestive heart failure, type 2 diabetes, and peripheral vascular disease were >or=1.20 for psoriasis patients. Elevated disease severity was associated with a higher rate of CVDR, but varied somewhat by dataset and condition. CONCLUSIONS: Elevated CVDR rates were found in psoriasis patients compared with controls. This pattern merits further examination.

Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: Results from the induction and maintenance psoriatic arthritis clinical trial 2.

OBJECTIVE: To evaluate the effect of infliximab on progression of structural damage over 1 year in patients with active psoriatic arthritis (PsA) enrolled in the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2. METHODS: In this double-blind, placebo-controlled study, 200 patients with active PsA were randomly assigned (1:1 ratio) to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6, and every 8 weeks thereafter through week 54. At week 24, patients initially assigned to receive placebo crossed over to receive infliximab (5 mg/kg). Based on predefined criteria, patients randomized to receive placebo could enter early escape by receiving infliximab (5 mg/kg) starting at week 16, and patients randomized to receive infliximab could have the dose increased to 10 mg/kg starting at week 38. Patients were analyzed according to the treatment they were randomized to receive. Radiographs of hands and feet were obtained at baseline and at weeks 24 and 54. Two readers blinded to treatment assignment and radiograph sequence independently evaluated erosions and joint space narrowing using the Sharp/van der Heijde scoring method modified for PsA. RESULTS: At week 24, patients randomized to receive infliximab 5 mg/kg had significantly less radiographic progression compared with patients randomized to receive placebo, with mean +/- SD changes from baseline in the total Sharp/van der Heijde score of -0.70 +/- 2.53 and 0.82 +/- 2.62, respectively (P < 0.001). At week 54, mean +/- SD changes from baseline in the total Sharp/van der Heijde score were -0.94 +/- 3.40 in patients randomized to receive infliximab and 0.53 +/- 2.60 in those receiving placebo/infliximab (P = 0.001). CONCLUSION: Infliximab significantly inhibits radiographic progression in patients with PsA as early as 6 months after starting treatment, and the beneficial effect continues through 1 year of infliximab therapy.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. METHODS: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. RESULTS: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin's lymphoma (infliximab). CONCLUSION: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial.

BACKGROUND: Psoriasis has a well-documented, markedly negative effect on patient quality of life. OBJECTIVES: To evaluate the impact of long-term infliximab maintenance therapy on health-related quality of life (HRQoL) in patients with psoriasis. METHODS: The Dermatology Life Quality Index (DLQI) and 36-item Short Form Health Survey (SF-36) were administered as part of the pivotal double-blind, placebo-controlled efficacy and safety EXPRESS study of infliximab in chronic plaque psoriasis. In total, 378 patients with moderate-to-severe psoriasis were enrolled at 32 centres in Europe and Canada. Patients were randomized to receive either placebo or infliximab 5 mg kg(-1) induction at weeks 0, 2 and 6 followed by maintenance every 8 weeks; placebo patients crossed over at week 24 to receive the infliximab induction and maintenance regimen. RESULTS: At week 10, infliximab-treated patients had significantly greater improvement in DLQI scores (P < 0.001) and SF-36 physical and mental component summary scores (P < 0.001) than placebo-treated patients. Significant improvement (P < 0.001) was also seen in all eight SF-36 subscales, and was greatest for the "Bodily Pain" and "Social Functioning" scales. Significant improvement in HRQoL persisted with maintenance infliximab treatment at week 24 (P < 0.001), with patients achieving a Psoriasis Area and Severity Index score of 0 reporting the greatest benefit. Treatment-related HRQoL improvement remained substantial at week 50. CONCLUSIONS: Infliximab induction and maintenance regimens resulted in rapid, substantial, sustained and clinically meaningful improvement in both dermatology-specific and general quality of life indices in patients with psoriasis, with total clearance resulting in maximum improvement.

Infliximab improves health related quality of life and physical function in patients with psoriatic arthritis.

OBJECTIVES: To evaluate the effect of infliximab on health related quality of life (HRQoL) and physical function in patients with active psoriatic arthritis (PsA) in the IMPACT 2 trial. METHODS: 200 patients with PsA unresponsive to conventional treatment were randomised to intravenous infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22; patients with inadequate response entered early escape at week 16. HRQoL was assessed using the Short Form-36 (SF-36) at weeks 0, 14, and 24. Functional disability was assessed using the Health Assessment Questionnaire (HAQ) at every visit through week 24. Associations between changes in quality of life (SF-36) and articular (American College of Rheumatology (ACR)) and dermatological (Psoriasis Area and Severity Index (PASI)) responses were examined. RESULTS: Mean percentage improvement from baseline in HAQ was 48.6% in the infliximab group compared with worsening of 18.4% in the placebo group at week 14 (p < 0.001). Furthermore, 58.6% and 19.4% of infliximab and placebo treated patients, respectively, achieved a clinically meaningful improvement in HAQ (that is, > or = 0.3 unit decrease) at week 14 (p < 0.001). Increases in physical and mental component summary (PCS and MCS) scores and all eight scales of the SF-36 in the infliximab group were greater than those in the placebo group at week 14 (p < or = 0.001). These benefits were sustained through week 24. Patients achieving ACR20 and PASI75 responses had the greatest improvements in PCS and MCS scores. CONCLUSIONS: In patients with PsA, infliximab 5 mg/kg significantly improved HRQoL and physical function compared with placebo through 24 weeks.

Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial.

BACKGROUND: Psoriasis is a chronic disease that significantly diminishes the health-related quality of life (HRQOL). Infliximab is a chimeric, tumour necrosis factor alpha monoclonal antibody that has been shown to improve the signs and symptoms of plaque psoriasis. OBJECTIVES: The objective of this study was to evaluate the effect of infliximab induction therapy on the HRQOL of patients with severe plaque psoriasis. METHODS: In this double-blind, placebo-controlled trial, 249 patients were randomly assigned to receive intravenous infusions of 3 or 5 mg kg(-1) of infliximab or placebo and were treated at weeks 0, 2 and 6. Patients completed the Dermatology Life Quality Index (DLQI) at baseline and week 10. RESULTS: Infliximab induction therapy resulted in a substantial improvement in HRQOL. At week 10, patients in the infliximab 3- and 5-mg kg(-1) groups showed a median percentage improvement in DLQI scores of 84.0% and 91.0%, respectively, compared with 0% in the placebo group (P < 0.001). The median decrease from baseline in DLQI score at week 10 was 8.0 and 10.0 for the 3 and 5 mg kg(-1) infliximab groups, respectively, compared with 0 in the placebo group (P < 0.001). Thirty-three per cent and 40% of patients in the 3 and 5 mg kg(-1) infliximab groups, respectively, had a DLQI score of 0 at week 10, compared with 2% in the placebo group (P < 0.001). There was a strong correlation between the percentage change from baseline at week 10 in Psoriasis Area and Severity Index (PASI) scores and the percentage change in DLQI scores during the same period (Spearman's correlation, 0.61, P < 0.001). When the infliximab and placebo treatment groups were combined, patients with at least 75% improvement in PASI scores between baseline and week 10 had a greater mean improvement in DLQI scores (81%) than those with 50-75% improvement in PASI during the same period (60%). CONCLUSIONS: Infliximab induction therapy resulted in significant improvement in HRQOL in patients with severe psoriasis.

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial.

OBJECTIVES: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. METHODS: 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. RESULTS: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. CONCLUSIONS: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.

Chronic urticaria and blastocystis hominis infection: a case report.

We report a case of a 45 year old woman which fulfilled the criteria of chronic urticaria (remitting and relapsing bouts of erythematous and pruriginuos lesions without angioedema, lasted four months). Cutaneous manifestations were not related to a specific inducing factor, had no benefit from antihystamine and steroid drugs and were associated sometimes with mild gastroentric disorders. Patient was submitted to extensive clinical, laboratory and intrumental investigations which permit to exclude many conditions: allergy to inhalants, food, insects and drug adverse reactions, autoimmune urticaria, autoimmune diseases, neoplastic and infectious diseases. Finally coprocolture disclosed the presence of Blastocystis hominis in stool samples thus permitting to associate urticaria to parasitic infection. Both cutaneous manifestations and mild abdomen disturbs disappeared after appropriate treatment. Despite the high diffusion the aetiopathogenesis of chronic urticaria remains often undefined. A large number of parasites have been correlated with urticaria but few data exist as regards Blastocystis hominis infection; then our findings may add evidence to the role of this parasite in inducing chronic urticaria. Considering that Blastocystis hominis is a modest pathogen for humans, the mechanism is probably the typical one of cutaneous allergic hypersensitivity; antigen parasites induce the activation of specific clones of Th2 lymphocytes, the release of related cytokines and the consequent IgE production.

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB(389)IL-2) in patients with severe psoriasis.

BACKGROUND: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. OBJECTIVE: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. METHODS: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. RESULTS: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. CONCLUSIONS: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.

Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.

Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

Failure to demonstrate therapeutic tachyphylaxis to topically applied steroids in patients with psoriasis.

BACKGROUND: Tachyphylaxis, defined as a rapidly decreasing response to a physiologically active agent after administration of a few doses, can be well demonstrated in the experimental setting. However, tachyphylaxis in the clinical setting lacks clear demonstration. OBJECTIVE: Our purpose was to identify dermatologists' perception of the clinical incidence of tachyphylaxis and then design a prospective study that would estimate the clinical incidence of tachyphylaxis. METHODS: Clinical and academic dermatologists completed a survey questionnaire about the incidence of tachyphylaxis and the time course to its occurrence. Subjects with plaque psoriasis applied topical corticosteroid twice daily for 12 weeks to their plaques, leaving an isolated plaque untreated for comparison. Plaques were evaluated every 2 weeks. By means of a 9-point scale, an end point for clinical detection of tachyphylaxis was defined as "an increase in plaque elevation of at least 2 occurring after a detectable decrease in plaque elevation with topical steroid." RESULTS: The survey found that 57% of dermatologists perceived that tachyphylaxis occurred after 8 weeks of therapy with topical corticosteroid. In the 12-week clinical study, none of 32 patients exhibited detectable signs of tachyphylaxis. CONCLUSION: What accounts for the commonly held belief of tachyphylaxis in the clinical setting may be related to the therapeutic efficacy of topical corticosteroids. Failure of topical corticosteroids to clear psoriasis after an initial improvement may give the impression of tachyphylaxis. The common clinical perception of tachyphylaxis may also be related to issues of compliance outside a study setting or a psoriasis flare unrelated to therapy.

Effects of acitretin on the liver.

BACKGROUND: Therapy with aromatic retinoids for psoriasis is associated with abnormal liver function test findings and toxic hepatitis (in 1.5% of patients). OBJECTIVE: Our purpose was to determine the safety of acitretin with respect to liver function, on the basis of biopsy. METHODS: We treated 128 adults (with chronic, stable psoriasis) with oral acitretin (25-75 mg/day) for four 6-month intervals in a prospective, open-label, 2-year multicenter study. Liver biopsies were performed before and after study completion (2 years). RESULTS: Eighty-three available pairs of pretreatment and posttreatment liver biopsies demonstrated no change in 49 patients (59%), improvement in 20 (24%), and worsening in 14 (17%). Of these 14 patients with decrements in biopsy status, most changes were mild. There was no correlation between liver function test abnormalities or cumulative acitretin dose and changes in liver biopsy status. CONCLUSION: Acitretin therapy elicited no biopsy-proven hepatotoxicity in this prospective 2-year study. These findings suggest that periodic liver biopsy may not be necessary with acitretin treatment.

Increased formation of thromboxane in vivo in humans with mastocytosis.

Clinical manifestations of mastocytosis are mediated, at least in part, by release of the mast cell mediators histamine and prostaglandin D2. It has been previously reported that in addition to prostaglandin D2, mast cells produce other eicosanoids, including thromboxane. Nonetheless, little information exists regarding the formation of other prostanoids in vivo. The most accurate method to examine the systemic production of eicosanoids in vivo is the quantitation of urinary metabolites. We previously developed a highly accurate assay employing mass spectrometry to measure a major urinary metabolite of thromboxane, 11-dehydro-thromboxane B2, in humans. We utilized this assay to quantitate thromboxane production in 17 patients with histologically proven mastocytosis. We report that thromboxane formation was significantly increased (>2 SD above the mean) in at least one urine sample from 65% of patients studied. Of these, 91% of patients with documented systemic involvement had elevated thromboxane generation. In addition, endogenous formation of thromboxane was highly correlated with the urinary excretion of the major urinary metabolite of prostaglandin D2 (r = 0.98) and Ntau-methylhistamine (r = 0.91), suggesting that the cellular source of increased thromboxane in vivo could be the mastocyte. Enhanced thromboxane formation in patients with this disorder is unlikely to be of platelet origin as other markers of platelet activation, platelet factor 4 and beta-thromboglobulin, were not increased in three patients with marked overproduction of thromboxane. Furthermore, the recovery of 11-dehydro-thromboxane B2 excretion in two patients after the administration of aspirin occurred significantly more rapidly than the recovery of platelet thromboxane generation. These studies, therefore, report that thromboxane production is significantly increased in the majority of patients with mastocytosis that we examined and provide the basis to elucidate the role of this eicosanoid in disorders of mast cell activation.

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Hormonal influences on women with psoriasis.

Various endogenous factors such as stress and infection are known to influence psoriasis. Previous data suggest that pregnancy has a significant influence on the course of psoriasis. This study explores the effect of pregnancy as well as other hormonal events on psoriasis in women.

Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis: a multicenter study.

Topical corticosteroids and keratolytics are both used widely in the management of patients with psoriasis. A combination of the two types of agents may provide enhanced relief. The purpose of this study was to compare the efficacy and safety of the combination ointment mometasone furoate 0.1% plus salicylic acid 5% with that of mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis vulgaris. A total of 408 patients were enrolled in this controlled, randomized, double-masked, parallel-group, multicenter comparison. Patients applied either mometasone furoate-salicylic acid ointment or mometasone furoate ointment alone to target lesions twice daily for 21 days. Severity of erythema, induration, and scaling were scored at baseline and at days 4, 8, 15, and 22. An evaluation of overall change in disease status of all treated lesions was performed at each follow-up visit. Adverse events were also monitored and scored, including signs of skin atrophy. Beginning on day 8, the combination of mometasone furoate-salicylic acid was significantly more effective than mometasone furoate alone, as indicated by the mean percentage of improvement in total disease scores, mean total disease sign scores, and the individual score for scaling. Similarly, the combination was more effective beginning on day 15, as indicated by the global evaluation of overall clinical response and individual scores for erythema and induration. Both treatments were well tolerated. Mometasone furoate-salicylic acid ointment provides more effective treatment of moderate-to-severe psoriasis than does mometasone furoate ointment alone and is safe and well tolerated.