Minimal clinically important difference (MCID) for work productivity and activity impairment (WPAI) questionnaire in psoriasis patients.

BACKGROUND: The clinical meaningfulness of improvements in the Work Productivity and Activity Impairment Questionnaire for Psoriasis (WPAI-PsO) reported by patients with psoriasis in response to treatment is unknown due to the lack of any publications that report minimal clinically importance differences (MCID) for WPAI-PsO outcomes. OBJECTIVE: To determine the MCIDs for the work productivity loss and activity impairment domains of the Work Productivity and Activity Impairment Questionnaire for Psoriasis (WPAI-PsO) using results from three Phase 3 trials of ixekizumab. METHODS: MCIDs for WPAI-PsO domains were derived using treatment agnostic data from patients participating in UNCOVER-1/-2/-3. The analysis included patients randomized to placebo and two ixekizumab treatment groups (ixekizumab either every 2 weeks or 4 weeks) from the trials. WPAI-PsO was administered at baseline and Week 12 for UNCOVER-1/-2/-3 and at Weeks 24, 36, 52 and 60 in UNCOVER-1/-2. MCIDs for the WPAI-PsO domains through Week 12 were derived using an anchor-based method supplemented with the distribution-based method. Anchors included 75%/90%/100% improvement in Psoriasis Area and Severity Index, Static Physicians Global Assessment (sPGA[0] and sPGA[0,1]) and Dermatology Life Quality Index MCID). MCIDs were triangulated using receiver operating characteristics (ROC) and distribution-based methods. RESULTS: The analyses included 3126 patients (Placebo: 792, Ixekizumab: 2334). All anchors were shown to be valid. Significant differences in the domains of WPAI-PsO were observed between patients achieving clinically meaningful improvement in the validated anchors (all P-values < 0.001). ROC analyses suggested a 20% improvement in the work productivity loss or activity impairment components best represented the benefit of meeting a clinical meaningful improvement in the validated anchors. The distribution-based method supported the results of the anchor-based method. CONCLUSION: The MCIDs for both the work productivity loss and the activity impairment domains of WPAI-PsO were estimated to be 20% in patients with PsO.

Ixekizumab treatment improves fingernail psoriasis in patients with moderate-to-severe psoriasis: results from the randomized, controlled and open-label phases of UNCOVER-3.

BACKGROUND: Fingernail psoriasis is difficult to treat. OBJECTIVE: The objective was to evaluate the effect of ixekizumab, a monoclonal antibody selectively targeting IL-17A, on fingernail psoriasis. METHODS: This Phase 3, double-blind trial (UNCOVER-3) randomized patients to placebo, etanercept (50-mg twice weekly), or 80 mg ixekizumab as one injection every 4 (IXE Q4W) or 2 weeks (IXE Q2W) after a 160-mg starting dose. At Week 12, ixekizumab patients received open-label IXE Q4W through Week 60; placebo patients received a 160-mg starting ixekizumab dose and etanercept patients a 4-week placebo washout before starting IXE Q4W. Efficacy was assessed by mean per cent Nail Psoriasis Severity Index (NAPSI) improvement at Weeks 12 and 60. RESULTS: Of 1346 patients in the UNCOVER-3 trial, this subgroup analysis included only patients with baseline fingernail psoriasis: 116 (60.1%) placebo, 236 (61.8%) etanercept, 228 (59.1%) IXE Q4W and 229 (59.5%) IXE Q2W. At Week 12, greater mean per cent NAPSI improvements were achieved in IXE Q4W (36.7%) and IXE Q2W (35.2%) vs. placebo (-34.3%, P < 0.001 each comparison) and etanercept (20.0%, P = 0.048 vs. Q4W, P = 0.072 vs. Q2W). At Week 60, mean per cent NAPSI improvement was >80% regardless of initial treatment. At Week 12 (nonresponder imputation), complete resolution (NAPSI = 0) was achieved in 19.7% (IXE Q4W), 17.5% (IXE Q2W), 4.3% (placebo, P < 0.001 each comparison) and 10.2% (etanercept, P < 0.05 each comparison) of patients. By Week 60, >50% of patients achieved complete resolution. CONCLUSIONS: At Week 12, significant improvements in fingernail psoriasis were achieved with ixekizumab therapy. With IXE Q4W maintenance dosing, additional improvement was demonstrated through 60 weeks, and >50% of patients achieved complete resolution. Registered at clinicaltrials.gov: NCT01646177.

Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis.

BACKGROUND: Scalp and nail psoriasis have a major impact on quality of life and are traditionally resistant to therapy. Ixekizumab is a monoclonal antibody that targets IL-17A, a key cytokine in psoriasis pathogenesis. OBJECTIVE: Changes in nail and scalp psoriasis associated with ixekizumab treatment were evaluated in a post hoc analysis of a phase 2 study comprising a 20-week randomized, placebo-controlled (RCT) period and 48 weeks of an open-label extension (OLE) period. METHODS: There were 142 patients with moderate-to-severe plaque psoriasis at baseline of the RCT. Patients were randomized to receive placebo, 10, 25, 75 or 150 mg of ixekizumab injected subcutaneously at weeks 0, 2, 4, 8, 12 and 16. In the OLE, all patients received 120 mg ixekizumab every 4 weeks. Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) were used to evaluate nail and scalp psoriasis respectively. Fifty-eight (41.0%) patients had nail psoriasis (NAPSI > 0) and 105 (74.0%) had scalp psoriasis (PSSI > 0) at baseline; these cases were evaluated for the present analyses. RESULTS: At RCT week 20, patients with scalp psoriasis in the 25-, 75- and 150-mg groups had significant mean change and percent improvement from baseline PSSI of -16.3 (75.3%; P = 0.001), -11.6 (83.7%; P = 0.001) and -18.2 (82.2%; P < 0.001) respectively compared to -6.0 (18.8%) in placebo. Patients with nail psoriasis in the 75- and 150-mg groups had significant improvements from baseline NAPSI of -26.3 (63.8%; P = 0.003) and -23.1 (52.6%; P = 0.009) respectively compared to 0.4 (-1.7%) in placebo. By OLE week 48, 78.0% of patients with scalp psoriasis and 51.0% of patients with nail psoriasis experienced complete resolution of lesions (PSSI = 0 or NAPSI = 0). CONCLUSIONS: Ixekizumab monotherapy improved scalp psoriasis quickly with maintenance of clinical response and complete resolution of plaques in the majority of patients. Additionally, over 50.0% of patients with nail psoriasis experienced complete resolution of nail lesions by OLE week 48.

Changes in C-reactive protein in patients with moderate-to-severe psoriasis switched to adalimumab therapy after suboptimal response to etanercept, methotrexate or phototherapy.

BACKGROUND: Psoriasis treatment can lower levels of the inflammatory biomarker C-reactive protein (CRP). OBJECTIVE: Evaluate CRP changes in patients with chronic plaque psoriasis who switched to adalimumab following suboptimal response to previous therapies. METHODS: C-reactive protein was measured at screening and after 16 weeks of adalimumab treatment following discontinuation of previous therapies: etanercept (substudy E; n = 77), methotrexate (substudy M; n = 38) or narrow-band ultraviolet B phototherapy (substudy P; n = 27). Associations of CRP with baseline characteristics and efficacy measures were evaluated. RESULTS: Median CRP change at the final visit was -0.3 mg/L overall and -0.4, -0.3 and -0.3 mg/L in substudies E, M and P respectively. Clinical response [Physician Global Assessment (PGA) 'clear' or 'minimal'] was associated with greater CRP reductions vs. no response (PGA 'mild' or worse) overall (-0.4 vs. -0.3 mg/L) and in substudies E (-0.4 vs. -0.1 mg/L) and M (-0.5 vs. -0.2 mg/L), but not P (-0.1 vs. -0.4 mg/L). CRP decreases were, respectively, -0.4 and -0.3 mg/L in patients with and without a history of psoriatic arthritis and -0.1, -0.3 and -0.6 mg/L in normal weight, overweight and obese patients, respectively. CRP decreases after 16 weeks correlated positively (ß = 0.004) with percentage change in Psoriasis Area and Severity Index (PASI; P = 0.0398) and negatively (ß = -0.360) with baseline CRP (P < 0.0001). CONCLUSION: C-reactive protein levels decreased during adalimumab therapy in patients with psoriasis who experienced suboptimal response to previous therapies. Clinical response was associated with greater CRP reductions overall and in substudies E and M, but not P. CRP reductions correlated with percentage reductions in PASI.

Efficacy of adalimumab across subgroups of patients with moderate-to-severe chronic plaque psoriasis of the hands and/or feet: post hoc analysis of REACH.

BACKGROUND: The Randomized Controlled Evaluation of Adalimumab in Treatment of Chronic Plaque Psoriasis of the Hands and Feet (REACH) trial demonstrated that adalimumab was efficacious and well-tolerated for the treatment of hand and/or foot psoriasis through 28 weeks. OBJECTIVE: To evaluate the effects of patient baseline characteristics on efficacy of adalimumab treatment of hand and/or foot psoriasis. METHODS: Patients with moderate-to-severe chronic plaque psoriasis of the hands and/or feet were randomized 2 : 1 to adalimumab or placebo during the 16 week, double-blind period of REACH. Primary endpoint was percentage of patients achieving Physician's Global Assessment of the hands and/or feet of clear/almost clear at week 16. Post hoc analyses evaluated effects of baseline patient characteristics on the primary endpoint. Patients with nail psoriasis at baseline were assessed for association of Nail Psoriasis Severity Index (NAPSI) 50 response with efficacy outcomes at week 16. RESULTS: Seventy-two patients (49 adalimumab : 23 placebo) were analysed. Greater percentages of adalimumab-treated patients achieved the primary endpoint vs. placebo across all subgroups. Among 31 patients with nail psoriasis, a greater percentage of adalimumab-treated patients achieved NAPSI 50 (56.5%) vs. placebo (12.5%) at week 16. In adalimumab-treated patients, greater percentages of NAPSI 50 Responders vs. Non-responders achieved the primary endpoint, and had greater improvements in erythema, scaling, induration and fissuring, Dermatology Life Quality Index, and pain scores. CONCLUSIONS: Adalimumab was efficacious in treating chronic plaque psoriasis of the hands and/or feet over 16 weeks, regardless of baseline characteristics. Marked improvement in nail psoriasis among adalimumab-treated patients correlated with significant improvements in skin disease and patient-reported outcomes.

Sleep quality and other patient-reported outcomes improve after patients with psoriasis with suboptimal response to other systemic therapies are switched to adalimumab: results from PROGRESS, an open-label Phase IIIB trial.

BACKGROUND: Psoriasis is associated with poor health-related quality of life, including sleep impairment. OBJECTIVE: To assess the extent of sleep impairment, the effect of adalimumab on sleep and other patient-reported outcomes, and correlations between changes in these outcomes and sleep quality in patients with psoriasis. METHODS: Patients in the 16-week, open-label, Phase IIIb PROGRESS trial had chronic plaque psoriasis and suboptimal response to prior therapy (etanercept, methotrexate or narrowband ultraviolet B phototherapy). Adalimumab was self-injected subcutaneously (80 mg at week 0, then 40 mg every other week from week 1). The focus for this analysis was the Medical Outcomes Study Sleep Scale. Other patient-reported outcomes included the Dermatology Life Quality Index (DLQI), Psoriasis Area and Severity Index (PASI), Physician's Global Assessment, a visual analogue scale for psoriasis/psoriatic arthritis (PsA) pain, and the Work Productivity and Activity Index Questionnaire-Specific Health Problems. RESULTS: Patients with psoriasis had impaired sleep at baseline. The degree of sleep impairment was significantly associated with the extent of work productivity for all sleep measures and, for some sleep measures, was associated with DLQI impairment, clinical severity measured by PASI, the presence of PsA, and depression. Adalimumab treatment significantly improved sleep quality by 15% from baseline, as well as DLQI score, pain and work productivity. The improvement in sleep was partially explained (R(2 ) = 0·16, P < 0·001) by improvements in the objectively measured psoriasis signs in PASI. CONCLUSIONS: Adalimumab treatment improved sleep outcomes and other patient-reported outcomes including health-related quality of life, work productivity, daily activity and disease-related pain.

Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti-tumour necrosis factor agents: subanalysis of BELIEVE.

BACKGROUND: Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti-TNFs) is likely to improve psoriasis in patients with prior anti-TNF treatment. OBJECTIVE: The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti-TNF treatment. METHODS: The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16-week, double-blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1-15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti-TNFs. RESULTS: Of 730 patients enrolled, 282 (38.6%) had prior anti-TNFs and 448 (61.4%) were anti-TNF-naïve. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti-TNFs achieved PASI 75 at week 16, compared with 71.7% of anti-TNF-naïve patients (P=0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti-TNF agent had been used, the number of prior anti-TNFs tried, or reasons for discontinuation of prior anti-TNF therapy. Adverse event incidences were similar between patients with and without prior anti-TNF therapy. CONCLUSION: Adalimumab was effective and well-tolerated in patients with psoriasis previously treated with anti-TNF therapy.

Using personal digital assistants to enhance outcomes.

Personal digital assistants (PDA) are attaining increased functionality in the medical community. Physicians can use PDAs to track patient information (namely, outcome parameters and medication errors). ePhysician's ePad is demonstrated here as a successful technology for tracking and analyzing both patient and practice data.

Electronic prescribing: criteria for evaluating handheld prescribing systems and an evaluation of a new, handheld, wireless wide area network (WWAN) prescribing system.

OBJECTIVE: The objectives of this study were: 1) to establish criteria for evaluating handheld computerized prescribing systems; and 2) to evaluate out-of-box performance and features of a new, Palm Operating System (OS)-based, handheld, wireless wide area network (WWAN) prescribing system. The system consisted of a Palm Vx handheld organizer, a Novatel Minstrel V wireless modem, OmniSky wireless internet access and ePhysician ePad 1.1, the Palm OS electronic prescribing software program. DESIGN: A dermatologist familiar with healthcare information technology conducted an evaluation of the performance and features of a new, handheld, WWAN electronic prescribing system in an office practice during a three-month period in 2000. System performance, defined as transmission success rate, was determined from data collected during the three-month trial. Evaluation criteria consisted of an analysis of features found in electronic prescribing systems. METHODS: All prescriptions written for all patients seen during a three-month period (August - November, 2000) were eligible for inclusion. Prescriptions written for patients who intended to fill them at pharmacies without known facsimile receiving capabilities were excluded from the study. The performance of the system was evaluated using data collected during the study. Criteria for evaluating features of electronic prescribing systems were developed and used to analyze the system employed in this study. RESULTS: During this three-month trial, 200 electronic prescriptions were generated for 132 patients included in the study. Of these prescriptions, 92.5 percent were successfully transmitted to pharmacies. Transmission failures resulted from incorrect facsimile numbers and non-functioning facsimile machines. Criteria established for evaluation of electronic prescribing systems included System (Hardware & Software), Costs, System Features, Printing & Transmission, Formulary & Insurance, Customization, Drug Safety and Security. CONCLUSION: This study is the first effort to establish comprehensive criteria for evaluating handheld prescribing systems and to evaluate the performance and features of a handheld, electronic prescribing system. The results demonstrated that the evaluated system: 1) was simple to install; 2) successfully interfaced with a commonly used practice management system; 3) was user-friendly and easy to operate; 4) offered a robust variety of standard features; and, 5) resulted in a high rate of success for transmitting electronic prescriptions. The criteria established for the evaluation of features of an electronic prescribing system can be used to critically evaluate the performance and features of other handheld and personal computer-based electronic prescribing systems.

Neonatal citrullinemia associated with cutaneous manifestations and arginine deficiency.

A patient with neonatal citrullinemia (argininosuccinic acid synthetase deficiency), a heritable disorder of the urea cycle, developed a generalized cutaneous eruption at 35 days of age. The skin lesions consisted of erosive, erythematous, scaling patches and plaques. The plasma arginine concentration at that time was low. After treatment with oral arginine supplements, the cutaneous lesions rapidly resolved and the plasma arginine concentration normalized. Histologic features of pretreated lesions included parakeratosis, crust formation, absence of a granular cell layer, pallor of the upper epidermal cells, and a mild, superficial, perivascular, mononuclear-cell infiltrate. Since the patient's skin lesions responded to arginine supplements, and since arginine is a component of keratin, we postulate that the skin lesions are the result of arginine deficiency.

Pseudo-Kaposi's sarcoma of the hand associated with an acquired, iatrogenic arteriovenous fistula.

Pseudo-Kaposi's sarcoma has been associated, in most cases, with an underlying congenital arteriovenous (AV) fistula. A patient with chronic renal failure and an acquired, iatrogenic AV fistula in his left wrist for hemodialysis developed pseudo-Kaposi's sarcoma on his left hand three years after placement of the AV fistula. Histologic findings included a proliferation of superficial dermal vessels and fibroblasts, extravasated red blood cells, and occasional fibrin thrombi in vessels. To our knowledge, this is the third case of an association between pseudo-Kaposi's sarcoma and an acquired, iatrogenic AV fistula, and the first to involve the hand. Pseudo-Kaposi's sarcoma occurs in association with underlying congenital and acquired AV fistulas.

Dimethyl sulfoxide (DMSO) does not affect epidermal wound healing.

We studied the effect of 95% DMSO on dermal/epidermal healing and microbiol flora in partial-thickness wounds. Wounds of 0.3 mm were made in the skin of Yorkshire pigs with a keratome and treated daily with either 95% DMSO, water, or they were left untreated. Wounds were excised on Days 2-7 and the dermis was separated from the epidermis. The dermis was assayed for collagen biosynthesis (by measuring the production of [14C]hydroxyproline (HP) and amount of radioactive peptides released after collagenase digestion) and absolute HP (by spectrophotometric analysis). The epidermis was evaluated macroscopically for resurfacing. Aerobic bacteria from unwounded and wounded skin were identified and quantitated. There were no significant differences between treatment groups in HP incorporation or absolute collagen content from Days 2-6 after wounding. HP incorporation in the total protein fractions and in the collagenase digestible fractions were analogous. Collagen biosynthesis was similar in both unwounded, untreated, and unwounded DMSO-treated skin. Epidermal healing did not differ between treatment groups. There were no differences in the number or types of bacteria in wounds between treatment groups. These results indicate that topical DMSO is neither beneficial nor harmful in the healing of superficial wounds.

Intragastric feeding in the neonatal dog. Its effect on intestinal osmolality.

Hypertonic formulas have been implicated in the etiology of necrotizing enterocolitis. We measured the osmolality of neonatal canine intestinal contents one hour after intragastric feeding of isotonic breast milk, isotonic formula, or hypertonic formula in 1-day-old and 9-day-old puppies. Regardless of the formula tonicity, all intestinal contents were hypertonic in both segments. Hypertonic formula had been diluted, and isotonic feedings concentrated in the neonatal canine intestine. Gastric contents could be recovered only from hypertonic-fed puppies, which implies delayed gastric emptying to permit formula dilution. We conclude that any form of neonatal feeding can lead to hypertonic intestinal contents. Factors other than tonicity of a formula should be considered in the pathophysiology of necrotizing enterocolitis.