Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Clinical utility of skin cancer and melanoma risk scores for population screening: TRoPICS study.

BACKGROUND: Screening for skin cancer can be cost-effective if focused on high-risk groups. Risk prediction tools have been developed for keratinocyte cancers and melanoma to optimize advice and management. However, few have been validated in a clinical setting over the past few years. OBJECTIVES: To assess the clinical utility of risk assessment tools to identify individuals with prevalent skin cancers in a volunteer-based screening clinic. METHODS: Participants were adults presenting for a skin check at a volunteer-based skin cancer screening facility. We used previously published tools, based on questionnaire responses, to predict melanoma and keratinocyte cancers [KCs; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and classified each participant into one of five risk categories. Participants subsequently underwent a full skin examination by a dermatologist. All suspicious lesions were biopsied, and all cancers were histopathologically confirmed. RESULTS: Of 789 people who presented to the clinic, 507 (64%) consented to the study. Twenty-two BCCs, 19 SCCs and eight melanomas were diagnosed. The proportion of keratinocyte cancers diagnosed increased according to risk category from <1% in the lowest to 24% in the highest risk category (P < 0.001). Subtype analysis revealed similar proportionate increases in BCC or SCC prevalence according to risk category. However, a similar proportion of melanoma cases were detected in the low-risk and high-risk groups. CONCLUSION: The risk prediction model for keratinocyte cancers can reliably identify individuals with a significant skin cancer burden prior to a skin examination in the community setting. The prediction tool for melanoma needs to be tested in a larger sample exposed to a wider range of environmental risk factors.

Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).

BACKGROUND: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. METHODS: In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. RESULTS: At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1-13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8-16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5-17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8-27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. CONCLUSIONS: Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

Secukinumab-Induced Inflammatory Bowel Disease in a Patient Treated for Chronic Plaque Psoriasis and Psoriatic Arthritis: A Case Report and Review of the Role of Novel Biologic Agents Targeting the p19 Subunit of IL-23.

Chronic plaque psoriasis and psoriatic arthritis are common autoimmune inflammatory conditions, often existing as comorbidities that have a significant impact on a patient's quality of life. The availability of a range of novel, targeted therapies for their treatment, most notably the availability of biologic agents, has revolutionised management of these conditions and allowed for significant improvements in patient outcomes. Secukinumab (Cosentyx), a fully-human monoclonal antibody that acts by selectively binding to and neutralising the proinflammatory cytokine IL-17A, is used widely for the treatment of both chronic plaque psoriasis and psoriatic arthritis. In this report, we discuss the case of a 54-year-old female with chronic plaque psoriasis and psoriatic arthritis, who experienced the onset of symptoms and was subsequently diagnosed with Crohn's disease during treatment with secukinumab. It was determined by the gastroenterologist that this may represent secukinumab-induced inflammatory bowel disease. We will review the current understanding of the role of IL-17 in inflammatory bowel disease and the important role of novel agents that target the p19 subunit of IL-23 which have shown significant promise in the management of not only chronic plaque psoriasis and psoriatic arthritis, but also inflammatory bowel disease itself.

Hidradenitis Suppurativa Recurrence in a Caesarean Scar.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic, relapsing inflammatory skin condition characterised by the presence of painful nodules, abscesses, and sinus tracts or scarring. Affecting up to 4% of the population, it is not uncommon and is seen predominantly in females at a ratio of 3 : 1. HS carries a substantial burden for those who suffer from it, from the significant psychosocial impact, to the cost of the multitude of topical and systemic treatments which often do not successfully control its symptoms. In this case report, we discuss a 33-year-old female known to our clinic, who presented with a recurrence of her HS in a caesarean scar, with otherwise silent disease. From our review of the literature, this appears to be only the second case of recurrence of HS in a caesarean scar reported to date. With a predilection for females of reproductive ages, involvement of sensitive areas, and an average of greater than seven years from onset of symptoms until diagnosis, the ability to recognise HS and ensure referral for specialist management is essential for all who are regularly involved in the management of this patient group.

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

An indirect comparison of long-term efficacy of every-2-week dosing vs. recommended dosing of ixekizumab in patients who had static Physician's Global Assessment > 1 at week 12.

BACKGROUND: Long-term efficacy and safety of ixekizumab [160 mg at week 0, then 80 mg every 2 weeks (Q2W) for 12 weeks, followed by every 4 weeks (Q4W) thereafter (i.e. Q2W/Q4W), which is the labelled psoriasis dosing where approved, except in Japan] have been established for the treatment of adults with moderate-to-severe plaque psoriasis. However, some patients may benefit from remaining on Q2W dosing beyond 12 weeks. METHODS: Among patients who had static Physician's Global Assessment (sPGA) > 1 at week 12, efficacy through week 52 of continuous Q2W dosing in the IXORA-P study was compared indirectly with Q2W/Q4W in the integrated data from the UNCOVER-1, UNCOVER-2 and UNCOVER-3 studies. The continuous Q4W dose group, which had comparable results across studies, was used as the common comparator. RESULTS: In the IXORA-P study, among patients with sPGA > 1 at week 12, 64% of patients in the continuous Q2W group achieved sPGA ≤ 1 at week 52, which was statistically significantly higher than the 36% of patients with sPGA > 1 in the Q2W/Q4W group based on the integrated data from the UNCOVER studies (P = 0·0007). There were no clinically meaningful differences in frequencies of safety events between patients with sPGA ≤ 1 and patients with sPGA > 1 at week 12 in the IXORA-P study. CONCLUSIONS: Among patients who did not have clear or almost clear skin at week 12, nearly 30% more patients who were treated continuously with ixekizumab Q2W in IXORA-P had clear or almost clear skin at week 52 when compared indirectly with those who were treated using the labelled psoriasis dosing in integrated UNCOVER studies. What's already known about this topic? Most patients with moderate-to-severe psoriasis who were given the labelled psoriasis dosing of ixekizumab [160-mg loading dose at week 0, 80 mg every 2 weeks (Q2W) through week 12, and 80 mg every 4 weeks (QW4) thereafter] respond quickly with a high percentage of skin clearance. Additionally, patients who achieve static Physician's Global Assessment (sPGA) ≤ 1 by week 12 tend to maintain this response, even after switching to Q4W. What does this study add? Here, we assessed whether patients with sPGA > 1 at week 12 benefited from receiving more frequent dosing beyond the first 12 weeks. The results showed that Q2W dosing beyond 12 weeks resulted in more patients achieving sPGA ≤ 1 by week 52 than the labelled psoriasis dosing among patients with sPGA > 1 at week 12.

Quality of life and social functioning of former long-stay psychiatric patients transferred into the community: a 10 year follow up study.

PURPOSE: Deinstitutionalisation in Ireland began following the impetus of the successful transfer of psychiatric patients into the community in other countries. This study sought to evaluate the quality of life (QoL) and social functioning (SF) of former long-stay institutionalised patients with severe and enduring mental illness who had been relocated into local community settings and followed up 10 years later. METHOD: One month prior to hospital closure, 87 former long-stay psychiatric patients, the majority of whom had a diagnosis of schizophrenia, were assessed on a range of QoL and SF measures. Patients were followed-up 10 years later in the community, to evaluate baseline predictors of quality of life and social functioning. RESULTS: Study completers (n = 35) improved significantly on a range of QoL and SF measures over the 10 year period. Specific improvements were noted in domestic skills (t = - 2.8, p < 0.0008), community skills (t = - 4.9, p < 0.001), as well as the activity and social relations measure (t = - 4.1, p < 0.001). Increased social function (t = - 6.3, p < 0.001) and improvement on the social behaviour scale (t = 7.6, p < 0.001) were noted at follow-up. Linear regression analysis found that less social behaviour problems at baseline predicted QoL 10 years later (t = - 2.6, p < 0.02). CONCLUSION: This study demonstrated that transfer into the community from an institutional environment was associated with long-term improvements in quality of life and social functioning, even in those who spent many years in the institution. Those who demonstrated the greatest improvement in QoL had less social behavioural problems at baseline assessment, providing further evidence of the success of community living for former long-stay patients.

Biosimilars: what the dermatologist should know.

Biosimilars are highly similar versions of approved branded biologics. In contrast to generics, which are identical copies of the originator medicines, biosimilars are considered unique but related molecules that differ from the originator reference product as well as from each other. Owing to the complexity of biologic medicines, such as therapeutic monoclonal antibodies, minor differences between biosimilars and the reference products are acceptable provided these differences do not result in any clinically meaningful differences in safety or efficacy. In addition, minor changes in structure and function may occur over time in originator biologic products as a result of alterations in production materials (e.g. cell lines), processes or conditions. The developmental process for biosimilars focuses on a 'totality of evidence' approach that emphasizes a stepwise investigational process, including comprehensive structural, functional, pharmacologic and clinical assessment for similarity. The goal of the phase 3 clinical development programme for a biosimilar is not to establish efficacy, per se, but to demonstrate that there are no clinically meaningful differences between the proposed biosimilar and the reference product. The requirement to show clinical similarity informs biosimilar study design, including the selection of the patient population, disease state (indication), study endpoints and statistical methods. Based on the clinical trial results in a representative patient population, results may be extrapolated to other indications provided scientific justification is demonstrated based on, among other things, similar mechanism of action in the extrapolated indications. This review presents the current state of knowledge with respect to biosimilars. We aim to provide the practising clinician with a working knowledge of biosimilars as well as provide some practical guidance on their use and potential benefits in treating dermatologic diseases.

Clinical similarity of the biosimilar ABP 501 compared with adalimumab after single transition: long-term results from a randomized controlled, double-blind, 52-week, phase III trial in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: ABP 501, a U.S.A. Food and Drug Administration- and European Medicines Agency-approved biosimilar, is highly similar to adalimumab in structure, function and pharmacokinetics. OBJECTIVES: To demonstrate similarity in efficacy, safety and immunogenicity of ABP 501 vs. adalimumab for moderate-to-severe plaque psoriasis (clinical trial: NCT01970488). METHODS: Patients were randomized (1 : 1) to receive ABP 501 or adalimumab 40 mg every 2 weeks for 16 weeks. At week 16, patients with ≥ 50% improvement from baseline in Psoriasis Area and Severity Index (PASI) score were eligible to continue to week 52. Patients receiving ABP 501 continued; adalimumab patients were rerandomized (1 : 1) to continue adalimumab or undergo a single transition to ABP 501. Key efficacy assessments included percentage PASI improvement from baseline, PASI responders and mean change in affected body surface area from baseline to weeks 16, 32 and 50. Safety was monitored via adverse events (AEs) and antidrug antibodies (ADAs) were assessed. RESULTS: A total of 308 patients were rerandomized at week 16 (ABP 501/ABP 501, n = 152; adalimumab/adalimumab, n = 79; adalimumab/ABP 501, n = 77). PASI percentage improvements from baseline were similar across groups for weeks 16, 32 and 50 (range: 85·8-88·2%), with no significant differences detected across groups in percentages of PASI 50, 75, 90 and 100 responders. Changes from baseline in percentage body surface area affected were similar across groups and time points. No new safety signals were detected. AEs were balanced between groups. Percentages of patients with binding and neutralizing ADAs were similar across treatments. CONCLUSIONS: ABP 501 and adalimumab have similar clinical efficacy, safety and immunogenicity profiles over 52 weeks, including after single transition, in this patient population.

Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies.

Atopic dermatitis (AD), a chronic, relapsing, inflammatory skin disease that is characterized by intense pruritus and eczematous lesions with up to 90% of patients presenting with mild to moderate disease. Current topical treatments for AD have not changed in over 15 years and are associated with safety concerns. In AD, overactivity of phosphodiesterase 4 (PDE4), leads to inflammation and disease exacerbation. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical anti-inflammatory PDE4 inhibitor currently being investigated for the treatment of mild to moderate AD. Preliminary studies in children and adults demonstrated favorable efficacy and safety profiles. Crisaborole may represent an anti-inflammatory option that safely minimizes the symptoms and severity of AD and that can be used for both acute and long-term management.

Frequency of undiagnosed psoriatic arthritis among psoriasis patients in Australian dermatology practice.

BACKGROUND: Psoriatic arthritis commonly develops in psoriasis patients and, if undiagnosed, can lead to potentially avoidable joint damage and an increased risk of comorbidity and mortality. Increased awareness of PsA symptoms among dermatologists provides an opportunity for earlier diagnosis, more timely therapy and prevention of disability. OBJECTIVE: To provide Australian epidemiological data on the frequency of undiagnosed PsA among psoriasis patients in dermatology practice, and to investigate the impact of psoriasis on quality of life and work productivity. METHODS: Nine tertiary centre dermatology practices enrolled patients presenting with plaque psoriasis and no prior rheumatologist-confirmed PsA diagnosis. Patients were screened using the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire and were referred to a rheumatologist for assessment of PsA status using CASPAR criteria if they had a PASE score ≥44. RESULTS: Based on the composite and sequential application of PASE and CASPAR criteria, undiagnosed PsA among psoriasis patients in this study is 9% [95% CI: 6, 12]. The PPV of PASE in this setting is 26% [95% CI: 19, 34]. Nail involvement and chronic large plaque psoriasis were identified as independent positive predictors of PsA, whereas scalp psoriasis was an independent negative predictor of PsA. Patients with moderate-to-severe psoriasis (PASI ≥15) had lower quality of life scores than patients with less severe psoriasis. CONCLUSION: In this study, the frequency of undiagnosed PsA in Australian dermatology practice was 9% among plaque psoriasis patients with no prior PsA diagnosis. Compared with psoriasis alone, the impact of undiagnosed PsA on health-related quality of life of psoriasis patients is substantial.

Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial.

BACKGROUND: Daylight photodynamic therapy (DL-PDT) of actinic keratosis (AK) has shown preliminary efficacy and safety results comparable to conventional photodynamic therapy (c-PDT), using methyl aminolevulinate (MAL) cream. OBJECTIVES: To demonstrate the efficacy and safety of DL-PDT vs. c-PDT in treating mild facial/scalp AK. MATERIALS AND METHODS: This 24-week randomized, controlled, investigator-blinded, multicentre, intra-individual efficacy (non-inferiority) and safety (superiority regarding pain) study enrolled 100 subjects. AKs on the face/scalp were treated once, with DL-PDT on one side and c-PDT on the contralateral side. Primary end points for DL-PDT at week 12 were efficacy [non-inferiority regarding complete lesion response (mild AK)] and safety (superiority regarding subject's assessment of pain). Lesions with complete response 12 weeks after one treatment session were followed until week 24. The safety evaluation included incidence of adverse events. Subject satisfaction was classified using a questionnaire. RESULTS: At week 12, the complete lesion response rate with DL-PDT was non-inferior to c-PDT (89·2% vs. 92·8%, respectively; 95% confidence interval -6·8 to -0·3), confirmed by intention-to-treat analysis. Additionally, regardless of the treatment used, 96% of mild lesions were maintained in complete response 24 weeks after the PDT session. For DL-PDT, subject-reported pain was significantly lower (0·8 vs. 5·7, respectively; P < 0·001), with better tolerability and significantly higher subject satisfaction regarding convenience and outcome. CONCLUSIONS: Daylight-mediated PDT was not inferior in efficacy to Metvix c-PDT (mild AK response rate), better tolerated, nearly painless and more convenient for patients.

Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities.

BACKGROUND: Methyl aminolaevulinate-photodynamic therapy (MAL-PDT) is an effective treatment in facial/scalp actinic keratosis (AK). OBJECTIVES: The aims of this study were to compare efficacy, safety, cosmetic outcome and patient preference of MAL-PDT vs. cryotherapy in patients with AK at other locations. METHODS: A multicentre, controlled, randomized, open, intraindividual, right-left comparison was performed. Patients with nonhyperkeratotic AK were treated once with MAL-PDT and cryotherapy on either side of the body. At week 12, lesions showing noncomplete response were retreated. The primary efficacy variable was the lesion response at week 24. Investigator's assessment of cosmetic outcome, patient's preference in terms of cosmetic outcome and a patient preference questionnaire were also analysed at week 24. RESULTS: In total, of 121 patients with 1343 lesions (98% located on the extremities and the remainder on the trunk and neck) were included. Both treatments provided a high mean percentage reduction in lesion count at week 24 with significantly higher efficacy for cryotherapy: 78% for MAL-PDT and 88% for cryotherapy (P=0.002, per protocol population). Investigator's assessment of cosmetic outcome was significantly better for MAL-PDT than cryotherapy (P<0.001), 79% of lesions having an excellent cosmetic outcome with MAL-PDT vs. 56% with cryotherapy at week 24. The cosmetic outcome achieved by MAL-PDT compared with cryotherapy was also preferred by patients (50% vs. 22%, respectively, P<0.001), and 59% of patients would prefer to have any new lesions treated with MAL-PDT compared with 25% with cryotherapy (P<0.001). Both treatment regimens were safe and well tolerated. CONCLUSIONS: MAL-PDT showed inferior efficacy for treatment of non-face/scalp AK compared with cryotherapy. However, both treatments showed high efficacy, and MAL-PDT conveyed the advantages of better cosmesis and higher patient preference.

Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia.

AIMS: To determine whether there is an association between Type 2 diabetes mellitus and schizophrenia, independent of medication. METHODS: In this cross-sectional study we performed an oral glucose tolerance test on 38 non-obese white Caucasians who fulfilled the criteria for first-episode drug-naïve schizophrenia, 38 control subjects (matched for age, gender, smoking status, alcohol intake and ethnicity) and 44 first-degree relatives of the patients. RESULTS: The frequency of impaired glucose tolerance (IGT), defined by World Health Organization criteria, was 10.5% (n = 4) in patients with schizophrenia, 18.2% (n = 8) in unaffected relatives and 0.0% in healthy control subjects (chi(2) = 4.22, d.f. = 2, P < 0.05). CONCLUSIONS: The high point prevalence of IGT in never-treated patients and relatives supports either shared environmental or genetic predisposition to IGT. Both patients and their relatives present an ideal cost-effective opportunity to screen for Type 2 diabetes mellitus, as they are both easily identifiable.

Is the L-tryptophan metabolite quinolinic acid responsible for eosinophilic fasciitis?

The eosinophilia-myalgia syndrome is accompanied by alterations in L-tryptophan metabolism with elevated levels of L-kynurenine and quinolinic acid having been recorded. It has been suggested that this is due to activation of indoleamine 2,3-dioxygenase by interferon-gamma. It is unknown whether these products of tryptophan metabolism play a role in the pathogenesis of this syndrome and the closely related condition of eosinophilic fasciitis. To explore this possibility, the principal author (RN) received a series of subcutaneous injections of quinolinic acid. A total of 1200 mg was administered over a 1-month period. Peripheral blood eosinophil counts were monitored and biopsies taken for H&E and immunohistochemical stains. Over the 1-month period the eosinophil count rose from 0.3x10(9)/l to 0.8x10(9)/l before falling to 0.4x10(9)/l approximately 5 weeks later. H&E sections showed a mixed infiltrate of eosinophils and neutrophils extending through the reticular dermis and septa of the panniculus. No deep fascia was obtained on biopsy. The immunohistochemical stain for transforming growth factor beta 1 showed staining of endothelial cells and dendritic cells. The interleukin-5 stain was negative. Our results suggest that quinolinic acid may play a role in cutaneous eosinophilic disorders.

Photodynamic therapy with topical methyl aminolaevulinate for 'difficult-to-treat' basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) may be difficult to treat by conventional means, particularly if the lesions are large or located in the mid-face (H-zone). Photodynamic therapy (PDT) using topical methyl aminolaevulinate (MAL) may be a good noninvasive option for these patients. OBJECTIVES: To investigate the efficacy and safety of PDT using MAL for BCCs defined as 'difficult to treat', i.e. large lesions, in the H-zone, or in patients at high risk of surgical complications. METHODS: This was a prospective, multicentre, noncomparative study. Patients were assessed 3, 12 and 24 months after the last PDT treatment. One hundred and two patients with 'difficult-to-treat' BCC were treated with MAL PDT, using 160 mg g(-1) cream and 75 J cm(-2) red light (570-670 nm), after lesion preparation and 3 h of cream exposure. Results Ninety-five patients with 148 lesions were included in the per protocol analysis. The histologically confirmed lesion complete response rate at 3 months was 89% (131 of 148). At 12 months, 10 lesions had reappeared, and therefore the cumulative treatment failure rate was 18% (27 of 148). At 24 months, an additional nine lesions had reappeared, resulting in a cumulative treatment failure rate of 24% (36 of 148). The estimated sustained lesion complete response rate (assessed using a time-to-event approach) was 90% at 3 months, 84% at 12 months and 78% at 24 months. Overall cosmetic outcome was judged as excellent or good in 79% and 84% of the patients at 12 and 24 months, respectively. Follow-up is continuing for up to 5 years. CONCLUSIONS: MAL PDT is an attractive option for 'difficult-to-treat' BCC. Because of the excellent cosmetic results, the treatment is particularly well suited for lesions that would otherwise require extensive surgical procedures.

A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study.

BACKGROUND: Actinic keratosis (AK) is a very common condition, which has the potential of progressing to squamous cell carcinoma. The present study is a prospective, randomized study comparing the lesion response, cosmetic outcome, patient satisfaction and tolerability of a new treatment modality, photodynamic therapy (PDT), using topical methyl aminolevulinate (Metvix), with the most commonly used standard therapy for AK, cryotherapy. METHODS: A total of 204 patients with clinically diagnosed AK were randomized to either cryotherapy or PDT. The PDT patients were further assigned to an active or placebo group in a random, double-blind manner. Cryotherapy was performed using liquid nitrogen spray in a single freeze-thaw cycle. PDT was performed using 160 mg/g methyl aminolevulinate cream or placebo, a 3-hour application time, red light (570-670 nm) and a total light dose of 75 J/cm(2). PDT was repeated after 7 days. Two sessions of PDT were undertaken, as a previous study had shown a single session had similar efficacy to cryotherapy. Lesion response was assessed clinically after 3 months (complete response or non-complete response). RESULTS: The lesion response rate was 91% in the methyl aminolevulinate PDT group, 68% in the cryotherapy group and 30% in the placebo PDT group. Methyl aminolevulinate PDT was statistically significantly better than both cryotherapy and placebo PDT in terms of response rates and cosmetic outcome. Most patients preferred PDT to other treatments. CONCLUSIONS: PDT with methyl aminolevulinate is an excellent treatment option, particularly for patients with widespread damage or AK lesions in cosmetically sensitive areas.