Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta-analysis.

BACKGROUND: The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development. OBJECTIVES: To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis. METHODS: We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency. RESULTS: We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution. CONCLUSIONS: Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.

Persistence and effectiveness of nonbiologic systemic therapies for moderate-to-severe psoriasis in adults: a systematic review.

BACKGROUND: The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized. OBJECTIVES: To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months. METHODS: MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771. RESULTS: Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA. CONCLUSIONS: The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Paediatric vulval lichen sclerosus: a retrospective study.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory dermatosis with a predilection for the anogenital region, which mainly affects prepubertal girls and postmenopausal women. The cause is unknown, but a number of potential aetiological factors have been identified. AIM: To examine a cohort of patients with prepubertal-onset vulval LS (VLS) and assess baseline characteristics, clinical presentation, potential precipitating and predisposing factors, and response to treatment. METHODS: Data were collected from case notes on patients aged < 18 years diagnosed with prepubertal-onset VLS attending a specialist vulval dermatology service. Data included clinical presentation, comorbidities, family history, therapy and response to treatment. RESULTS: In total, 26 paediatric patients were identified. The median age at onset of symptoms was 5 years (range 2-8.5 years). Many previously identified potential aetiological factors for the development of VLS were identified, including family history, trauma, autoimmune disease and hormonal factors. A significant proportion of patients had a history of urinary tract symptoms, including incontinence and urinary tract infection. Most patients responded well to a standard course of induction topical therapy followed by maintenance therapy, but some, including three patients with ongoing urinary incontinence and three postpubertal patients, continued to have active disease. CONCLUSION: A detailed assessment is essential in patients with VLS so that potential predisposing factors and comorbidities can be identified and managed. Urinary incontinence may be implicated in the development of paediatric VLS and may prevent adequate disease control. Paediatric VLS can persist through puberty, thus long-term follow-up is advised.

Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

BACKGROUND: Treatment modifications, including dose escalations, dose reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined. OBJECTIVES: To examine the treatment utilization patterns of adalimumab, etanercept and ustekinumab among biologic-naïve and non-naïve patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register (BADBIR). METHODS: The study cohort included adults with chronic plaque psoriasis who were followed up for ≥ 12 months. Treatment modifications were assessed during the first year of therapy. The time-trend method, comparing the cumulative dose (CD) patients received with the recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant use of other systemic treatments was also examined. RESULTS: In total, 2980 patients (adalimumab: 1675; etanercept: 996; ustekinumab: 309) were included; 79·2% were biologic-naïve. Over 12 months, 77·4% of patients continued the biologic, 2·6% restarted therapy after a break of ≥ 90 days, 2·5% discontinued, and 17·5% switched biologic therapy. Most patients (85·7%) received the RCD of the biologic, although 8·1% were exposed to a higher CD. In total, 749 (25·1%) patients used conventional systemic therapies concomitantly with a biologic at some stage; methotrexate was used most commonly (458; 61·2%). Of those using combination therapy, 454 (60·6%) continued the use of the conventional systemic therapy for > 120 days after the start of the biologic. CONCLUSIONS: More than one-third of patients experienced treatment modifications within the first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate, were commonly used concurrently, which should be considered when evaluating treatment response and adverse events to biologics in real-world observational studies.

Mid-face toddler excoriation syndrome (MiTES): a new paediatric diagnosis.

Chronic ulcerating lesions on the face are rarely seen in toddlers. Blistering disease, vasculitis, infections and self-mutilation due to neurometabolic disease can usually be excluded on clinical and histological grounds. In the absence of identifiable disease, such lesions are sometimes attributed to child abuse or fabricated illness. We describe three toddlers with chronic mid-face erosions, two from India and one from the UK. One had moderate developmental delay and one had had seizures. The lesions appeared to be self-inflicted, no underlying disease was identified and there was no suspicion of child abuse. Recognition of the same disease pattern in different continents implies a distinct pathological entity. The pattern closely resembles that seen in some patients with mutations in the pain-insensitivity genes PRDM12 and SCN11A. We suggest the term 'mid-face toddler excoriation syndrome' (MiTES) to acknowledge the existence of this condition, encourage further reports and help clarify the pathogenesis.

A case of human to human transmission of orf between mother and child.

Orf is caused by a parapoxvirus. In adults, it is commonly associated with specific occupations, whereas cases in children tend to be associated with household or recreational exposure. Spontaneous recovery usually occurs within 6 weeks. Infection in humans is believed to be through exposure to an infected animal or fomite. We present a case of a 13-month-old boy who was exposed to orf through his mother, a farmer, who had contracted the disease through administering medication to an infected animal. We believe that this may represent only the fifth case of human to human transmission of orf reported in the literature.

Steady state visual evoked potential (SSVEP) changes in response to olfactory stimulation.

The location, nature and characteristics of brain activity during detection and identification of odors are of importance if brain function techniques are to be of value to sensory systems. Steady state probe topography (SSPT) has been used in our laboratory to record steady state visual evoked potentials (SSVEP), which have demonstrated cognitive task-related changes in a variety of testing paradigms. The enhanced spatial (when using 64 channels) and temporal resolution (380 ms) of the system enable the brain electrical activity changes occurring before, during and after delivery of an odor to be examined. We have developed a system which can deliver odors during normal respiration and the accurate timing needed for SSVEP recordings. The system is based on the premise that a subject breathing butanol compared with filtered medical air will demonstrate SSVEP topographic changes associated with detection and identification of butanol. During our experiments the subject has either an air sample or an equal volume of butanol injected into the inspiratory airflow. These are randomized, and every breath has the same stimulus system with no known clues as to the differences apart from detection. The results from a panel of 10 female subjects--who all identified the butanol correctly--showed that butanol delivery resulted in sequences of changes in SSVEP topography (amplitude and latencies) which involved parietal, frontal and temporal regions. While consistent with other studies (parietal changes), our results revealed more dynamic temporal changes involving prefrontal and parietal regions at different periods around odor delivery.

Interventions for guttate psoriasis.

BACKGROUND: Guttate psoriasis is a distinctive acute form of psoriasis which characteristically occurs in children and young adults. Very little specific evidence-based guidance is available in standard texts to help make rational decisions about treatment options. OBJECTIVES: To assess the effectiveness of treatments for guttate psoriasis. SEARCH STRATEGY: We searched the Cochrane Clinical Trials Register (Cochrane Library, Issue 3, 1999), Medline (1966- September 1999), Embase (1988-September 1999), Salford Database of Psoriasis Trials (to November 1999) and European Dermato-Epidemiology Network (EDEN) Psoriasis Trials Database (to November 1999) for terms GUTTATE and PSORIASIS. We also searched 100 unselected RCTs of psoriasis therapy and all 112 RCTs of phototherapy for psoriasis in the Salford Database of Psoriasis Trials for separate stratification for guttate psoriasis. SELECTION CRITERIA: Randomised trials in which patients with acute guttate psoriasis were randomised to different treatments, except those trials examining antistreptococcal interventions which are addressed in a separate Cochrane review. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. MAIN RESULTS: No published report could be found to support or to challenge current commonly used methods of management. Only one trial which met the selection criteria was identified. In this small study of 21 hospitalised patients with guttate psoriasis, intravenous infusion of an n-3 fatty acid rich lipid emulsion was compared with placebo emulsion containing n-6 fatty acids. The n-3 preparation appeared to be of some benefit for patients with guttate psoriasis. REVIEWER'S CONCLUSIONS: There is currently no firm evidence on which to base treatment of acute guttate psoriasis. Studies comparing standard treatment modalities, including phototherapy and topical regimens, are required to enable informed decisions on treatment choices to be made.

Antistreptococcal interventions for guttate and chronic plaque psoriasis.

BACKGROUND: Guttate psoriasis is a distinctive acute form of psoriasis which characteristically occurs in children and young adults. It is closely associated with preceding streptococcal sore throat or tonsillitis. Some authorities have claimed that ordinary (chronic plaque) psoriasis may also be made worse by infection at distant sites. Although many dermatologists have recommended using antibiotics for guttate psoriasis in particular, it is not clear whether they influence the course of either form of psoriasis. Some dermatologists have also recommended tonsillectomy for psoriasis in patients with recurrent streptococcal sore throat. OBJECTIVES: To assess the evidence for effectiveness of antistreptococcal interventions including antibiotics and tonsillectomy in the management of acute guttate and chronic plaque psoriasis. SEARCH STRATEGY: We searched the Cochrane Clinical Trials Register (Cochrane Library, Issue 3, 1999), Medline (1966- September 1999), Embase (1988-September 1999), the Salford Database of Psoriasis Trials (to November 1999) and the European Dermato-Epidemiology Network (EDEN) Psoriasis Trials Database (to November 1999) for terms [STREPTOCOCC* or ANTIBIOTIC* or TONSIL*] and PSORIASIS using the Cochrane Skin Group search strategy. SELECTION CRITERIA: Randomised trials of one or more antistreptococcal interventions in patients with guttate or chronic plaque psoriasis. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined each retrieved trial for eligibility and quality. MAIN RESULTS: The one eligible trial we identified compared the use of two oral antibiotic schedules in 20 psoriasis patients, predominantly of guttate type, who had evidence of beta-haemolytic streptococcal colonisation. Either rifampicin or placebo was added to the end of a standard course of antistreptococcal antibiotic (phenoxymethylpenicillin or erythromycin). No patient in either arm of the study improved during the observation period. No randomised trials of tonsillectomy for psoriasis were identified. REVIEWER'S CONCLUSIONS: Although it is well known that guttate psoriasis may be precipitated by streptococcal infection, there is no firm evidence to support the use of antibiotics either in the management of established guttate psoriasis or in preventing the development of guttate psoriasis following streptococcal sore throat. Although both antibiotics and tonsillectomy have frequently been advocated for patients with recurrent guttate psoriasis or chronic plaque psoriasis, there is to date no good evidence that either intervention is beneficial.