Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers.

BACKGROUND: Observations with rituximab suggest B-cell independent mechanisms of cutaneous lupus erythematosus (CLE) in systemic lupus erythematosus (SLE), especially discoid lupus erythematosus (DLE). Type-I interferon receptor blockade with anifrolumab shows efficacy in SLE, but efficacy for cutaneous disease of specific morphologies has not been studied. Interferon has pleotropic immune effects and it is unknown which of these are critical to therapeutic response. OBJECTIVES: We evaluated clinical efficacy and quality-of-life impact of type-I interferon-blockade in: (i) rituximab-refractory CLE; (ii) DLE and other morphologies and (iii) transcriptomic and flow cytometric biomarkers. METHODS: We conducted a prospective single-centre study of anifrolumab in refractory mucocutaneous SLE. CLE Disease Area and Severity Index (CLASI) activity score, health-related quality of life, 96-probe TaqMan® gene expression analysis capturing key SLE blood transcriptome signatures, and eight-colour flow cytometry were undertaken at baseline, 1, 3 and 6 months. RESULTS: Seven patients [DLE (n = 5), chilblain lupus erythematosus (n = 1), subacute CLE (n = 1)] were evaluated. The median number of prior therapies was six (range 3-15), including rituximab in six of seven patients. Median CLASI-A showed rapid and sustained improvement from 17 at baseline to 6 (P = 0.016) at 1 month and 0 (P < 0.001) by 3 months. The median percentage reduction in CLASI-A at 3 months was 60%. Significant improvements were observed in Dermatology Life Quality Index scores (P < 0.001), EuroQol 5D visual analogue scale (P = 0.002) and LupusQoL fatigue, image and planning domains (P ≤ 0.05). One patient discontinued treatment owing to severe herpes zoster. Clinical responses paralleled discrete suppression of interferon-stimulated genes (ISGs) from SLE blood transcriptome module M1.2 with more varied downregulation in other interferon modules. Myeloid and inflammation-annotated genes remained upregulated throughout treatment. Intermediate monocytes (CD14++CD16+) reduced to normal levels during therapy (P = 0.014), while other flow subsets showed no substantive changes. CONCLUSIONS: These data indicate rapid efficacy of anifrolumab in DLE and rituximab-resistant CLE. Response is associated with suppression of a subset of ISGs and decline in intermediate monocytes. Suppression of all ISGs or the wider SLE blood transcriptome is not required for response.

Effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters and methotrexate for patients with moderate-to-severe psoriasis: a cohort study from BADBIR.

BACKGROUND: Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis. METHODS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data. RESULTS: In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively]. CONCLUSIONS: The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

Four-Week Daily Calcipotriene/Betamethasone Dipropionate Foam Is Highly Efficacious in Patients With Psoriasis (PSO-LONG Lead-in Phase).

BACKGROUND: Psoriasis is a chronic disease requiring long-term treatment strategies. Optimal strategies should include initial rapid relief of symptoms followed by long-term management to maintain remission. This 4-week open-label phase of a long-term proactive management phase 3 trial aimed to select responders to once daily, fixed-dose combination calcipotriene 0.005% and betamethasone dipropionate 0.064% (Cal/BD) foam in adults with psoriasis and assess patient-reported outcomes. METHOD: This phase 3 trial in adults with psoriasis included a 4-week open-label lead-in phase to determine treatment success prior to entering the randomized maintenance phase. Success was defined as Physician Global Assessment (PGA) score ‘clear’/‘almost clear’ (PGA <2) with ≥2-grade improvement from baseline. Those achieving treatment success at week 4 entered the maintenance phase; non-responders were withdrawn from the trial. RESULTS: 650 patients enrolled in the open-label phase, and 623 were treated with Cal/BD foam for 4 weeks; 521 (80%) patients achieved treatment success and were included in the maintenance phase. In those patients achieving success (responders), 21.1% and 78.9% achieved a PGA score of ‘clear’ and ‘almost clear’, respectively. Mean change from baseline in modified Psoriasis Area and Severity Index (± standard deviation [SD]) and body surface area (± SD) in responders at week 4 was −82.1% (16.4%) and −56.6% (38.3%), respectively. Mean Dermatology Life Quality Index score reduced by 6.0 from baseline to week 4 (n=521). 17.7% of patients experienced AEs; with only one severe AE reported. CONCLUSION: Cal/BD foam was highly efficacious and well tolerated during the 4-week lead-in phase of PSO-LONG. J Drugs Dermatol. 2021;20(4):436-441, doi:10.36849/JDD.5728.

Primary Localized Cutaneous Amyloidosis Affecting Female Individuals of a Pakistani Pedigree.

Primary localized cutaneous amyloidosis is a group of rare conditions where amyloid deposition is limited to the skin without systemic manifestations. Most cases are sporadic; however, mutations in the oncostatin M receptor (OSMR) and interleukin-31 receptor A (IL31RA) genes can cause a familial form of the condition in up to 10% of cases. Here, we describe a family in which 8 female individuals are affected by either macular amyloidosis or amyloidosis cutis dyschromica. To the best of our knowledge, a sex-specific expression or the coexistence of 2 different phenotypes of primary localized cutaneous amyloidosis in 1 pedigree has not yet been reported.

A Case of Squamous Cell Carcinoma Developing Within a Red-Ink Tattoo.

Cutaneous reactions to tattoos are well reported and include allergic reactions, infections, and foreign body granuloma or may be a presenting sign of sarcoidosis. There have been very few reported cases of squamous cell carcinoma (SCC) arising in tattoo-treated skin. We report a case of SCC arising within a red-ink tattoo and discuss the potential the role of chronic low-grade inflammation in pathogenesis. This should serve to raise awareness of potential tattoo-related serious adverse effects.

Childhood mycosis fungoides: experience of 28 patients and response to phototherapy.

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is rare in childhood. The prognosis and response to treatment are poorly described in children. The objective of the current study was to evaluate the response to phototherapy in a pediatric cohort. A retrospective cohort study of all patients diagnosed with MF before the age of 18 years and referred to the regional CTCL phototherapy service was performed between January 1990 and April 2012. Twenty-eight patients were identified (13 boys, 15 girls). The mean age at presentation was 11.6 ± 3.9 years. The hypopigmented variant was noted in 79% of patients. All patients had stage I disease (IA = 10, IB = 17, unknown = 1). The median follow-up after diagnosis was 43 months (range 6-274 mos). Narrowband ultraviolet B (NbUVB; 311 nm) was used as first-line phototherapy in 18 patients and psoralen (bath) plus ultraviolet A (PUVA) was used in 8 patients. Complete or partial response was observed in 19 of 22 patients (86%). A further course of phototherapy was required in 7 of 12 patients (58%) treated with NbUVB after a median of 4 months (range 4-29 mos). A further course of phototherapy was required in four of eight patients (50%) successfully treated with PUVA after a median of 45.5 months (range 30-87 mos). No disease progression was noted over the follow-up (median 43 mos). The majority of patients in our cohort had hypopigmented MF. Phototherapy offers an effective option for treatment of childhood MF, although the period of remission may be greater in patients treated with PUVA.

Epidemiology of severe drug hypersensitivity.

Epidemiological studies of severe drug hypersensitivities are important to understanding the morbidity and mortality of this heterogeneous group of disorders. These insights also allow greater identification of at-risk patient groups. However, epidemiological studies of drug hypersensitivity reactions are challenging due to the variable diagnostic criteria applied and incomplete data sets studied. We review the epidemiology of severe drug hypersensitivity reactions with a particular focus on severe cutaneous adverse reactions (SCARs). SCAR diseases include: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, serum-sickness-like reaction and acute generalized exanthematous pustulosis.

Patient-reported well-being in value-based care using tildrakizumab in a real-world setting: protocol of a multinational, phase IV, 1-cohort prospective observational study (the POSITIVE study).

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease that negatively impacts the quality of life of patients and their families. However, the most commonly used decision-making tools in psoriasis, Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA) and Dermatology Life Quality Index (DLQI), do not fully capture the impact of psoriasis on patients' lives. In contrast, the well-established 5-item WHO Well-being Index (WHO-5) assesses the subjective psychological well-being of patients. Moreover, while drug innovations became available for psoriasis, data on the impact of these therapies on patients' lives and their closest environment (family, physicians) are limited. This study will assess the effect of tildrakizumab, an interleukin-23p19 inhibitor, on the overall well-being of patients with moderate-to-severe psoriasis. Moreover, the long-term benefit of tildrakizumab on physicians' satisfaction and partners' lives of patients with psoriasis will be evaluated. METHODS AND ANALYSIS: This non-interventional, prospective, observational, real-world evidence study will involve multiple sites in Europe and approximately 500 adults with moderate-to-severe psoriasis treated with tildrakizumab. Each patient will be followed for 24 months. The primary endpoint is well-being measured by the WHO-5 questionnaire. Key secondary endpoints include Physician's Satisfaction and partner's quality of life (FamilyPso). Other endpoints will evaluate skin-generic quality of life (DLQI-R), Treatment Satisfaction Questionnaire for Medication (TSQM-9), Treatment-related Patient Benefit Index 'Standard', 10 items (PBI-S-10) and work productivity and activity impairment due to psoriasis (WPAI:PSO). Statistical analyses will be based on observed cases. Multiple imputations will be performed as a sensitivity analysis, and adverse events will be reported. ETHICS AND DISSEMINATION: The study will be conducted according to the protocol, which received ethics committee approval and applicable regulatory requirements of each participating country. The results will be disseminated through scientific publications and congress presentations. TRAIL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04823247 (Pre-results).

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.

Autoinflammation: Interferonopathies and Other Autoinflammatory Diseases.

The family of autoinflammatory diseases (AIDs) continues to expand and now includes over 40 genetically defined disorders. Their defining feature is a dysregulated inflammatory innate immune response. Many AIDs have overlapping clinical characteristics, and dermatological manifestations are common. Autoinflammatory features have also been recognized in more common dermatological conditions such as psoriasis. Furthermore, there is an increasing understanding that immunodeficiencies, autoimmune disorders, and even some allergic disorders share overlapping autoinflammatory features. The discovery that certain somatic mutations, arising within the bone marrow and restricted to the myeloid cell lineage can cause acquired AID heralds a new era of discoveries in this field.

Drug Survival Associated With Effectiveness and Safety of Treatment With Guselkumab, Ixekizumab, Secukinumab, Ustekinumab, and Adalimumab in Patients With Psoriasis.

Importance: Drug survival of biologic therapies for psoriasis is a proxy for longer-term treatment effectiveness and safety. Patient factors that are associated with the survival of each biologic differently (effect modifiers) may inform the decision to choose between biologics. Objective: To assess the drug survival associated with the effectiveness and safety of commonly used biologics for psoriasis in the UK and Ireland and identify effect modifiers for these biologics and their survival. Design, Setting, and Participants: We conducted a prospective cohort study of patients with psoriasis using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2021. Exposures: Adalimumab, ustekinumab, secukinumab, guselkumab, ixekizumab. Main Outcomes and Measures: We conducted a survival analysis and fitted separate flexible parametric models for drug survival as a proxy for effectiveness and safety. Results: A total of 16 122 treatment courses were included: 6607 (41.0%) in which treatment with adalimumab was initiated, 5405 (33.5%) with ustekinumab, 2677 (16.6%) with secukinumab, 730 (4.5%) with guselkumab, and 703 (4.4%) with ixekizumab. The crude survival functions at year 1 for measures of effectiveness for treatment with adalimumab was 0.81 (95% CI, 0.80-0.82), 0.89 for ustekinumab (95% CI, 0.88-0.89), 0.86 for secukinumab (95% CI, 0.85-0.87), 0.94 for guselkumab (95% CI, 0.92-0.96), and 0.86 for ixekizumab (95% CI, 0.83-0.89). The adjusted survival curves from the multivariable model for effectiveness showed that treatment with guselkumab had the higher survival (adjusted hazard ratio, 0.13; 95% CI, 0.03-0.56) and adalimumab had the lower survival (adjusted hazard ratio, 2.37; 95% CI, 2.03-2.76) compared with ustekinumab. Secukinumab and ixekizumab had similar survival curves over time. Psoriatic arthritis, previous biologic exposure, nail involvement, and ethnicity were effect modifiers for survival in association with treatment effectiveness. The crude survival functions at year 1 for safety were 0.91 for treatment with adalimumab (95% CI, 0.90-0.91), 0.94 for ustekinumab (95% CI, 0.94-0.95), 0.94 for secukinumab (95% CI, 0.92-0.94), 0.96 for guselkumab (95% CI, 0.94-0.98), and 0.92 for ixekizumab (95% CI, 0.89-0.94). Guselkumab, ustekinumab, and secukinumab had similar adjusted survival curves for safety, while adalimumab (adjusted hazard ratio, 1.66; 95% CI, 1.46-1.89) and ixekizumab (adjusted hazard ratio, 1.52; 95% CI, 1.13-2.03) had lower survival compared with ustekinumab. Conclusions and Relevance: The results of this cohort study suggest that guselkumab had the highest drug survival in BADBIR of the included biologics for treatment persistence that was associated with effectiveness, and guselkumab had highest drug survival for safety compared with other biologics except ustekinumab. Psoriatic arthritis, nail involvement, previous biologic exposure, and ethnicity were effect modifiers for biologics and their survival in association with treatment effectiveness. This information on longer-term treatment persistence, safety, and tolerability may help patients and their clinicians make an informed decision to initiate treatment with a biologic therapy.

No deaths associated with patient refusal of transport after naloxone-reversed opioid overdose.

INTRODUCTION: Naloxone is widely used in the treatment and reversal of opioid overdose. Most emergency medical services (EMS) systems administer naloxone by standing order, and titrate only to reverse respiratory depression without fully reversing sedation. Some EMS systems routinely administer sufficient naloxone to fully reverse the effects of opioid overdose. Frequently patients refuse further medical evaluation or intervention, including transport. OBJECTIVES: The purpose of this study was to evaluate the safety of this practice and determine whether increased mortality is associated with full reversal of opioids. As a component of a comprehensive quality assurance initiative, we assessed mortality during the 48 hours after patients received naloxone to reverse opioid overdose followed by patient-initiated refusal of transportation. METHODS: The setting was a large urban fire-based EMS system. Investigators provided the Bexar County Medical Examiner's Office (MEO) with a list of patients who were treated by the San Antonio Fire Department with naloxone, and not transported. Inclusion criteria were administration of naloxone and patient-initiated refusal. Patient dispositions also included aid only, referral to the MEO, or referral to law enforcement. The list was then compared with the MEO database. A chart review was completed on all patients treated and subsequently presented to the MEO within two days. A secondary time period of 30 days was also assessed. RESULTS: The list identified 592 patients treated with naloxone and not transported to the emergency department. Five-hundred fifty-two patients received naloxone and refused transport or were not transported. The remaining 40 patients all presented to EMS in cardiac arrest, naloxone was administered during the course of resuscitation, and subsequent efforts were terminated in the field. None of the patients receiving naloxone with a subsequent patient-initiated refusal were examined at the MEO within the two-day end point. The 30-day assessment revealed that nine individuals were treated with naloxone and subsequently died, but the shortest time interval between date of service and date of death was four days. CONCLUSION: The primary outcome was that no patients who were treated with naloxone for opioid overdose and then refused care were examined by the MEO within a 48-hour time frame.

Nonhealing vegetating plaque on the finger: tuberculosis verrucosa cutis.

Tuberculosis verrucosa cutis is an uncommon form of tuberculosis that typically presents as a chronic warty plaque. It develops in individuals with moderate to high immunity to Mycobacterium tuberculosis due to inoculation of an open wound. We present the case of a Somali man born in the United Kingdom who presented with a nonhealing ulcer on the right hand of 10 years' duration. The patient was diagnosed with tuberculosis verrucosa cutis based on clinical suspicion, which was confirmed by several investigations including strongly positive results of a Mantoux test, IFN-gamma release assay, typical histology on skin biopsy, and polymerase chain reaction (PCR) analysis positive for mycobacterial DNA. Treatment with quadruple antituberculous therapy produced rapid resolution of the ulcer. This unusual condition often is overlooked in the differential diagnosis of nonhealing ulcers, yet it has an excellent prognosis with treatment. A high index of suspicion is required.

Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

BACKGROUND: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions. OBJECTIVES: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources. METHODS: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS). RESULTS: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices. CONCLUSIONS: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS.