An expert consensus on managing dupilumab-related ocular surface disorders in people with atopic dermatitis 2024.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory skin condition which affects all ages. New therapies, including the monoclonal antibody therapy dupilumab, offer excellent efficacy. However, in clinical trials, and emphasised in real-world observations, the unexpected increased frequency of ocular adverse effects became apparent. The effectiveness of dupilumab and the unpredictability of ocular adverse effects mean that clinicians need guidance on counselling patients prior to treatment and on managing them if they arise. OBJECTIVES: The British Association of Dermatologists (BAD) and Royal College of Ophthalmologists collaborated on this consensus guidance on managing dupilumab-related ocular surface disorders (DROSD). METHODS: A multidisciplinary group was formed of adult and paediatric dermatologists and ophthalmologists with DROSD expertise, patient representation, and BAD Clinical Standards Unit. A literature search was conducted, and the results reviewed. All recommendations were reviewed, discussed and voted on. RESULTS: The recommendations pertain to dermatology and ophthalmology management, and apply to all ages, unless otherwise stated. Importantly, initiation of dupilumab for AD should not be delayed for most eye disorders except acute new problems, e.g. infections, or potentially severe conditions, e.g. a history of corneal transplant (ophthalmology advice should be sought first). There is insufficient evidence to recommend lubricant drops prophylactically. Dermatologists should assess eye complaints to diagnose DROSD; a severity grading system is provided. DROSD management differs slightly in those aged <7 years as ocular complications may affect neuro-ocular development; therefore, irrespective of DROSD severity, this population should be referred for ophthalmology advice. In those aged ≥7 years, dermatologists should feel confident to trial treatment and reserve ophthalmology advice for severe or non-responding cases. Discussion about dupilumab withdrawal should be prompted by a significant impact on quality of life, threat to sight, or other complications. CONCLUSIONS: Although dupilumab is a highly effective agent for treating AD, the risk of ocular adverse effects should not inhibit clinicians or patients from using it, but clinicians should be aware of them. If a patient develops DROSD, there are clear pathways to assess severity and offer initial management; where ineffective, dermatologists should assess the urgency and seek advice from or initiate referral to ophthalmology. While the evidence reviewed for these guidelines reflects the extensive literature on dupilumab, we believe our advice has relevance for ocular surface disorders in atopic dermatitis (AD) patients treated with tralokinumab and lebrikizumab.

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.

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.

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).

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.

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.

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.

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.

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.

Defining Pre-Clinical Psoriatic Arthritis in an Integrated Dermato-Rheumatology Environment.

In excess of three quarters of patients with psoriatic arthritis (PsA) have preceding psoriasis (PsO), which offers a clinical biomarker for the recognition of early PsA. Numerous surveys have shown a remarkably high frequency of clinically occult musculoskeletal symptoms in psoriasis patients. Imaging studies, particularly ultrasound, show a high prevalence of subclinical enthesitis and other inflammatory changes in psoriasis subjects. Since a serum biomarker, such as the case of anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis, neither exists nor seems biologically plausible at this point, this article explores how integration of rheumatological and dermatological assessment can be facilitated for the early recognition of potential PsA. Given that scalp disease is a PsA predictor, but may be managed in the community, then a particular need to access this group is needed. An integrated approach between rheumatology and dermatology can involve joint clinics, parallel clinics with discussion of relevant cases or virtual contact between specialties. Early therapy evaluation and integrated strategies have considerable implications for minimizing suffering and joint damage in PsA.

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.

IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis.

The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence.

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.

Pemphigus herpetiformis: a case series and review of the literature.

BACKGROUND: Pemphigus herpetiformis (PH) is a rare subtype of pemphigus that presents challenges in diagnosis. OBJECTIVE: To review the presentation, diagnosis, and management of PH. METHODS: We reviewed the charts of all patients diagnosed and treated for PH in an immunobullous referral center between September 2007 and June 2013. RESULTS: Eight patients were identified with a diagnosis of PH. All presented initially with pruritus. Clinical disease was manifest as either urticated erythematous plaques or a vesiculobullous eruption. Histological evaluation demonstrated eosinophilic spongiosis in all patients with acantholysis in half of cases (n = 4/8). Peripheral eosinophilia was noted in three of eight (37.5%) patients. In all cases, direct immunofluorescence showed intercellular deposition of immunoglobulin G in the epidermis. All patients required high-dose corticosteroid initially. All patients treated with dapsone or sulfasalazine (n = 4) achieved at least partial control. Other effective treatments included intravenous immunoglobulin (n = 2), azathioprine (n = 2), and leflunomide (n = 1). Rituximab was ineffective in two patients. CONCLUSION: The clinical and histological features of PH develop over time and with treatment, making distinction between pemphigus subtypes challenging and delay in diagnosis common. Diagnosis of PH requires a high index of suspicion and is made on clinical grounds (urticated erythema) in the context of compatible histology and immunofluorescence findings. Treatment may be challenging, although efficacy of sulfonamide derivatives appears to offer a therapeutic effect.