Unravelling morphoea aetiopathogenesis by next-generation sequencing of paired skin biopsies.

BACKGROUND: Morphoea can have a significant disease burden. Aetiopathogenesis remains poorly understood, with very limited existing genetic studies. Linear morphoea (LM) may follow Blascho's lines of epidermal development, providing potential pathogenic clues. OBJECTIVE: The first objective of this study was to identify the presence of primary somatic epidermal mosaicism in LM. The second objective was tTo explore differential gene expression in morphoea epidermis and dermis to identify potential pathogenic molecular pathways and tissue layer cross-talk. METHODOLOGY: Skin biopsies from paired affected and contralateral unaffected skin were taken from 16 patients with LM. Epidermis and dermis were isolated using a 2-step chemical-physical separation protocol. Whole Genome Sequencing (WGS; n = 4 epidermal) and RNA-seq (n = 5-epidermal, n = 5-dermal) with gene expression analysis via GSEA-MSigDBv6.3 and PANTHER-v14.1 pathway analyses, were performed. RTqPCR and immunohistochemistry were used to replicate key results. RESULTS: Sixteen participants (93.8% female, mean age 27.7 yrs disease-onset) were included. Epidermal WGS identified no single affected gene or SNV. However, many potential disease-relevant pathogenic variants were present, including ADAMTSL1 and ADAMTS16. A highly proliferative, inflammatory and profibrotic epidermis was seen, with significantly-overexpressed TNFα-via-NFkB, TGFß, IL6/JAKSTAT and IFN-signaling, apoptosis, p53 and KRAS-responses. Upregulated IFI27 and downregulated LAMA4 potentially represent initiating epidermal 'damage' signals and enhanced epidermal-dermal communication. Morphoea dermis exhibited significant profibrotic, B-cell and IFN-signatures, and upregulated morphogenic patterning pathways such as Wnt. CONCLUSION: This study supports the absence of somatic epidermal mosaicism in LM, and identifies potential disease-driving epidermal mechanisms, epidermal-dermal interactions and disease-specific dermal differential-gene-expression in morphoea. We propose a potential molecular narrative for morphoea aetiopathogenesis which could help guide future targeted studies and therapies.

How toxic is an old friend? A review of the safety of hydroxychloroquine in clinical practice.

Hydroxychloroquine (HCQ) and its close relative chloroquine (CQ) were initially used as antimalarial agents but are now widely prescribed in rheumatology, dermatology and immunology for the management of autoimmune diseases. HCQ is considered to have a better long-term safety profile than CQ and is therefore more commonly used. HCQ has a key role in the treatment of connective tissue diseases including systemic lupus erythematosus (SLE), where it provides beneficial immunomodulation without clinically significant immunosuppression. HCQ can also assist in managing inflammatory arthritis, including rheumatoid arthritis (RA). Debate around toxicity of HCQ in COVID-19 has challenged those who regularly prescribe HCQ to discuss its potential toxicities. Accordingly, we have reviewed the adverse effect profile of HCQ to provide guidance about this therapeutic agent in clinical practice.

Systemic sclerosis in adults. Part II: management and therapeutics.

The management of systemic sclerosis (SSc) is complex, evolving, and requires a multidisciplinary approach. At diagnosis and throughout the disease course, clinical assessment and monitoring of skin involvement is vital using the modified Rodnan Skin Score, patient-reported outcomes, and new global composite scores (such as the Combined Response Index for Systemic Sclerosis, which also considers lung function). Immunomodulation is the mainstay of skin fibrosis treatment, with mycophenolate mofetil considered first line. Meanwhile vasculopathy-related manifestations (Raynaud's phenomenon, digital ulcers) and calcinosis, require general measures combined with specific pharmacologic (calcium-channel blockers, phosphodiesterase type 5 inhibitors, and prostanoids), nonpharmacologic (digital sympathectomy and botulinum toxin injections), and often multifaceted, management approaches. Patients should be screened at the time of diagnosis specifically for systemic manifestations and then regularly thereafter, with appropriate treatment. Numerous targeted therapeutic options for SSc, including skin fibrosis, are emerging and include B-cell depletion, anti-interleukin 6, Janus kinase, and transforming growth factor ß inhibition. This second article in the continuing medical education series discusses these key aspects of SSc assessment and treatment, with particular focus on skin involvement. It is vital that dermatologists play a key role in the multidisciplinary approach to SSc management.

Systemic sclerosis in adults. Part I: Clinical features and pathogenesis.

Systemic sclerosis (SSc), also referred to as systemic scleroderma or scleroderma, is a rare, complex immune-mediated connective tissue disease characterized by progressive skin fibrosis and other clinically heterogenous features. The etiopathogenesis of SSc involves vasculopathy and immune system dysregulation occurring on a permissive genetic and epigenetic background, ultimately leading to fibrosis. Recent developments in our understanding of disease-specific autoantibodies and bioinformatic analyses has led to a reconsideration of the purely clinical classification of diffuse and limited cutaneous SSc subgroups. Autoantibody profiles are predictive of skin and internal organ involvement and disease course. Early diagnosis of SSc, with commencement of disease-modifying treatment, has the potential to improve patient outcomes. In SSc, many of the clinical manifestations that present early signs of disease progression and activity are cutaneous, meaning dermatologists can and should play a key role in the diagnosis and management of this significant condition. The first article in this continuing medical education series discusses the epidemiology, clinical characteristics, and pathogenesis of SSc in adults, with an emphasis on skin manifestations, the important role of dermatologists in recognizing these, and their correlation with systemic features and disease course.

Comparing paediatric- and adult-onset linear morphoea in a large tertiary-referral scleroderma centre.

Background: Linear morphoea is a severe morphoea subtype associated with extracutaneous manifestations, potentially permanent disfigurement and functional impairment. Linear morphoea is more prevalent in paediatric patients, and knowledge of disease in adults is limited. The objective of this study was to compare paediatric- and adult-onset linear morphoea, in an exclusively adult population. Methodology: This was a retrospective cohort study of adult patients with linear morphoea seen over a 3-year period at a single-site adult tertiary-referral Connective Tissue Disease centre. Clinical markers of disease severity and course, including anatomical distribution, extracutaneous manifestations, cutaneous symptoms, associated autoimmunity, inflammatory blood parameters, Dermatology Life Quality Index scores, treatment requirements and modified Localised Scleroderma Activity Tool were assessed and compared in paediatric- and adult-onset linear morphoea. Results: Of 298 patients with morphoea seen during the study period, 135 had linear morphoea and 133 were included in the study. Most were female (78.9%), the mean age was 36.5 years and almost half (43.6%) had adult-onset disease. Disease was similarly severe between groups with regard to anatomical distribution, cutaneous symptoms (n = 89, 66.9%), extracutaneous manifestations (n = 76, 57.1%), antinuclear antibody-positivity (n = 40, 40.4%), raised erythrocyte sedimentation rate (n = 27, 25.0%) and associated autoimmune diagnoses (n = 15, 11.3%). Prescribed treatments were similar between groups; 73.7% receiving methotrexate and almost one-third (32.3%) requiring more than one steroid-sparing agent. Those with paediatric-onset had more disease-related damage, with a mean modified Localised Scleroderma Skin Damage Index score of 19.5 (95% confidence interval: 17.0-22.0) versus 8.1 (95% confidence interval: 4.4-11.8; p < 0.001). Significantly more patients with adult-onset linear morphoea had quiescent disease (p = 0.0332), and even after correcting for disease duration, paediatric-onset patients still had 2.6 times greater odds of active disease (odds ratio = 2.59, 95% confidence interval: 0.9-7.6; p = 0.083). Conclusion: Linear morphoea in adults can be a severe disease with extracutaneous, autoimmune and systemic features. Adults with paediatric-onset disease appear to have more severe cumulative damage, greater functional impairment and ongoing disease activity. This patient subgroup may require particularly close monitoring and more aggressive therapy.

Hydroxychloroquine in dermatology: New perspectives on an old drug.

Hydroxychloroquine is an age-old drug whose use as an immunomodulatory agent with a low side-effect profile continues to expand. We present a review of this drug including recently updated prescribing recommendations and a summary of its clinical application in dermatology. A maximum daily dose of 5.0 mg/kg based on actual body weight and no greater than 400 mg is advised in order to reduce the risk of retinopathy, which is potentially permanent and has an estimated prevalence of 7.5% at 5 years on standard dosing. Baseline ophthalmologic assessment followed by annual screening after 5 years is recommended; however, closer monitoring should be considered in the setting of existing retinopathy, a cumulative dose > 1000 g or renal dysfunction. Hydroxychloroquine is now considered to be safe in pregnancy, and routine glucose-6-phosphate dehydrogenase (G6PD) deficiency testing is not required. Smoking can significantly decrease its efficacy although the reason is still uncertain. Hydroxychloroquine appears to also demonstrate antineoplastic and cardioprotective benefits.

Assessment of Response to B-Cell Depletion Using Rituximab in Cutaneous Lupus Erythematosus.

Importance: Cutaneous lupus erythematosus (CLE) can be severe and treatment resistant. B-cell depletion therapy (BCDT) with rituximab is well recognized in organ involvement in systemic lupus erythematosus (SLE), but its efficacy in cutaneous manifestations is less well established. Objective: To evaluate the outcomes of BCDT in CLE and its clinical subtypes in the setting of associated SLE. Design, Setting, and Participants: This single-center, retrospective, cohort study was performed at the adult tertiary referral Rheumatology Department of University College London Hospital, London, United Kingdom, from January 1, 2000, through March 31, 2016, with 12-month follow-up completed on March 31, 2017. Adult patients with carefully classified CLE and mucocutaneous British Isles Lupus Assessment Group (BILAG) grade A or B who were treated with rituximab BCDT were selected from a prospective database of 709 patients with SLE. Data were analyzed from April through December 2017. Main Outcomes and Measures: Clinical response was examined at 6 and 12 months after treatment for CLE and its subtypes acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and nonspecific LE (NSLE). A complete response was defined as achieving BILAG grade D; partial response, BILAG grade C; stable disease, no change; and disease flare, change from BILAG grade C or D to grade A or B. Results: A total of 50 patients with SLE were eligible for inclusion; mean (SD) age at diagnosis was 26.9 (12.1) years, and 49 (98%) were women. Twenty-one patients had ACLE; 6, SCLE; 10, CCLE; and 11, NSLE (including 2 with concurrent ACLE and CCLE). Overall, at 6 months, 38 patients (76%) improved their mucocutaneous BILAG grade A or B status, including 20 (40%) with a complete response. At 12 months, 28 of 46 patients (61%) maintained this response, including 24 (52%) with a complete response. Two of 6 patients (33%) with SCLE showed a complete response at 6 and 12 months. Five of 12 patients (42%) with CCLE showed a complete response at 6 months, and 5 of 11 (45%), at 12 months. Fifteen patients (30%) required further rituximab therapy within 12 months for cutaneous involvement. Conclusions and Relevance: B-cell depletion therapy using rituximab appears effective in patients with SLE and severe active CLE; however, outcomes are variable in those with SCLE and CCLE subtypes.