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.

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.

Intralymphatic granulomas in lymphoedema secondary to anogenital granulomatosis.

The granulomatous inflammation seen in filariasis, orofacial granulomatosis (OFG), rosacea and sarcoidosis can be associated with lymphoedema. In the setting of OFG, the finding of intralymphatic granulomas has been reported as a possible mechanism for lymphoedema. Anogenital granulomatosis (AGG) is a similar chronic inflammatory condition of unknown pathogenesis. It presents as granulomatous genital or anoperineal inflammation and associated lymphoedema, with histological findings of non-caseating granulomas and a perivascular infiltrate. We report a case of AGG and lymphoedema with intralymphatic granulomas seen on biopsy. This finding is unique and we propose that the intralymphatic granulomatous inflammation causes a partial or complete occlusion of lymphatic drainage, thus resulting in the clinical situation of lymphoedema.

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.

Pyoderma gangrenosum requiring inpatient management: a report of 26 cases with follow up.

We present a case series of inpatients with pyoderma gangrenosum (PG), an ulcerative neutrophilic skin condition of unknown aetiology. Twenty-six patients were admitted with PG, nine men and 17 women. At the time of the chart review, seven patients (26.9%) had died. Patients had a mean of 2.0 active ulcerative lesions and 22 patients' ulcers (84.6%) were on the lower limb. Systemic diseases were coexistent in 15 patients (57.7%), the most common being rheumatoid arthritis (19.2%). Thirty-eight wound cultures were taken and were positive for Staphylococcus aureus in 22 cases (57.8%) and Pseudomonas aeruginosa in 20 (52.6%). After prednisolone, cyclosporin was the next most commonly prescribed systemic therapy (34.6%). Surgical debridement was undertaken in seven cases (26.9%) and two patients had skin grafts. Upon discharge from hospital, 21 patients' ulcers (80.8%) had improved. At 6 months 50% showed complete ulcer healing. Our results highlight the potential severity of PG requiring hospital admission, the need for aggressive therapy and the overall high associated morbidity and mortality.

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.

Validation of a verbal rating scale for breathlessness amongst patients referred for cardiac stress tests.

BACKGROUND: Acute shortness of breath (SOB) is a common symptom and a potentially significant marker of cardiorespiratory disease. The subjective and unmeasurable nature of breathlessness can make its clinical evaluation difficult. This study aimed to investigate the convergent validity of a verbal 0-10 rating scale for SOB. METHODS: This prospective observational study used a convenience sample of patients presenting for cardiac stress tests. Objective and subjective breathlessness parameters were collected before, during and after stress test exercise. Objective measures included respiratory rate (RR), oxygen saturation (S(a)O2), heart rate (HR), systolic blood pressure (SBP) and the subjective breathlessness parameter was verbal dyspnea scores (VDS) for present dyspnea obtained using the SOB rating scale question, "On a scale from 0-10, how bad is your SOB, with zero being no SOB and ten the worst SOB you could ever imagine?" RESULTS: Within subjects, VDS correlated significantly with RR (mean r=0.95, CI: 0.93-0.97), HR (mean r=0.90, CI: 0.86-0.93) and SBP (mean r=0.95, CI: 0.93-0.97); p<0.05. Between subjects, correlations were significant at all time points for RR only (r=0.45-0.65, p<0.05), indicating high individual variability in dyspnea perception.. CONCLUSIONS: A verbal numerical rating scale is a valid measure of breathlessness and may provide useful insight into a prognostically significant symptom.

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.

Review of dyspnoea quantification in the emergency department: is a rating scale for breathlessness suitable for use as an admission prediction tool?

Acute shortness of breath is a potential marker of serious cardiopulmonary disease and requires rapid assessment. In our current health-care system, increasing pressure on the ED to limit costs and waiting times has resulted in the development of many clinical decision aids and admission prediction tools designed to assist ED physicians in meeting these demands. However, most of these tools are disease specific, and none are currently available for application to patients presenting to the ED with shortness of breath. Although somewhat limited, current evidence supports the utilization of a simple dyspnoea rating scale, to assist in the streamlining of clinical severity assessments and urgency evaluations, and to potentially provide useful information to facilitate rapid and accurate site-of-care decisions in this setting.

Verbal dyspnoea score predicts emergency department departure status in patients with shortness of breath.

OBJECTIVES: We examined whether a previously validated verbal dyspnoea rating scale, and/or other demographic and clinical parameters, could predict ED departure status, among ED patients presenting with shortness of breath. METHODS: In this prospective observational study, a convenience sample of patients presenting to an inner urban adult tertiary hospital ED with shortness of breath were assessed at triage using objective and subjective breathlessness parameters. These included respiratory rate, oxygen saturation, heart rate, systolic blood pressure and verbal dyspnoea scores. A verbal dyspnoea score for worst dyspnoea during the current episode and basic demographic and presentation characteristics were also collected. These variables were assessed as predictors of ED departure status (inpatient admission or ED discharge) using logistic regression. RESULTS: From a sample of 253 participants, verbal dyspnoea scores > or =8 predicted inpatient admission 89% specificity (95% confidence interval [CI] 82.1-93.4), and scores < or =3 predicted discharge with 95% specificity (95% CI 89.5-98.0). For patients with shortness of breath as the primary complaint, the combination of verbal dyspnoea score > or =6, heart rate > or =94 bpm at triage and ambulance arrival predicted admission with 90% sensitivity (95% CI 82-95%) and 84% specificity (95% CI 73-92%). These same variables predicted admission for all patients with 84% sensitivity (95% CI 75.8-89.2) and 79% specificity (95% CI 71.5-85.5). CONCLUSION: Verbal dyspnoea score, alone and in combination with heart rate and arrival transport, can accurately predict admission. Once validated they might be useful in assessing, prioritizing and making rapid site of care decisions for breathless patients presenting to the ED.

Validation of a verbal dyspnoea rating scale in the emergency department.

OBJECTIVE: Use of a verbal dyspnoea rating scale in the emergency department (ED) has many potential benefits, providing information to clinicians otherwise not afforded by objective parameters. In the present study, we aimed to investigate the validity of a verbal dyspnoea rating scale, previously validated in the setting of cardiac stress tests, among patients presenting to the ED with acute shortness of breath (SOB). METHODS: This was a prospective observational study conducted at an inner-urban adult tertiary hospital. A convenience sample of patients presenting with SOB to the ED had objective data collected at triage and 30 min later, including respiratory rate (RR), oxygen saturation (S(a)O(2)), heart rate (HR) and systolic blood pressure (SPB). These were correlated with the participants' subjective response to the question: 'On a scale from 0 to 10, how bad is your SOB, with zero being no SOB and 10 the worst SOB you could ever imagine?' Spearman correlations were then calculated between objective and subjective breathlessness measures. RESULTS: For 253 breathless ED patients (mean age 60.6 years, 126 male), verbal dyspnoea scores at triage correlated with RR (r = 0.77, P < 0.001), S(a)O(2) (r =-0.43, P < 0.001), HR (r = 0.35, P < 0.001) and SPB (r = 0.19, P < 0.05). Thirty minutes later, correlations remained significant for RR (r = 0.74, P < 0.001), S(a)O(2) (r =-0.39, P < 0.001) and HR (r = 0.40, P < 0.001). CONCLUSION: A verbal numerical SOB rating scale is a valid measure of breathlessness in the ED, and might therefore provide useful insight into a symptom that is otherwise unmeasurable.