Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxoedema and scleroedema.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

Polyautoimmunity in patients with cutaneous lupus erythematosus: A nationwide sex- and age-matched cohort study from Denmark.

Background: Polyautoimmunity is defined as having 2 or more autoimmune diseases. Little is known about polyautoimmunity in patients with cutaneous lupus erythematosus (CLE). Objectives: To estimate prevalence and 5-year incidence of non-lupus erythematosus (LE) autoimmune diseases in patients with CLE. Methods: Patients with CLE were identified In the Danish National Patient Registry and each patient was age- and sex-matched with 10 general population controls. Outcome information on non-LE autoimmune diseases was obtained by register-linkage between Danish National Patient Registry and the National Prescription Register. The risk ratio (RR) for prevalent non-LE autoimmune disease at time of CLE diagnosis was calculated in modified Poisson regression; and hazard ratios (HRs) for incident non-LE autoimmune disease were estimated in Cox regression analyses. Results: Overall, 1674 patients with CLE had a higher prevalence of a non-LE autoimmune disease than the comparators (18.5 vs 7.9%; RR 2.4; 95% CI, 2.1 to 2.6). Correspondingly, the cumulative incidence of a non-LE autoimmune disease during 5 years of follow-up was increased for the patients with CLE: HR 3.5 (95% CI, 3.0 to 4.0). Limitations: Risk of detection and misclassification bias, mainly pertaining to the CLE group. Conclusion: Patients with CLE had higher prevalence and 5-year cumulative incidence of a non-LE autoimmune disease than the general population.

Use of hydroxychloroquine and risk of major adverse cardiovascular events in patients with lupus erythematosus: A Danish nationwide cohort study.

BACKGROUND: Limited data suggest that hydroxychloroquine may affect risk of cardiovascular disease in patients with lupus erythematosus (LE). OBJECTIVE: To investigate whether hydroxychloroquine treatment is associated with major adverse cardiovascular events (MACE) (myocardial infarction, ischemic stroke, or cardiovascular-associated death) in patients with cutaneous LE (CLE) or systemic LE (SLE). METHODS: Based on the Danish nationwide registers, an observational cohort study was conducted including patients with first-time diagnosis of CLE or SLE (between 1997 and 2017). Cox regression models calculating the hazard ratio (HR) analyzing the risk of MACE were performed comparing time on and off hydroxychloroquine (including never users). The models were adjusted for age, sex, socioeconomic status, concomitant treatment, and cardiovascular risk factors. RESULTS: Among 4587 patients with LE, 51% (n = 2343) were treated with hydroxychloroquine during the study period. An inverse association between use of hydroxychloroquine and MACE risk was observed among patients with SLE (adjusted HR, 0.65; 95% confidence interval, 0.46-0.90) and patients with CLE (adjusted HR, 0.71; 95% confidence interval, 0.42-1.19). Consistent results were found in sensitivity analyses including a case-time control design. LIMITATIONS: No information on disease activity/severity was available. CONCLUSION: Our findings indicate an opportunity to reduce the risk of cardiovascular events in patients with LE through use of hydroxychloroquine.

Association Between Drug Use and Subsequent Diagnosis of Lupus Erythematosus.

Importance: It has been estimated that up to 30% of all subacute cutaneous lupus erythematosus (CLE) cases and up to 15% of systemic lupus erythematosus (SLE) cases are drug induced. Based on numerous case reports and several epidemiologic studies, more than 100 drugs from more than 10 drug classes are suspected to cause drug-induced lupus erythematosus. Objective: To examine the association between drug use and a subsequent diagnosis of CLE or SLE based on a systematic screening process of the drugs in the Anatomical Therapeutic Chemical classification system in a nationwide setting. Design, Setting, and Participants: A matched case-control study was conducted using all incident cases of CLE and SLE registered in the Danish National Patient Register between January 1, 2000, and December 31, 2017. Patients with CLE and patients with SLE were matched (1:10) on age and sex, with individuals from the general population serving as controls. Exposures: To select which drugs to examine for an association with CLE or SLE, a screening process of all drugs was performed, including drugs filled at pharmacies and drugs administered in hospitals. Main Outcomes and Measures: Odds ratios (ORs) were calculated for the association between exposures to certain drugs and the subsequent diagnosis of CLE or SLE. Results: In all, 3148 patients with CLE (n = 1298; 1022 women [78.7%]; median age at diagnosis, 50.5 years [interquartile range, 39.4-62.2 years]) or SLE (n = 1850; 1537 women [83.1%]; median age at diagnosis, 45.0 years [interquartile range, 33.6-56.4 years]) and 31 480 controls (25 590 women [81.3%]; median age, 47.5 years [interquartile range, 35.9-59.5 years]) were found. Many significant associations between drug use and a subsequent diagnosis of CLE and SLE were observed. Many associations were likely due to protopathic bias. However, new plausible causal associations were observed between CLE or SLE and some drugs, including fexofenadine hydrochloride (SLE: OR, 2.61 [95% CI, 1.80-3.80]; CLE: OR, 5.05 [95% CI, 3.51-7.26]), levothyroxine sodium (SLE: OR, 2.46 [95% CI, 1.97-3.07]; CLE: OR, 1.30 [95% CI, 0.96-1.75]), metoclopramide hydrochloride (SLE: OR, 3.38 [95% CI, 2.47-4.64]; CLE: OR, 1.47 [95% CI, 0.85-2.54]), and metronidazole hydrochloride (SLE: OR, 1.57 [95% CI, 1.09-2.27]; CLE: OR, 1.93 [95% CI, 1.25-2.97]). Conclusions and Relevance: The study's findings suggest that physicians should be cognizant about whether a new case of CLE or SLE could be drug induced. Furthermore, the results highlight that the reported associations in the published literature may be due to publication or protopathic bias.

Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection.

In recent years, cases involving terbinafine-resistant Trichophyton isolates have been reported increasingly, particularly in India. We present 14 cases of terbinafine treatment failure in Trichophyton-infected Danish patients due to acquired resistance. Patients infected with Trichophyton rubrum (n = 12) or Trichophyton interdigitale (n = 2) with elevated terbinafine MICs during 2013-2018 were included. Antifungal susceptibility testing (AFST) was performed following a modified EUCAST E.Def 9.3.1 method (5 days of incubation) with or without cycloheximide and chloramphenicol (CC) supplementation of the growth medium. The squalene epoxidase (SE) target gene was sequenced, and 3-dimensional enzyme homology modeling was performed. Most patients (12/14 [86%]) were male. The mean age was 53.5 years (range, 11 to 77 years). The mean duration of infections was 4.8 years at the time of resistance detection. Prior systemic terbinafine treatment was documented for all patients, and topical therapy for 62% (information was missing in one case). Overall, nine isolates (64%) displayed high terbinafine resistance (MICs, 4 to >8 mg/liter), while two (14%) displayed moderate (MICs, 1 to 2 mg/liter) and three (21%) displayed low (MICs, 0.125 to 0.25 mg/liter) terbinafine resistance compared with control isolates. MICs generated with or without CC supplementation were similar, but CC prevented contamination. Known and novel SE amino acid substitutions (F397L, L393F, L393S, F415S, H440Y F484Y, and I121M V237I) were detected in resistant but not control isolates. Three-dimensional homology modeling suggested a role of the novel I121M and V237I alterations. Terbinafine resistance has been detected in Denmark using a modified EUCAST method, which facilitated susceptibility testing of dermatophytes. Action is needed for this emerging public health problem.

[Ano-genital warts are more than benign lesions].

Ano-genital warts are in general considered as benign lesions, as they are mostly caused by the non-oncogenic HPV types 6 and 11. In this review, there is a focus on the problematic issues, that these lesions and their treatments can cause. Both topical and ablative treatments are associated with side effects, and the varying effect of the treatments combined with an uncertain timeline to clearance are known to cause psychological distress. Vaccination against HPV-6 and -11 has been shown to reduce the incidence of this troublesome infection substantially in both women and men in countries with high vaccine coverage.

[Multicentric reticulohistiocytosis is a rare form of paraneoplasia].

A 59-year-old woman developed a rash and severe arthralgia, which primarily affected her fingers. She displayed digital arthritis and nodules on the hands, chest, face, and oral cavity. Blood samples were normal. Skin biopsies revealed histiocytic proliferation. The surface marker profile and clinical findings were consistent with multicentric reticulohistiocytosis, which may occur as a paraneoplastic phenomenon. On workup, she was diagnosed with an otherwise asymptomatic stage IVC fallopian tube cancer. She experienced little effect of prednisolone, but her condition improved on antineoplastic treatment.

Localized Scleroderma, Systemic Sclerosis and Cardiovascular Risk: A Danish Nationwide Cohort Study.

Recent findings indicate that patients with systemic sclerosis have an increased risk of cardiovascular disease. To determine whether patients with systemic sclerosis or localized scleroderma are at increased risk of cardiovascular disease, a cohort study of the entire Danish population aged ≥ 18 and ≤ 100 years was conducted, followed from 1997 to 2011 by individual-level linkage of nationwide registries. Multivariable adjusted Cox regression models were used to estimate the hazard ratios (HRs) for a composite cardiovascular disease endpoint. A total of 697 patients with localized scleroderma and 1,962 patients with systemic sclerosis were identified and compared with 5,428,380 people in the reference population. In systemic sclerosis, the adjusted HR was 2.22 (95% confidence interval 1.99-2.48). No association was seen between patients with localized scleroderma and cardiovascular disease. In conclusion, systemic sclerosis is a significant cardiovascular disease risk factor, while patients with localized scleroderma are not at increased risk of cardiovascular disease.

Correlation Between Dermatology Life Quality Index and Psoriasis Area and Severity Index in Patients with Psoriasis Treated with Ustekinumab.

Monitoring of biological treatment efficacy for psoriasis is based on clinical evaluation and patient's quality of life. However, long-term correlation between Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) in real life has not been studied in patients treated with ustekinumab. All patients with psoriasis treated with ustekinumab at our department were included (n = 120) in this study. Correlation analyses between the change in PASI and DLQI and the individual subquestions in DLQI were performed using Spearman's rank correlation coefficient. A correlation value of 0.57 (p-value <0.001) and 0.45 (p-value < 0.001) between PASI and DLQI were found in the period baseline - 4 months and baseline - 12 months, respectively. In DLQI subquestions, the greatest association was found for the questions on "Symptoms and feelings". Objective improvements in the severity of psoriasis were weakly to moderately associated with improvements in quality of life in patients with psoriasis treated with ustekinumab.

[Mucosal malignant melanomas in the gastrointestinal tract and urogenital organs].

The aim of this article is to investigate the latest knowledge of the aetiology, pathogenesis and treatment of mucosal malignant melanomas (MMM) in the gastrointestinal tract (GIT) and urogenital organs. MMM constitute 1.4% of all melanomas with an incidence rate in USA of 2.2 per million a year. MMM in the GIT occur mostly in the anal canal and rectum, but can also occur in the small intestine, gallbladder and the large intestine, though very rarely. Melanomas can occur in almost any part of the urinary tract. The aetiology and pathogenesis are unknown. Surgery appears to be the most effective treatment.

Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency.

Factor I is an important regulator of the complement system. Lack of Factor I causes uncontrolled activation of the complement system leading to consumption of C3. Complete deficiency of Factor I is a rare condition and only around 40 cases has been reported in the literature. The clinical presentation of Factor I deficiency varies and includes severe recurrent bacterial infections, glomerulonephritis and autoimmune diseases. The patient, a 28-years old woman with consanguineous parents, presented with recurrent leukocytoclastic vasculitis in the lower extremities with no associated systemic involvement, and without increased infection tendency. Initial testing showed low C3 concentration and a detailed complement evaluation absence of complement Factor I. Sequencing revealed a homozygous missense mutation in exon 2 of the CFI gene (SCV000221312). Even though the clinical symptoms of CFI mutations vary among patients sole association with leukocytoclastic vasculitis redefines the clinical spectrum of complete Factor I deficiency.

Low prevalence of oral and nasal human papillomavirus in employees performing CO2-laser evaporation of genital warts or loop electrode excision procedure of cervical dysplasia.

Risk of human papillomavirus (HPV) transmission during laser vaporisation of genital warts or loop electrode excision procedure is controversial. An oral rinse, a nasal swabs, history of HPV related diseases and data on HPV exposure were collected from 287 employees at departments of dermato-venerology and gynaecology in Denmark. A mucosal HPV type was found among 5.8% of employees with experience of laser treatment of genital warts as compared to 1.7% of those with no experience (p = 0.12). HPV prevalence was not higher in employees participating in electrosurgical treatment or cryotherapy of genital warts, or loop electrode excision procedure compared with those who did not. HPV 6 or 11 were not detected in any samples. Hand warts after the age of 24 years was more common among dermatology than among non-dermatology personnel (18% vs. 8.0%, p = 0.03). Mucosal HPV types are infrequent in the oral and nasal cavity of health care personnel, however, employees at departments of dermato-venereology are at risk of acquiring hand warts.

New drugs and treatment targets in psoriasis.

In recent years, the increased understanding of the pathophysiology of psoriasis has resulted in several new treatments. The success of ustekinumab proved the importance of the IL-23/T helper cell 17 axis in psoriatic diseases. Several new biologics targeting this axis will reach the clinic in the next years. Biologics are costly, require injections, and some patients experience tacaphylaxis, thus, the development of orally available, small-molecule inhibitors is desirable. Among small-molecules under investigation are A3 adenosine receptor agonists, Janus kinase inhibitors, and phosphodiesterase inhibitors. We review published clinical trials, and conference abstracts presented during the last years, concerned with new drugs under development for the treatment of psoriasis. In conclusion, our psoriasis armamentarium will be filled with several new effective therapeutic options the coming years. We need to be aware of the limitations of drug safety data when selecting new novel treatments. Monitoring and clinical registries are still important tools.