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).

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.

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.

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.

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.

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.

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.

Prevalence of human papillomavirus in anal and oral sites among patients with genital warts.

Genital warts are caused by human papillomavirus (HPV). HPV is a leading cause of anogenital malignancies and a role of HPV in the aetiology of oro-pharyngeal cancers has been demonstrated. The frequency of oral HPV infection in patients with genital warts and the association between concomitant genital, anal and oral infection is unclear. A total of 201 men and women with genital wart-like lesions were recruited. Swab samples were obtained from the genital warts and the anal canal and an oral rinse was collected. Anal HPV was found in 46.2% and oral HPV in 10.4% of the participants. Concordance between anal and genital wart HPV types was 78.1%, while concordance between oral and genital wart types was 60.9%. A lower concordance of 21.7% was observed between anal and oral HPV types. Significantly more women than men had multiple HPV types and anal HPV. In conclusion, extra genital HPV is common in patients with genital warts. A gender inequality seems to exist.

A reduced national incidence of anogenital warts in young Danish men and women after introduction of a national quadrivalent human papillomavirus vaccination programme for young women--an ecological study.

In January 2009 the human papillomavirus (HPV) vaccine was included in the Danish childhood vaccination programme for girls aged 12 years. A catch-up programme for girls up to 16 years of age was started a couple of months earlier. Based on national register data, anogenital wart (AGW) incidences between January 2001 and December 2011 were estimated. We used χ2 analysis to identify significant trends in proportions of patients diagnosed with AGW in the period before and after inclusion of the HPV vaccine in the program. The development of chlamydia infections was included in this study as a proxy for possible behaviour changes that could affect the AGW incidence. Between 2008 and 2011, a 50% (95% CI 44-56) decrease in AGW incidence was seen among 15-19-year-old men (p = 0.041), from 5.2 to 2.6/1,000. Among women, a 67% (95% CI 63-72) decrease from 11.7 to 3.8/1,000 was seen (p < 0.0001). The decline in frequency of AGW in young Danish women seems to result from the high coverage of the HPV vaccination programme and young men probably benefit from herd immunity.

The nasal mucosa contains a large spectrum of human papillomavirus types from the Betapapillomavirus and Gammapapillomavirus genera.

BACKGROUND: Human papillomavirus (HPV) types from the Betapapillomavirus and Gammapapillomavirus genera are common at cutaneous sites. The aim of this study was to analyze the prevalence of these HPV types in oral and nasal samples. METHODS: Nasal samples and oral samples were obtained from 312 volunteer Danish healthcare staff (240 women and 72 men), among whom the mean age was 42 years. A total of 311 oral samples and 304 nasal samples were eligible for HPV DNA analysis. HPV types were detected by use of polymerase chain reactions with modified general primers (MGP) and Forslund-Antonsson primers (FAP) and identified by Luminex (for types detected by MGP PCR) or direct sequencing or cloning before sequencing (for types detected by FAP PCR). RESULTS: HPV DNA was detected in 6% of the oral samples and 50% of the nasal samples. Seventy-five diverse HPV types or putative HPV types were identified. HPV types within the Alphapapillomavirus, Betapapillomavirus, and Gammapapillomavirus genera were detected in 3%, 31%, and 23% of the nasal samples, respectively. A putative subtype of HPV76, originally isolated from a feline oral squamous cell carcinoma, was detected in 7 nasal samples. CONCLUSION: A large spectrum of HPV types from Betapapillomavirus and Gammapapillomavirus have tropism for the nasal mucosa. The implication of the relatively high prevalence of these viruses in the nasal mucosa is unknown.

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.

Incidence and cost of anal, penile, vaginal and vulvar cancer in Denmark.

BACKGROUND: Besides being a causative agent for genital warts and cervical cancer, human papillomavirus (HPV) contributes to 40-85% of cases of anal, penile, vaginal and vulvar cancer and precancerous lesions. HPV types 16 & 18 in particular contribute to 74-93% of these cases. Overall the number of new cases of these four cancers may be relatively high implying notable health care cost to society. The aim of this study was to estimate the incidence and the health care sector costs of anal, penile, vaginal and vulvar cancer. METHODS: New anogenital cancer patients were identified from the Danish National Cancer Register using ICD-10 diagnosis codes. Resource use in the health care sector was estimated for the year prior to diagnosis, and for the first, second and third years after diagnosis. Hospital resource use was defined in terms of registered hospital contacts, using DRG (Diagnosis Related Groups) and DAGS (Danish Outpatient Groups System) charges as cost estimates for inpatient and outpatient contacts, respectively. Health care consumption by cancer patients diagnosed in 2004-2007 was compared with that by an age- and sex-matched cohort without cancer. Hospital costs attributable to four anogenital cancers were estimated using regression analysis. RESULTS: The annual incidence of anal cancer in Denmark is 1.9 per 100,000 persons. The corresponding incidence rates for penile, vaginal and vulvar cancer are 1.7, 0.9 and 3.6 per 100,000 males/females, respectively. The total number of new cases of these four cancers in Denmark is about 270 per year. In comparison, the total number of new cases cervical cancer is around 390 per year. The total cost of anogenital cancer to the hospital sector was estimated to be 7.6 million Euros per year. Costs associated with anal and vulvar cancer constituted the majority of the costs. CONCLUSIONS: Anogenital cancer incurs considerable costs to the Danish hospital sector. It is expected that the current HPV vaccination program will markedly reduce this burden.

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.

Performance of the TREAT decision support system in an environment with a low prevalence of resistant pathogens.

OBJECTIVES: To evaluate a decision support system (TREAT) for guidance of empirical antimicrobial therapy in an environment with a low prevalence of resistant pathogens. METHODS: A retrospective trial of TREAT has been performed at Copenhagen University, Hvidovre Hospital. The cohort of patients included adults with systemic inflammation and suspicion of community-acquired bacterial infection. The empirical antimicrobial treatment recommended by TREAT was compared with the empirical antimicrobial treatment prescribed by the first attending clinical physician. RESULTS: Out of 171 patients recruited, 161 (65 with microbiologically documented infections) fulfilled the inclusion criteria of TREAT. Coverage achieved by TREAT was significantly higher than that by clinical practice (86% versus 66%, P = 0.007). There was no significant difference in the cost of future resistance between treatments chosen by TREAT and those by physicians. The direct expenses for antimicrobials were higher in TREAT when including patients without antimicrobial treatment, while there was no significant difference otherwise. The cost of side effects was significantly lower using TREAT. CONCLUSIONS: The results of the study suggest that TREAT can improve the appropriateness of antimicrobial therapy and reduce the cost of side effects in regions with a low prevalence of resistant pathogens, however, at the expense of increased use of antibiotics.

Cytokine expression during syphilis infection in HIV-1-infected individuals.

BACKGROUND: Little is known about cytokine responses to syphilis infection in HIV-1-infected individuals. METHODS: We retrospectively identified patients with HIV-1 and Treponema pallidum coinfection. Plasma samples from before, during, and after coinfection were analyzed for interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha. RESULTS: Thirty-six patients were included. IL-10 levels increased significantly in patients with primary or secondary stage syphilis from a median of 12.8 pg/mL [interquartile range (IQR), 11.0-27.8] before infection to 46.7 pg/mL (IQR, 28.4-78.9) at the time of diagnosis (P = 0.027) and decreased to 13.0 pg/mL (IQR, 6.2-19.4) after treatment of syphilis (P <0.001). TNF-alpha levels showed no significant change from before to during syphilis in patients with primary or secondary stage syphilis (median 3.9 pg/mL (IQR, 3.3-9.6) and 9.0 pg/mL (IQR, 5.4-12.6), respectively (P = 0.31); however, treatment of syphilis was associated with a significant decrease in TNF-alpha to a median of 4.2 pg/mL (IQR, 2.7-6.8) (P <0.001). No significant changes in cytokine levels were observed in coinfected with latent stage syphilis.IL-10 and TNF-alpha levels correlated positively with plasma HIV RNA values at the time of diagnosis (r = 0.38, P = 0.023, and r = 0.64, P <0.001, respectively) and correlated inversely with CD4 T cell counts (-0.35, P = 0.036 and r = -0.34, P = 0.042, respectively). CONCLUSION: HIV-1 and early stage syphilis coinfection were associated with an increase in IL-10. IL-10 and TNF-alpha both decreased after treatment of syphilis. TNF-alpha and IL-10 correlated with low CD4 T cell counts and high plasma HIV RNA values.