Downregulation of miR-885-5p Promotes NF-κB Pathway Activation and Immune Recruitment in Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) has a specific microRNA expression profile. MiR-885-5p has been found to be downregulated in the epidermis of CLE lesions; however, its biological role in the disease has not been studied. In this study, we show that miR-885-5p is markedly reduced in CLE keratinocytes (KCs) with IFN-α and UVB being strong miR-885-5p regulators in vitro. Microarray expression profiling of anti‒miR-885-5p‒transfected KCs identified PSMB5 as a direct target. Specific inhibition of miR-885-5p increased epidermal proliferation by modulating keratin 16 gene K16, BIRC5, TP63, and CDK4 proliferative genes and promoted NF-κB signaling pathway in human primary KCs by increasing IκBα degradation. Silencing PSMB5 rescued the effect of miR-885-5p inhibition, indicating that miR-885-5p regulates proliferation and NF-κB activation by targeting PSMB5 in KCs. In addition, inhibition of miR-885-5p increased the ability of KCs to attract leukocytes in a PSMB5-independent manner. We identified TRAF1 as another direct target, and its silencing reduced leukocyte migration. Collectively, our findings suggest that UVB and IFN-ɑ downregulate miR-885-5p in CLE KCs, leading to epidermal inflammation by NF-κB activity enhancement and proliferation through PSMB5 and immune recruitment through TRAF1. Our data indicate that miR-885-5p is a potential therapeutic target in CLE.

Guselkumab effectiveness and survival in patients with psoriasis and psoriatic arthritis: Multicenter analysis in daily clinical practice by the Spanish Psoriasis Group.

Guselkumab is a monoclonal antibody that selectively blocks the p19 subunit of interleukin 23 and has been approved for the treatment of moderate to severe psoriasis and active psoriatic arthritis in adult patients due to its efficacy in different clinical trials. Therefore, itis important to know the performance of guselkumab in this setting of patients in clinical practice given that a high percentage of them are not represented in these clinical trials. Our objective was to evaluate the effectiveness and tolerability of guselkumab in clinical practice in the first patients with psoriasis and psoriatic arthritis treated since the date of its approval for psoriasis in Spain, in joint dermatology-rheumatology clinics. A multicenter retrospective data collection was carried out, in which 14 hospitals participated, including a total of 90 patients with psoriatic arthritis confirmed by a rheumatologist. Data collection was recorded at baseline and at weeks 12, 24, and 52 for both the articular and cutaneous domains. Ninety PsA patients started treatment with guselkumab and therefore were included in this study. The vast majority had already failed to at least to one biologic therapyprior guselkumab prescription. The median age was 55 years, 61% were female and 46% had a BMI ≥ 30 kg/m2 . Sixty-nine percent suffered from peripheral arthritis, and in 34% an axial involvement was also detected; dactylitis or enthesitis was present in 24% and 29% of patients, respectively. Guselkumab was effective in controlling both articular and skin manifestations of PsA patients. Absolute PASI significantly decreased from 10.5 to 4.8, 1.9 and 1.3 at weeks 12, 24, and 52, respectively. In 29 out of 61 (48%) of cases, DAPSA was moderate or high, and patients showed a significant reduction in DAPSA at 12, 24, and 52 weeks of treatment (mean DAPSA values at baseline and follow up were 29, 20, 16, and 14, respectively). Patients with DAPSA in low activity or in remission at the time of initiation of guselkumab maintained response at the end of the study period. No new safety concerns were detected. Seventy-eight out of 90 patients (84.4%) persisted on treatment after 2 years follow-up. Our experience suggests that guselkumab isan effective drug for PsA and PsO patients in clinical practice with good tolerability and no additional safety signals, making it a new therapeutic alternative for the treatment of PsA and PsO patients.

Changes in the microbiological diagnosis and epidemiology of cutaneous leishmaniasis in real-time PCR era: A six-year experience in a referral center in Barcelona.

BACKGROUND: Leishmaniasis is a neglected disease caused by different species of the protozoa Leishmania spp. Cutaneous lesions are the most common clinical manifestation. This disease is prevalent in tropical and subtropical areas, including the Mediterranean basin. In Spain, Leishmania (L.) infantum is the only endemic species, but imported cases are often diagnosed. Different classical parasitological methods can be performed for cutaneous leishmaniasis (CL) diagnosis; but currently molecular techniques serve as a relevant tool for the detection and characterization of Leishmania parasites. We aimed to evaluate clinical and epidemiological characteristics of CL diagnosed patients by real-time PCR in a tertiary hospital over a six-year period. METHODOLOGY/PRINCIPAL FINDINGS: Clinical, epidemiological and microbiological data were retrospectively collected and analyzed. In our study, CL was confirmed in 59 (31.4%) out of 188 patients by real-time PCR, showing an increase over recent years: 11 cases of CL between 2014 and 2016 and 48 between 2017 and 2019. Real-time PCR was performed on skin swabs and/or biopsies samples, with a positivity of 38.5% and 26.5%, respectively. Results were 100% concordant when biopsy and skin swab were performed simultaneously. L. (L.) infantum was the most frequent species detected (50%), followed by L. (L.) major (45%) and Viannia subgenus (5%), which were detected only in imported cases. L. (L.) major was almost entirely detected in travelers/migrants from Morocco. Multiple and atypical skin lesions were more common in imported cases than in autochthonous cases (44.4% vs. 21.8%). CONCLUSIONS/SIGNIFICANCE: An increase in both autochthonous and imported CL cases has been observed in past years in our hospital. Molecular techniques assist in improving CL diagnosis and characterization of the Leishmania species, mainly in imported cases.

Angioid streaks and obstructive sleep apnea syndrome: are they related?

BACKGROUND: Sleep apnea syndrome (OSAS) has been associated with different ocular manifestations including glaucoma, floppy eye syndrome, punctate keratitis, keratoconus, and optic neuropathy. Angioid streaks are mainly associated with pseudoxanthoma elasticum (PXE) although they can appear in other systemic conditions affecting the elastic fibers. METHODS: This is a prospective, cross-sectional study. A complete ophthalmic examination was performed in 92 patients undergoing overnight polysomnography for suspicion of OSAS. Diagnosis and classification of OSAS were made based on apnea-hypopnea index (AHI). Stereoscopic optic disc photographs were taken in all patients and independently evaluated by two ophthalmologists. Patients with angioid streaks were referred to a dermatologist for axillary skin biopsy in order to rule out pseudoxanthoma elasticum or other skin abnormalities. RESULTS: Bilateral angioid streaks were observed in three patients who had been diagnosed with severe OSAS (AHI > 30/h). No clinical features characteristic of pseudoxanthoma elasticum or other pathological skin signs were observed. Skin biopsies were normal for all three patients, supporting the diagnosis of idiopathic angioid streaks. One of the patients developed bilateral choroidal neovascularization secondary to the angioid streaks over subsequent years. CONCLUSIONS: In view of the low prevalence of idiopathic angioid streaks in the general population, the finding of angioid streaks in patients with severe OSAS suggests OSAS as a possible risk factor for its development. The hypothesis of a connective tissue abnormality that could explain an association between both entities deserves further elucidation.

Manifestations, clinical course and prognostic markers in cutaneous polyarteritis nodosa.

BACKGROUND AND OBJECTIVES: Cutaneous polyarteritis nodosa (CPAN) is a comparatively rare form of vasculitis that affects small arteries and arterioles in the panniculus and dermo-subcutaneous junction. Limited information is available regarding its course in the European population. The aim of this study is to characterize the manifestations and prognostic markers of recurrence in CPAN. PATIENTS AND METHODS: We report a retrospective study of patients with clinical and histopathologic evidence of CPAN, which was treated at two tertiary referral centers in Spain between 1989 and 2019. RESULTS: 31 patients were included. The most frequent manifestation was subcutaneous nodules (90.3 %); ulcers were frequent at diagnosis (35.5 %). Two thirds of the patients had at least one extracutaneous manifestation. Seventeen patients (54.8 %) experienced relapse. The strongest predictor of recurrence was ulceration in the initial episode (OR 18.6; 95 % CI 2.73-38; p < 0.01). The pre-treatment results of laboratory parameters associated with inflammation (such as C-reactive protein and neutrophil-to-lymphocyte ratio) were significantly higher in the relapsing group. There were no disease-related deaths and none of the patients developed systemic PAN. CONCLUSIONS: Although CPAN is a vasculitis limited to the skin, symptoms may involve adjacent skeletal muscle or peripheral nerves. While the condition is not life-threatening, the presence of ulceration and elevation of certain laboratory parameters predicts a worse prognosis.

Effectiveness and safety of ustekinumab 90 mg in patients weighing 100 kg or less: a retrospective, observational, multicenter study.

Background: Scant information from clinical practice is available on the effectiveness and safety of ustekinumab (UST) 90 mg in patients with psoriasis weighing 100 kg or less.Objectives: To assess the effectiveness and safety at weeks 16 and 24 of UST 90 mg in patients with psoriasis weighing ≤100 kg, and to study the impact on clinical outcomes of body mass index (BMI) and prior exposure to UST 45 mg.Methods: A retrospective, observational, and multicenter study of 74 adult patients who were treated with UST 90 mg at least 24 weeks.Results: Mean (standard deviation [SD]) score on psoriasis area and severity index (PASI) was 7.9 (4.8) at baseline, 3.3 (3.5) at week 16, and 2.2 (2.4) at week 24, when 69.7% of the patients had a PASI under 3. Overweight and obese patients achieved a mean PASI of 2.2 by week 24 (p= .995). In patients who had previously been treated with UST 45 mg (52/74) with insufficient response, mean (SD) absolute PASI score was 2.7 (2.6) at week 24. No serious adverse events were reported.Conclusions: In patients who weigh 100 kg or less but are overweight or obese and do not present an adequate response with UST 45 mg, increasing the dose to UST 90 mg could be an alternative option.

Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported. METHODOLOGY: We performed a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis. Patients diagnosed in our hospital from 2008 to 2018 were included. Moreover, a systematic review of the literature was performed and cases fulfilling the inclusion criteria were also included. PRINCIPAL FINDINGS: Forty-nine patients were analyzed including nine cases from our series. Twenty-seven (55.1%) cases were male and median age was 55 years. Twenty-five (51%) patients were under infliximab treatment, 20 (40.8%) were receiving adalimumab, 2 (4.1%) etanercept, one (2%) golimumab and one (2%) a non-specified TNF-α blocker. Regarding clinical presentation, 28 (57.1%) presented as cutaneous leishmaniasis (CL), 16 (32.6%) as visceral leishmaniasis (VL) and 5 (10.2%) as mucocutaneous leishmaniasis (MCL). All VL and MCL patients were treated with systemic therapies. Among CL patients, 13 (46.4%) were treated with a systemic drug (11 received L-AmB, one intramuscular antimonials and one miltefosine) while 14 (50%) patients were given local treatment (13 received intralesional pentavalent antimonials, and one excisional surgery). TNF-α blockers were interrupted in 32 patients (65.3%). After treatment 5 patients (10.2%) relapsed. Four patients with a CL (3 initially treated with local therapy maintaining TNF-α blockers and one treated with miltefosine) and one patient with VL treated with L-AmB maintaining TNF-α blockers. CONCLUSIONS: This data supports the assumption that the blockage of TNF-α modifies clinical expression of leishmaniasis in endemic population modulating the expression of the disease leading to atypical presentations. According to the cases reported, the best treatment strategy would be a systemic drug and the discontinuation of the TNF-α blockers therapy until clinical resolution.

Safety and effectiveness of conventional systemic therapy and biological drugs in patients with moderate to severe psoriasis and HIV infection: a retrospective multicenter study.

Background: The management of HIV-positive patients with psoriasis is controversial and limited to individual cases or short series of patients. Objectives: To evaluate the safety and effectiveness of conventional and biologic immunosuppressive drugs in the treatment of patients with psoriasis and concomitant HIV infection. Methods: A retrospective multicenter study was conducted. The study included data from 2008 to 2016. Inclusion criteria were: HIV adult patients with moderate-to-severe psoriasis, HIV viral load determinations at baseline and at least after 6 months of treatment, and systemic immunosuppressive treatment for at least 6 months. A descriptive analysis was performed. Results: Twenty-three patients with plaque-type psoriasis and HIV infection (five with AIDS) were included. Median follow-up time was 3.2 years. The main drugs used were etanercept, methotrexate, and ustekinumab. In most cases, viral load and CD4 cell count not only remained stable but also improved throughout the follow-up. Six patients presented severe adverse events during the follow-up, four of them in the AIDS stage. At the end of the follow-up period, 76.5% of the patients had achieved a PASI 75. Conclusion: Biologic drugs, both anti-TNF alpha agents and ustekinumab, seem to have an acceptable safety profile and high effectiveness in HIV-positive patients.

Cutaneous infections by dematiaceous opportunistic fungi: Diagnosis and management in 11 solid organ transplant recipients.

BACKGROUND: The incidence of cutaneous infections by dematiaceous fungi is rising in our environment due to the high number of solid organ transplant recipients (SOTR). OBJECTIVE: To review our experience in the management of cutaneous phaeohyphomycoses in a Spanish reference centre for dermatological care of SOTR. METHODS: Retrospective clinical, histopathological and microbiological review of all SOTR diagnosed of a phaeohyphomycosis in a 7-year period. RESULTS: Eleven SOTR were identified (8 lung and 3 kidney). The lesions were solitary in six patients and multiple in five, affecting mostly the lower extremities. Early lesions showed epidermal hyperplasia and a diffuse dermal suppurative granulomatous infiltrate that was progressively substituted by fibrosis when the lesions were treated. Septated fungal structures with refractile walls were identified. DNA sequencing confirmed the presence of Alternaria spp (8 cases), Cladosporium cladosporioides, Microsphaeropsis arundinis and Exophiala oligosperma. Three patients with single lesions were treated with surgery, while the other 8 required long-term antifungal therapy, including itraconazole, voriconazole and/or terbinafine, combined with surgery and reduction in tacrolimus doses. CONCLUSION: A clinical, histopathological and microbiological correlation is essential to corroborate this diagnosis. Solitary lesions are easily treated with surgery, but larger or multiple lesions may require long medical treatments combined with surgery and modification of immunosuppressive medication. The list of dematiaceous fungi implicated in cutaneous infections is expanding, in line with the availability of more sophisticated identification methods and the increasing number of immunosuppressed patients.

Is there any association between Sarcoidosis and infectious agents?: a systematic review and meta-analysis.

BACKGROUND: During the last few years, investigators have debated the role that infectious agents may have in sarcoidosis pathogenesis. With the emergence of new molecular biology techniques, several studies have been conducted; therefore, we performed a meta-analysis in order to better explain this possible association. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement from the Cochrane collaboration guidelines. Four different databases (Medline, Scopus, Web of Science, and Cochrane Collaboration) were searched for all original articles published from 1980 to 2015. The present meta-analysis included case-control studies that reported the presence of microorganisms in samples of patients with sarcoidosis using culture methods or molecular biology techniques. We used a random effects or a fixed-effect model to calculate the odds ratio (OR) and 95% confidence intervals (CI). Sensitivity and subgroup analyses were performed in order to explore the heterogeneity among studies. RESULTS: Fifty-eight studies qualified for the purpose of this analysis. The present meta-analysis, the first, to our knowledge, in evaluation of all infectious agents proposed to be associated with sarcoidosis and involving more than 6000 patients in several countries, suggests an etiological link between Propionibacterium acnes and sarcoidosis, with an OR of 18.80 (95% CI 12.62, 28.01). We also found a significant association between sarcoidosis and mycobacteria, with an OR of 6.8 (95% CI 3.73, 12.39). Borrelia (OR 4.82; 95% CI 0.98, 23.81), HHV-8 (OR 1.47; 95% CI 0.02, 110.06) as well as Rickettsia helvetica, Chlamydia pneumoniae, Epstein-barr virus and Retrovirus, although suggested by previous investigations, were not associated with sarcoidosis. CONCLUSION: This meta-analysis suggests that some infectious agents can be associated with sarcoidosis. What seems clear is that more than one infectious agent might be implicated in the pathogenesis of sarcoidosis; probably the patient's geographical location might dictate which microorganisms are more involved. Future investigations and more clinical trials are need to bring these evidences to a more global level.

Prognostic value of skin lesions in sarcoidosis: clinical and histopathological clues.

BACKGROUND: Although tremendous advances have been made, a significant gap exists between the vast knowledge accumulated concerning sarcoidosis in recent years and our understanding of this disease. OBJECTIVE: Describe the main clinical and histopathological findings associated with cutaneous sarcoidosis and to investigate the relationship of these skin lesions with systemic involvement. METHODS: A retrospective review of 41 patients who were diagnosed with cutaneous sarcoidosis was done. RESULTS: The study included 34 females and 7 males. Systemic disease occurred frequently in patients with lupus pernio and nodulo-plaque type lesions. Systemic symptoms were observed more commonly in patients with raised serum ACE levels (84.6% vs. 40%; p<0.05). Our study also indicated that patients with skin lesions that were associated with systemic symptoms had a more chronic form of the disease than patients with only cutaneous lesions (91.6% vs. 29.4%; p<0.001). Additionally, complete resolution of cutaneous lesions was observed more frequently in patients with no associated systemic symptoms (66.6% vs. 23.5%; p<0.05). Interestingly, we found that patients with a moderate/severe granulomatous infiltrate in their biopsies had a more severe clinical presentation during the course of the disease, with a more generalized skin involvement (65.6% vs. 30%) as well as a more chronic course of the disease (56.3% vs. 30%). Another interesting histopathological finding observed was the presence of a grenz zone in 20 cases (47.6%). CONCLUSION: A correct and methodical clinicopathological correlation is important for our clinical practice because it can give us useful clues to the diagnosis and prognosis of this disease.

Evaluation of cytokine profile and HLA association in benznidazole related cutaneous reactions in patients with Chagas disease.

BACKGROUND: Benznidazole is the drug of choice for Chagas disease. The major drawback of this drug is the high adverse events rate, being cutaneous reactions the most frequent one, leading to definitive withdrawal of treatment in 15%-30% of patients. METHODS: Prospective observational study where adult Chagas disease patients accepting to receive benznidazole (100 mg/8 hours for 60 days) were included. The objective was to characterize the skin toxicity of benznidazole in patients with Chagas disease, determine the serum cytokine profile, and evaluate the potential association with specific HLA alleles and benznidazole concentration. Serum cytokine levels were measured at day 0, 15, and 60 of treatment. Class I and II HLA alleles were determined. When cutaneous reaction was detected, a skin biopsy was performed. Serum benznidazole concentration was determined at the time of cutaneous reaction, or at day 15 of treatment. RESULTS: Fifty-two patients were included, 20(38.5%) had cutaneous reaction, and median time of appearance was 9 days. Skin biopsies showed histopathological findings consistent with drug eruption. Patients with cutaneous drug-reaction had higher proportion of eosinophilia during treatment, and higher interleukin (IL)-5 and IL-10 serum concentrations at day 15 of treatment than those without cutaneous reaction. Treatment interruption (that included moderate-severe cutaneous reactions) was more frequent in patients carrying HLA-B*3505 allele (45.5% vs 15.4%, P = .033). No differences in benznidazole serum concentration were found. CONCLUSIONS: Benznidazole related cutaneous reaction rate is high, and it was produced by a delayed hypersensitivity reaction with a Th2 response. Carrying HLA-B*3505 allele could be associated with moderate-severe cutaneous reaction.

Infant de 17 mesos amb plaques eritematodescamatives generalitzades i onicodistròfia / No disponible

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Eruptive juvenile xanthogranuloma associated with relapsing acute lymphoblastic leukemia.

Juvenile xanthogranuloma is a benign, self-healing disorder with characteristic lesions mainly involving the skin. Although most patients with juvenile xanthogranuloma have only cutaneous symptoms, recent articles have documented extracutaneous manifestations: systemic involvement of many organs has been reported and there is a known association between juvenile xanthogranuloma and childhood leukemia, most commonly juvenile chronic myelogenous leukemia. This case provides further corroboration, that in rare instances, juvenile xanthogranuloma may be associated with hematologic malignancies.