Recommendations from the Spanish Academy of Dermatology and Venereology Psoriasis Working Group on the Management of Patients with Cancer and Psoriasis. / Recomendaciones del Grupo de Psoriasis de la Academia Española de Dermatología y Venereología sobre el manejo de la psoriasis en pacientes oncológicos.

Several studies suggest that patients with psoriasis have a higher incidence of neoplasms, especially of the skin, which could be associated with the use of therapies to treat psoriasis. Furthermore, the evidence available on the safety profile of some treatments in this context, and the management of these patients is scarce, which is why clinical practice guidelines with recommendations on the management of psoriasis in cancer patients are ambiguous. This study provides recommendations on the management and use of the therapies currently available for these patients. They are the result of a Delphi consensus reached by 45 dermatologists of the Spanish Academy of Dermatology and Venereology Psoriasis Working Group, whose goal is to help specialists in the field in their decision-making processes.

Validation of the Spanish Version of the PURE-4 Questionnaire for the Early Detection of Psoriatic Arthritis in Psoriatic Patients. / Validación de la versión española del cuestionario PURE-4 para la detección precoz de la artritis psoriásica en pacientes con psoriasis.

BACKGROUND AND OBJECTIVE: Psoriasis often precedes the onset of psoriatic arthritis (PsA), so dermatologists often face the challenge of early identifying signs of PsA in patients with psoriasis. Our aim was to validate the Spanish version of the PURE-4 questionnaire as a screening tool for PsA, evaluate its performance in terms of sensitivity, specificity, feasibility, reliability, and build validity. METHODS: This was a cross-sectional, observational, multicenter trial of adult patients with psoriasis. Initially, patients were assessed by a dermatologist and completed 2 self-administered versions (in print and online) of the PURE-4 questionnaire. Afterwards, the rheumatologist, blinded to the PURE-4 results, assessed the presence/absence of PsA, being the reference to determine the performance of the PURE-4 questionnaire. RESULTS: A total of 268 patients were included (115 [42.9%] women; mean age, 47.1±12.6). The prevalence of PsA according to rheumatologist diagnosis was 12.7% (34 patients). The mean PURE-4 score for patients with psoriasis diagnosed with PsA was 2.3±1.1, and 1.3±1.3 for patients without PsA (P<.001). The cutoff value ≥2 demonstrated the best performance for detecting PsA, with a negative predictive value of 95.1% (95% confidence interval, 90.3-97.6). CONCLUSIONS: The PURE-4 questionnaire demonstrated good performance in detecting PsA, with an optimal cutoff point ≥2. This simple tool could facilitate early referral of patients to the rheumatology unit.

Subclinical enthesopathy of extensor digitorum tendon is highly prevalent and associated with clinical and ultrasound alterations of the adjacent fingernails in patients with psoriatic disease.

BACKGROUND: Nail psoriasis disease is associated with an increased probability of psoriatic arthritis, and its clinical signs may have different correlates with the pathogenesis of adjacent bone destruction and have different prognostic value. Recent publications about psoriasis and nail psoriatic disease describe different ultrasonographic findings but the relationship between these ungueal alterations measured by ultrasonography and the presence of enthesopathy of the extensor digitorum has yet to be discovered. OBJECTIVE: To describe which ultrasonographic characteristics of nail psoriasis are associated with the presence of subclinical enthesopathy in patients with PsO and asymptomatic PsA. METHODS: Patients with psoriasis and asymptomatic psoriatic arthritis were included in the prospective study. Demographic, clinical data and PASI and NAPSI indexes were recorded of all the patients in the assessment visit. The US assessment included Achilles tendon, extensor digitorum tendon and US scan of the nail plate, nail matrix, nail bed and adjacent skin over nail matrix of the five nails of each hand. RESULTS: Forty-eight patients were included in the study; 33 of them presented ultrasound evidence of extensor digitorum tendon enthesopathy. Nails of the patients with subclinical enthesopathy had a higher NAPSI and skin thickness than the nails of the patients without subclinical enthesopathy (P = 0.047). Patients with asymptomatic enthesopathy had significantly thicker proximal nail folds (1.44 ± 0.312 vs. 1.23 ± 0.27, P = 0.023). Nail beds and matrices were also thicker but the differences were not statistically significant (1.77 ± 0.27 vs. 1.74 ± 0.21, P = 0.66, and 1.79 ± 0.28 vs. 1.67 ± 0.19, P = 0.10, respectively). No statistically significant differences in the trilaminar structure were found between both groups. Patients with and without asymptomatic enthesopathy of extensor digitorum tendons did not statistically differ as regards ultrasonographic alterations of the Achilles tendons (60.6% vs. 46.4%, P 0.368). CONCLUSION: Enthesopathy abnormalities can be detected by US in patients with psoriasis without musculoskeletal complaints frequently. There is a close relationship between subclinical enthesopathy of the extensor digitorum tendon and the presence of nail alterations. Further studies are required to research what implications have the presence of these ungual alterations measured by US, and how it affects later development of a PsA.

The safety of ustekinumab for the treatment of psoriatic arthritis.

INTRODUCTION: The cytokines interleukin (IL)-12 and IL-23 have been involved in the pathogenesis of psoriasis and psoriatic arthritis. Ustekinumab is a fully human monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23. Ustekinumab prevents the interaction of IL-12 and IL-23 binding to their receptors, blocking the T1 and T17 inflammatory pathways. Ustekinumab has been evaluated for the treatment of various chronic immune mediated diseases including psoriasis and psoriatic arthritis (PsA). Most of the data regarding the safety of ustekinumab come from the experience treating patients with psoriasis, but clinical trials have demonstrated its efficacy and safety in the treatment of both diseases. The most common adverse events observed during the clinical trials are mild in intensity, and include respiratory tract infections, nasopharyngitis, headache and injection site reactions. Throughout long-term ustekinumab treatment, serious infections or major cardiovascular adverse events occurred rarely. Areas covered: In this review we report the safety data that come from phase II and phase III clinical trials that assay the efficacy and safety of ustekinumab in PsA, including recently published data corresponding to long-term studies. Relevant references were obtained through a literature search in MEDLINE/Pubmed (search strategy: ustekinumab AND psoriatic arthritis) for articles published until November 2016, complemented by a manual search. Expert opinion: In clinical practice, ustekinumab is generally a well-tolerated treatment, and the safety profile in psoriatic arthritis is similar to that reported in plaque psoriasis.

Etanercept in the treatment of psoriatic arthritis.

The aim of the present review is to provide an update on the most important recent studies on the use of etanercept in psoriatic arthritis (PsA). Using various assessment tools, such as the Disease Activity Score 28-joint count (DAS28), the PsA Response Criteria (PsARC), and the American College of Rheumatology (ACR) score, several authors have shown that etanercept can reduce the signs and symptoms of psoriatic arthritis and inhibit radiographic progression in studies with follow-up periods of up to 2 years. There is evidence that etanercept is effective in the treatment of psoriatic enthesitis, dactylitis, and axial joint disease as well as in disease affecting the skin and nails. In clinical trials, etanercept had a safety profile similar to that of placebo and this profile did not change over time. Cost-effectiveness models have found etanercept to be the most cost-effective tumor necrosis factor inhibitor in patients with psoriatic arthritis and mild to moderate psoriasis. Etanercept has a favorable risk-benefit profile in the short term. The concomitant use of methotrexate does not alter etanercept survival.

Vismodegib: a review.

In January 2012, vismodegib (Erivedge, manufactured by Genentech) became the first selective inhibitor of the Hedgehog signaling pathway to be approved by the US Food and Drug Administration for the treatment of locally advanced and metastatic basal cell carcinoma. The drug selectively binds to Smoothened, a 7-helix transmembrane receptor, thereby inhibiting activation of transcription factors of the glioma-associated oncogene family and suppressing tumor proliferation and growth. Studies published to date have assessed the efficacy of vismodegib according to clinical and radiologic outcomes but little information is available on the molecular mechanisms underpinning the proven clinical efficacy of the drug. This review will cover recent data on the Hedgehog signaling pathway and data from clinical trials with vismodegib in the treatment of basal cell carcinoma, and will consider its use in other types of tumor.

[Psoriatic arthritis: what the dermatologist needs to know, Part 2]. / Artritis psoriásica. Lo que el dermatólogo debe saber (Parte 2).

This review aims to cover all aspects related to the treatment of psoriatic arthritis and the evaluation of the response to treatment. We define the various evaluation methods currently used to assess response to treatment in patients with psoriatic arthritis and the complementary examination techniques used to ensure adequate follow-up. These tools enable both the dermatologist and the rheumatologist to carry out an ongoing evaluation of the clinical course, severity, and prognosis of the disease. The treatment lines proposed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spanish Society of Rheumatology are discussed. Emerging strategies for treating this condition and improving prognosis are examined.

MUC4 expression is increased in dysplastic cervical disorders.

The female uterine cervix has 2 characteristic populations of epithelial cells: the endocervix is composed by mucus-secreting cells that express several mucin genes, and the exocervix has a typical stratified squamous epithelium and does not express secreted mucins. Among human mucin genes, the MUC4 sequence has a transmembrane domain, and its molecular structure suggests that it has a protective role and also may be implicated in intracellular signalling. The aim of this study is to analyze whether changes in the expression of MUC4 can be detected associated with the squamous dysplastic transformation of exocervical epithelium. MUC4 expression has been analyzed by immunohistochemistry, Western blotting, and in situ hybridization. Using immunohistochemical techniques, MUC4 is found in normal endocervix (n = 11) and is absent or only focally detected in the normal stratified cervical epithelium (n = 18). In samples from squamous metaplasia (n = 9), MUC4 is variably expressed (10% to 50% positive cells), whereas MUC4 is strongly detected in dysplastic cervical epithelia. The greatest number of positive cells is found in samples with moderate and severe dysplasia in which MUC4 is detected in 100% of the analyzed samples (n = 16). These results have been confirmed by Western blotting and by detection of MUC4 transcripts using in situ hybridization. The present data suggest that MUC4 is activated during the process of squamous dysplastic transformation and may be used as a marker for this pathologic process.

Regulation of mucin and glycoconjugate expression: from normal epithelium to gastric tumors.

Gastric epithelium is protected by a mucus layer rich in MUC5AC and MUC6 mucins synthesised by the superficial epithelium and the glands, respectively. These cell populations also express specific fucosyltransferases that determine the glycosylation pattern of these gastric mucins. The maintenance of the structure and properties of the gastric mucus has been related to the degree of glycosylation and the oligomeric forms of the mucins. In gastric tumors, and in early preneoplastic lesions such as intestinal metaplasia, the glycosylation pattern detected in normal stomach is lost and, intestinal mucins, MUC2 and MUC4, can be ectopically detected in the gastric epithelium. These changes are biologically relevant because the binding of Helicobacter pylori to the gastric mucosa is mediated by blood group-related antigens. In vitro and animal models allowing the study of the gastric ecological niche and the requirements for its maintenance are essential for an understanding of the role of bacterial-mucosal interactions in pathological processes such as inflammation and cancer.

Apomucin expression and association with Lewis antigens during gastric development.

In normal stomach, MUC5AC and MUC6 apomucins are associated with Lewis types 1 and 2, respectively, and this association is lost during gastric carcinogenesis. The expression of gastric (MUC5AC, MUC6) and intestinal (MUC2, MUC4) apomucins and Lewis antigens during gastric development, using single and double labeling immunohistochemistry on fetal tissues (15-41 weeks), was analyzed and related to the tumor expression patterns. Apomucin expression in other fetal tissues was also analyzed. In gastric samples, MUC2 is detected in 14 of 19 showing no correlation with fetal age, and MUC4 is not detected. MUC5AC and MUC6 are always highly detected and are coexpressed and associated with both types of Lewis antigens. These patterns change progressively with the development of the adult gastric morphology. MUC2 is detected in the small intestine, colon, and pancreas; MUC4 is expressed in the colon; MUC5AC is detected in the small intestine; and MUC6 is found in the duodenum and pancreas. The patterns of apomucin expression and association with Lewis antigens during development are complex, but there is a trend toward the establishment of the adult pattern, with the exception of MUC4, which is not detected. These patterns found in fetal stomach indicate that alterations reported in gastric tumors do not fully recapitulate a developmental phenotype.

Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns.

UNLABELLED: Highly glycosylated apomucins are important to maintain the viscoelastic properties of the mucus. Changes in their expression are frequently associated with inflammatory and neoplastic conditions. We analyzed the expression of apomucins in normal respiratory tract (n = 8) and compared it with distal, peritumoral, and tumoral epithelia from patients with squamous cell carcinoma (n = 20), adenocarcinoma (n = 13), and small cell carcinoma (n = 12). Squamous metaplasia (n = 16) was also analyzed. MUC1, MUC2, MUC4, MUC5AC, MUC6, and MUC8 apomucins were detected by immunohistochemistry, and mucin transcripts by in situ hybridization and reverse transcriptase polymerase chain reaction. Bronchial epithelium from normal individuals and distal epithelium from cancer patients showed a similar expression pattern: MUC1, MUC4, and MUC8 were always present, MUC2 and MUC5AC showed more variability, and MUC6 was focally detected. MUC5AC was downregulated in peritumoral epithelium and in squamous metaplasia, and MUC6 was upregulated in peritumoral epithelium. A reduced expression of MUC4, MUC5AC, and MUC8 was observed in non-small cell carcinomas, regardless of their histologic subtype. In small cell tumors, only MUC1 was consistently expressed. CONCLUSIONS: (1) peritumoral epithelium and squamous metaplasia show an abnormal pattern of mucin expression; (2) squamous cell carcinomas and adenocarcinomas display a similar pattern of mucin gene expression, supporting the concept of a common cellular origin.

Role of fucosyltransferases in the association between apomucin and Lewis antigen expression in normal and malignant gastric epithelium.

BACKGROUND: In normal gastric epithelium, MUC5AC is detected in superficial epithelium associated with Lewis type 1 antigens and MUC6 is detected in antral glands with Lewis type 2. Therefore, the stomach constitutes an excellent model to examine the role of glycosyltransferases in determining the specificity of apomucin glycosylation. AIMS: To determine the molecular basis of this association and to examine changes in expression of gastric and intestinal apomucins and their association with Lewis antigens during the gastric carcinogenesis process. METHODS: Fucosyltransferase (FUT1, FUT2, FUT3) and mucin (MUC5AC, MUC6) transcripts were detected using reverse transcription-polymerase chain reaction. Apomucin (MUC2, MUC4, MUC5AC, MUC6) and Lewis antigen (types 1 and 2) expression were analysed using single and double immunohistochemistry and in situ hybridisation. RESULTS: In the normal stomach, FUT1 is exclusively detected associated with MUC6; FUT2 is only detected when MUC5AC is present. This co-regulation is lost in gastric tumours, as is differential expression of MUC5AC and MUC6 in normal gastric epithelial cells. In gastric tumours, especially those with the intestinal phenotype, MUC2 and MUC4 genes are upregulated, and gastric-type and intestinal-type mucins are coexpressed. These changes are early events in the gastric carcinogenesis process, as they are detected in intestinal metaplasia. CONCLUSIONS: The glycosylation pattern found in normal gastric epithelium is dictated by the specific set of fucosyltranferases expressed by the cells rather than by the apomucin sequence. The development of intestinal metaplasia and gastric cancer is associated with the appearance of cellular phenotypes that are absent from normal epithelium.

Mucins and mucin-associated carbohydrate antigens expression in gastric carcinoma cell lines.

Mucins are high-molecular-mass glycoproteins with high carbohydrate content and marked heterogeneity both in the apoprotein and in the oligosaccharide side chains. Mucin genes are expressed in a regulated manner, namely in the human stomach. The first aim of the present study was to characterise the expression of mucins and mucin-associated carbohydrate antigens in seven gastric carcinoma cell lines, and to compare their expression profiles with those of normal gastric tissues and human gastric carcinomas. Secondly, we aimed to see whether or not there is an association between the expression of mucins and mucin-associated carbohydrate antigens. Our results show that mucin expression in gastric carcinoma cell lines: (a) follows in part the mucin expression profile of normal gastric mucosa and gastric carcinomas with wide expression of MUC1 and MUC5AC; (b) parallels the aberrant pattern of mucin expression observed in human gastric carcinomas with occasional expression of MUC2, MUC3, MUC4 and MUC5B; (c) does not include, at least in our series, the expression of MUC6 mucin; and (d) follows in part the differentiation pattern of the carcinomas from which the cell lines originated, keeping S-Tn expression in cell lines derived from glandular carcinomas. Our results further demonstrate that there is no apparent relationship between the mucin core proteins and the simple mucin-type or Lewis carbohydrate antigens.