Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors.

BACKGROUND: The possible connection between psoriasis with cardiovascular disease and associated risk factors has been implied, but inconsistent results have been reported. OBJECTIVE: We sought to create an overview and statistical summary of the previous literature with elucidating subgroup analysis. METHODS: This was a meta-analysis of observational studies using random effect statistics. A systematic search of observational studies of psoriasis as study variable and cardiovascular disease and associated risk factors as outcome, published before October 25, 2012, was conducted. RESULTS: Of 835 references in the original search, 75 relevant articles were identified. We included 503,686 cases and 29,686,694 controls. Psoriasis was associated with cardiovascular disease in total (odds ratio [OR] 1.4; 95% confidence interval [CI] 1.2-1.7), ischemic heart disease (OR 1.5; 95% CI 1.2-1.9), peripheral vascular disease (OR 1.5; 95% CI 1.2-1.8), atherosclerosis (OR 1.1; 95% CI 1.1-1.2), diabetes (OR 1.9; 95% CI 1.5-2.5), hypertension (OR 1.8; 95% CI 1.6-2.0), dyslipidemia (OR 1.5; 95% CI 1.4-1.7), obesity by body mass index (OR 1.8; 95% CI 1.4-2.2), obesity by abdominal fat (OR 1.6; 95% CI 1.2-2.3), and the metabolic syndrome (OR 1.8; 95% CI 1.2-2.8), but not associated with cerebrovascular disease (OR 1.1; 95% CI 0.9-1.3) and cardiovascular mortality (OR 0.9; 95% CI 0.4-2.2). The strongest associations were seen in hospital-based studies and psoriatic arthritis. Population-based studies did not show significant associations, with the exception of dyslipidemia. LIMITATIONS: The heterogeneity of the studies makes clinical interpretation challenging. CONCLUSIONS: In aggregate, psoriasis was associated with ischemic heart disease and cardiovascular risk factors. The association was only significant for hospital-based studies, except for dyslipidemia, which was also significant in population-based studies.

Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls.

Global DNA hypomethylation associates with development of cancer. DNA hypomethylation also associates with hyperhomocysteinemia and MTHFR c.677C>T homozygosity, both of which may associate with increased risk of cancer. We tested the putative association of hyperhomocysteinemia with cancer and the association of the MTHFR c.677TC>T variant with hyperhomocysteinemia and with cancer. We performed a cross-sectional study of 5,949 Danish general population adults, a prospective study of 9,235 Danish general population adults with up to 60 years of registry surveillance, and meta-analyses of 231 studies including 74,671 cases and 93,344 controls. Cross-sectionally, plasma homocysteine levels were 12.9 and 11.6 µmol/L in those with and without cancer (p < 0.0001). However, homocysteine levels increased with age and age-adjusted odds ratio for any cancer in those with homocysteine levels >12.4 versus < 9.4 µmol/L did not differ from 1.0. In cancer-free participants, plasma homocysteine levels were 14.7 and 11.7 µmol/L in MTHFR c.677C>T homozygtes and noncarriers (p < 0.0001). Prospectively, hazard ratios for any cancer and for cancer subtypes in MTHFR c.677C>T homozygotes versus noncarriers did not differ from 1.0. However, in meta-analyses odds ratio for MTHFR c.677C>T homozygotes versus noncarriers were 1.07 (95% CI: 1.01-1.12) for any cancer, 1.77 (1.17-2.68) for esophagus cancer, 1.40 (1.19-1.66) for gastric cancer and 0.85 (0.77-0.94) for colorectal cancer. Increased plasma homocysteine levels are not associated with an increased age-adjusted risk of any cancer. However, MTHFR c.677C>T homozygosity with lifelong hyperhomocysteinemia and hence hypomethylation associate with increased risk of esophagus and gastric cancer, and with decreased risk of colorectal cancer.

Hidradenitis suppurativa: a review of cause and treatment.

PURPOSE OF REVIEW: Hidradenitis suppurativa is a chronic or relapsing inflammatory cutaneous disorder manifested by recurrent formation of abscesses, fistulating sinus and scarring in the apocrine-gland-bearing skin. This review discusses the different aetiological theories and management opportunities. RECENT FINDINGS: Current understanding of the pathogenesis suggests that hyperkeratosis of the infundibulum, leading to follicular occlusion of the pilosebaceous unit plays a role. Bacterial infection with staphylococci, Escherichia coli and streptococcus is considered as a secondary event in the pathogenesis. Smoking and obesity are both known as risk factors and are associated with more severe disease course. Recently, more attention has been put into the understanding of the immunopathology of the skin and the results indicate that hidradenitis suppurativa may be considered as an inflammatory disease of unknown cause based on a defect in the hair follicle immunity. The treatments are most appropriately chosen on the basis of disease severity and the existence of any associated risk factors or comorbidities. There are three levels in the management of hidradenitis suppurativa: topical options, systemic options and surgical methods including laser therapy. At each level several treatment principles have shown themselves to be efficient, and may therefore be used either alone or in combination. Therapies are generally effective against microorganisms, inflammation or infundibular hyperkeratosis. Where an antimicrobial therapy is used, the drugs used often have significant additional immunomodulatory effects. SUMMARY: The recent studies give us a better insight into the pathogenesis of hidradenitis suppurativa and should translate into improved therapies.

Dapsone therapy for hidradenitis suppurativa: a series of 24 patients.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory skin disease with a chronic intermittent course. HS is difficult to treat, and the evidence for the effect of most treatments consists of smaller open studies. The use of dapsone in the treatment of HS is based on a few published cases successfully treated. OBJECTIVE: To evaluate the potential of dapsone treatment for HS in an open case series. METHODS: An exploratory and retrospective review of case notes from HS patients treated with dapsone was performed. Patients were included irrespective of treatment outcome. Prior to the treatment the level of glucose-6-phosphate dehydrogenase in the blood was tested for all patients. RESULTS: A total of 24 HS patients were included and treated with dapsone. Improvement was seen in 9 out of 24 (38%) treated patients, whereas 15 out of 24 (62%) did not experience any improvement. None of the 4 cases with severe disease experienced improvement. Side effects leading to discontinuation of the treatment occurred in 2 of 24 patients (8%). Recurrence of disease at the cessation of treatment was described as rapid. LIMITATIONS: The study is limited by lacking a control group. CONCLUSION: Therapy with dapsone for patients with HS is possible, particularly in milder cases. The effect may be due to either antibacterial or anti-inflammatory effects of the drug, or both. Rapid recurrence after stopping treatment however suggests that anti-inflammatory effects may predominate. The effect appears to be smaller than that reported with combination therapy using clindamycin and rifampicin. To clarify the true effect of dapsone future randomized controlled trials are necessary.

Penetrance of NOD2/CARD15 genetic variants in the general population.

BACKGROUND: In case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater risk. However, the importance of these genetic variants if identified in particular individuals within the general population is unknown. We undertook this study to estimate the penetrance of these variants in the general population. METHODS: We genotyped 43,596 individuals from the Danish general population followed between January 1976 and July 2007. Using a logistic regression model, we estimated the risk of Crohn disease in relation to variants of the NOD2/CARD15 gene in the general population. Penetrance was calculated as the fraction of participants in whom Crohn disease was diagnosed before age 50 years. RESULTS: In the general population, 89% of participants were noncarriers of the genetic variants of interest (n = 38,594), 11% were heterozygotes (n = 4838), and 0.4% were compound heterozygotes or homozygotes (n = 164). For Crohn disease, multifactorially adjusted odds ratios were 1.2 (95% confidence interval [CI] 0.8-1.9) for heterozygotes and 3.3 (95% CI 0.8-13.6) for compound heterozygotes and homozygotes combined, relative to noncarriers. Only 2 compound heterozygotes received a diagnosis of Crohn disease, and this disease was not diagnosed in any of the homozygotes. The penetrance at age 50 years of NOD2/CARD15 genetic variants of Crohn disease was 0.30% (95% CI 0.29%-0.31%) for heterozygotes and 1.5% (95% CI 1.4%-1.6%) for compound heterozygotes and homozygotes. INTERPRETATION: The penetrance of NOD2/CARD15 genetic variants in relation to risk of Crohn disease for this Danish population was lower than might have been expected from previous European case-control studies. This should be considered when advising healthy individuals in whom these genetic variants are identified.

Concomitant Hidradenitis Suppurativa and Eruptive Xanthomas Presenting with Phimosis - The Importance of Timely Diagnosis.

A 49-year-old man diagnosed with metabolic syndrome (MetS) was referred to us for treatment of xanthoma elements. Physical examination revealed widespread confluent yellow firm papules on his fingers, toes, arms, legs, and back. The diagnosis of eruptive xanthoma (EX) was clinically confirmed. During the examination of scar tissues, tombstone comedones and an inflammatory nodule was noted on his abdominal folds and right groin. These are diagnostic signs of hidradenitis suppurativa (HS), a condition the patient had reportedly suffered for 15 years without being diagnosed. The patient's HS nodule was treated with intralesional triamcinolone injection, and prophylactic resorcinol was initiated, and he was referred to endocrinologists for xanthoma management. Three weeks later he returned due to newly developed lesions on his preputium, which caused a painful phimosis. Both HS and EX are correlated with MetS and causes increased all-cause cardiovascular mortality. As the average diagnostic delay of HS is 7.2 years, it is likely that timely diagnosis of HS would have identified the patient as being at risk of developing MetS. With proper preventive measures, the resulting EX lesions and increase in cardiac mortality could have been avoided.

Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis.

BACKGROUND: Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. METHODS: We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally important risk factors for Crohn disease. In addition, we used studies for which combined information from all genotypes was available to compare risks in simple heterozygotes, compound heterozygotes, and homozygotes. PubMed, EMBASE, and Web of Science were searched. Seventy-five articles (18 727 cases and 17 102 controls) met the inclusion criteria and contributed data to the metaanalyses. RESULTS: The odds ratios per allele for Crohn disease were 2.2 (95% CI, 2.0-2.5) for Arg702Trp, 2.6 (2.2-2.9) for Gly908Arg, and 3.8 (3.4-4.3) for Leu1007fsinsC (z-test results: Arg702Trp vs Gly908Arg, P = 0.03; Arg702Trp vs Leu1007fsinsC, P < 0.001; Gly908Arg vs Leu1007fsinsC, P < 0.001). When all 3 genotypes were combined, odds ratios for Crohn disease were 2.4 (95% CI, 2.0-2.8) for simple heterozygotes, 9.0 (6.0-13.5) for compound heterozygotes, and 6.7 (4.1-10.9) for homozygotes, compared with noncarriers (z-test results: simple heterozygotes vs compound heterozygotes, P < 0.001; simple heterozygotes vs homozygotes, P < 0.001; compound heterozygotes vs homozygotes, P = 0.18). CONCLUSIONS: The per-allele risk of Crohn disease was markedly higher for Leu1007fsinsC than for Arg702Trp and Gly908Arg. Combining all genotypes revealed the risks of Crohn disease for compound heterozygotes and homozygotes to be similar and markedly higher than for simple heterozygotes.

Pain during topical photodynamic therapy - comparing methyl aminolevulinate (Metvix®) to aminolaevulinic acid (Ameluz®); an intra-individual clinical study.

BACKGROUND: Actinic keratoses are often treated by photodynamic therapy. However, the main side effect of this treatment is pain during and shortly after illumination. OBJECTIVES: To evaluate, in an intra-individual study, whether the pain response differ in treatment of actinic keratoses in scalp and forhead, using branded methyl aminolevulinate (MAL) and aminolaevulinic acid (ALA). MATERIALS AND METHODS: Patients with mild to moderate actinic keratoses on forehead and scalp were treated with methyl aminolaevulinate (MAL)-PDT and aminolaevulinic acid (ALA)-PDT on two similar areas of forehead and scalp. The pain response were measured using visual analogue scale ranging from 0 to 10 during the illumination and 30min after the treatment. RESULTS: Fourteen patients completed treatment to MAL and ALA-PDT. We found no significant difference in pain intensity between MAL and ALA-PDT, neither during the treatment (p-value=1) nor 30min after the treatment (p-value of 0.19). CONCLUSIONS: This intra-individual study demonstrate no significant difference between the pain response during PDT using methyl aminolevulinate and aminolaevulinic acid.

Impact of T300A Variant of ATG16L1 on Antibacterial Response, Risk of Culture Positive Infections, and Clinical Course of Crohn's Disease.

OBJECTIVES: Autophagy-related 16-like 1 (ATG16L1) deficiency leads to impaired cellular autophagy and bacterial degradation as well as an altered cytokine production. The single-nucleotide polymorphism rs2241880 (T300A) is associated with an increased risk for Crohn's disease (CD). ATG16L1 polymorphisms could therefore have an impact on the risk of infectious complications and disease course in CD. We examined the impact of the T300A genotype on the antibacterial response toward a panel of pathogenic bacteria in vitro, as well as clinical infectious complications in vivo and the disease course in a Danish cohort of patients with CD. METHODS: A total of 236 CD patients were genotyped for ATG16L1(T300A); their clinical records were reviewed, and microbial, radiological, and surgical data were scrutinized. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and CD patients carrying the different ATG16L1 genotypes, and the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß was measured by enzyme-linked immunosorbent assay after stimulation with a panel of pathogenic bacteria of clinical relevance for the gastrointestinal tract, e.g., enteroinvasive Escherichia coli (EIEC), Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, or Mycobacterium avium paratuberculosis. RESULTS: Fifty-seven healthy controls (15, 29, 13) and 236 patients with CD (50, 108, 78) were genotyped for the T300A ATG16L1 polymorphism (AA homozygous, GG homozygous risk variant, AG heterozygous variant, respectively). The median duration of disease was 128 months (range, 30-175). The cumulative follow-up of this cohort was 2,366 patient-years. ATG16L1 gene variations interfered with the production of IL-1ß, which was significantly increased in PBMCs from GG patients in response to all tested bacteria, whereas the TNF-α production was decreased in PBMCs from GG patients stimulated with EIEC, L. monocytogenes, and S. typhimurium, but unaffected by the other bacteria tested. Moreover, the GG variant showed a nonsignificant increase in the risk of bowel resections (P=0.07) and postsurgical infections (P=0.08), whereas the risk of non-disease-related infections was unaffected by genotype in the observation period. In addition, patients with AA and AG variants had a higher frequency of complicated fistulizing disease (P=0.03) with an overall more aggravated disease course with an increased number of surgical procedures for fistulous disease from a median 6.5 operations (2.0 in GG patients; P=0.002). This risk was independent on disease phenotype (penetrating vs. non-penetrating) and immunomodulating medication. CONCLUSIONS: The T300A variant in patients with CD strongly increases the risk for complicated fistulizing disease, and significantly affects antibacterial responses in vitro, but the latter effect seems to have a minor role for the infectious risk in CD.