Clinical characteristics and response to biological therapies for inverse psoriasis: a real-life comparison between the therapeutic effects of anti-IL-23 and anti-IL-17 agents.

BACKGROUND: Inverse psoriasis (IP) is a variant of plaque psoriasis involving flexor surfaces. A clear definition of IP is still lacking. Therapy is based on topical and systemic treatments, including classic systemic drugs and biologic agents, but a well-defined therapeutic strategy is absent. MATERIALS AND METHODS: This retrospective study investigated the general characteristics of patients with IP or vulgar psoriasis and compared the effectiveness of anti-interleukin-17 or anti-interleukin-23 agents in the same groups. Second, treatment effectiveness and the demographic characteristics of IP patients treated with IL-23 and IL-17 inhibitors were also compared. IP patients were included if they had specific psoriatic involvement of the axillary, inguinal, or submammary lines, breast folds, antecubital and popliteal pits, intergluteal fold, and perianal area. Patients with vulgar plaque psoriasis and concomitant intertriginous involvement were included in the vulgar psoriasis cohort. RESULTS: Patients with IP were prevalently female and treated with IL-17 inhibitors compared to those with vulgar psoriasis. They also had a greater risk of drug discontinuation and subsequent therapeutical switch (32.1% vs. 18.1%, P = 0.002). At later time points, those with IP showed progressively slower achievement of PASI100 and 90 compared to the cohort with vulgar psoriasis. In the IP cohort, there was greater joint involvement in patients treated with an anti-IL-17 agent (P = 0.011), who also had a lower median age of onset (P = 0.011) compared to patients treated with an anti-IL-23 agent. Patients with IP treated with an anti-IL-23 agent initiated with a lower mean PASI and showed a slower response than patients on an anti-IL-17 agent. At later time points, progressively greater effectiveness of IL-23 inhibitors was observed compared to IL-17 inhibitors. CONCLUSIONS: Patients with IP responded less to biologic agents than those with vulgar psoriasis. In the IP cohort, IL-17 inhibitors had a faster onset than IL-23 inhibitors, but long-term anti-IL-23 agents seem to be associated with better outcomes.

Drug survival, effectiveness, and safety of brodalumab for moderate-to-severe psoriasis up to 3 years.

BACKGROUND: Brodalumab is a monoclonal antibody and IL-17 RA inhibitor that is approved for the treatment of moderate-to-severe psoriasis. The present study aims to estimate the drug survival (DS), effectiveness, and safety of brodalumab over a period of 156 weeks. METHODS: The primary objectives were: (i) to determine the treatment response rate at Weeks 16, 28, 52, 78, 104, and 156 as defined by PASI100, PASI90, and an absolute PASI ≤ 3 and (ii) long-term DS. Secondary objectives included the evaluation of possible predictive factors associated with the achievement of response outcomes, and possible predictive factors associated with lower DS. RESULTS: The treatment response was rapid, with 80.3% of patients achieving PASI ≤ 3, 66% PASI90, and 54.3% the complete clearance of disease at Week 16. The response improved at Week 28, when a plateau was achieved with mild loss of response at later time points, in particular for PASI100 and PASI90 in 55.2 and 65.5% of patients, respectively, at Week 156. After 156 weeks of treatment, 66.22% of patients were still on therapy, and the previous use of IL-17 inhibitors appeared to be associated with an increased risk of treatment discontinuation (HR: 2.51, CI: 1.06-5.98, P = 0.037), and achievement of PASI ≤ 3 until Week 16 with less risk (HR: 0.27 CI: 0.14-0.51, P < 0.001). Bio-naïve status was favorably associated with treatment response, while high BMI negatively affected the achievement of outcomes. CONCLUSION: Our study confirms the good effectiveness and favorable safety profile of brodalumab in a real-world setting for up to 3 years of treatment.

Drug survival and clinical effectiveness of secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, tildrakizumab for psoriasis treatment.

BACKGROUND: Biologics targeting IL-23 and IL-17 show efficacy and safety in the treatment of moderate-to-severe psoriasis. OBJECTIVE: To investigate drug survival in patients with psoriasis treated with biologics. PATIENTS AND METHODS: We performed a comparative evaluation of the achievement of PASI 90 and PASI ≤ 3 at 16, 28, and 52 weeks along with a DS (drug survival) analysis with IL-17 and IL-23 inhibitors brodalumab, ixekizumab, secukinumab, risankizumab, tildrakizumab, and guselkumab on 1,057 patients. RESULTS: IL-17 inhibitors showed a faster achievement of PASI 90 and PASI ≤ 3 with significant superiority over IL-23 inhibitors at week 16 (p < 0.001; 56% vs. 42% and 70% vs. 59%, respectively). A difference was shown in favor of IL-23 inhibitors regarding DS (p < 0.001), which was 88% at 24 months vs. 75% for IL-17 inhibitors. In multivariate analysis, IL-23 inhibitors (HR 0.54 CI 0.37-0.78, p = 0.001), and male sex (HR 0.57 CI 0.42-0.76, p < 0.001) were all associated with a lower probability of drug interruption. Risankizumab (HR 0.42 CI 0.26-0.69, p = 0.001), guselkumab (HR 0.49 CI 0.24-0.99, p = 0.046), and male sex (HR 0.57 CI 0.43-0.77, p < 0.001) were associated with a lower probability of drug interruption than secukinumab. CONCLUSIONS: IL-23 inhibitors showed the best performance on DS. Overall, the most effective class was IL-17 inhibitors considering the short-term effectiveness, but long-term effectiveness is in favor of anti-IL-23.

Interclass Switch between IL17 and IL23 Inhibitors in Psoriasis: A Real-Life, Long-Term, Single-Center Experience.

BACKGROUND: Interleukin 23 (IL-23) inhibitors, such as guselkumab, risankziumab, and tildrakizumab, have proved to be highly effective and safe for psoriasis treatment either in bio-naïve or bio-experienced patients. A substantial proportion of patients show a primary or secondary inefficacy to IL-17 inhibitors and can benefit from an alternative line of treatment, like IL-23 inhibitors. To date, no sufficient data are available on the effectiveness of IL-23 inhibitors after an anti-IL-17 agent. METHODS: Our study includes 48 patients with moderate to severe psoriasis undergoing a switch from IL-17 to IL-23 inhibitors. This trial is registered with SS_DERMO_20. RESULTS: The mean PASI (Psoriasis Area Severity Index) decreases from 11.6 to 3.3 at week 16, with responses maintained at weeks 28 and 52 (2 and 1.4, respectively), and a PASI100 achievement in more than 24% of patients at 16 weeks and 61.9 at 48 weeks, with no occurrence of serious adverse events. However, almost one in six patients interrupted the IL-23 inhibitors mainly due to primary ineffectivenss. CONCLUSIONS: Our data support the evidence that an interclass switch among IL-17 inhibitors is a safe and effective therapeutic option for these patients.

Clinical effectiveness of IL-17 and IL-23 inhibitors on difficult-to-treat psoriasis areas (scalp, genital, and palmoplantar sites): a retrospective, observational, single-center, real-life study.

INTRODUCTION: Psoriasis affecting the genital, palmoplantar, and scalp regions is recognized as difficult-to-treat, and data on the efficacy of biologics in these areas remains limited. RESEARCH DESIGN AND METHODS: This single-center study evaluated the effectiveness of anti-IL-17 and anti-IL-23 agents on scalp, genital, and palmoplantar psoriasis. We retrospectively analyzed data from all patients with psoriasis being treated with IL inhibitors at our clinic. Effectiveness was evaluated at 16, 28, and 52 weeks, according to the achievement of relative and mean PSSI, PGA-G, and ppPASI. RESULTS: In all, 308 patients showed involvement of the scalp, 136 in the genital area, and 94 in the palmoplantar regions. On scalp psoriasis, anti-IL-17 agents demonstrated superiority in disease control compared to anti-IL-23 agents. PSSI100 at week 16 was reached by 59% of patients on an anti-IL17 vs 39.8% on an anti-IL-23 (p < 0.003). At genital sites, no significant differences between anti-IL-17 and anti-IL-23 agents were observed, and all classes achieved PGA-G 0/1. No significant differences between anti-IL-17 and anti-IL-23 agents were observed in palmoplantar areas. CONCLUSIONS: The present data support the utility of both anti-IL-17 and anti-IL-23 agents for the treatment of difficult-to-treat areas in patients with psoriasis. Anti-IL-17 agents achieved better control of scalp psoriasis.

Efficacy, safety, and drug survival of IL-23, IL-17, and TNF-alpha inhibitors for psoriasis treatment: a retrospective study.

BACKGROUND: Real-life studies in psoriasis are lacking. Many monoclonal antibodies targeting tumor-necrosis factor (TNF)-alpha, interleukin 17, and 23 are approved drugs for psoriasis treatment. OBJECTIVES: To compare the short and long-term efficacy, safety, and drug survival of anti TNF-alpha, anti-IL-17, and anti-IL-23 in a large case series. METHODS: Psoriasis area severity index (PASI) and retention rates for adalimumab, secukinumab, guselkumab, ixekizumab, and brodalumab were analised. RESULTS: A total of 263 patients were randomly selected among the five drugs register of the patients attending the Psoriasis Unit at the Turin University Hospital. The mean PASI at baseline was 14.3. Ixekizumab showed a significantly higher efficacy profile compared to other drugs in terms of PASI90 and PASI100 at week 12, 24, and week 48 even when adjusted for other confounding factors. This superiority was not followed by an expected higher drug survival. On the contrary, secukinumab was the only drug that showed a higher drug survival among bio-naïve patients.

Gender differences in genital lichen sclerosus: data from a multicenter Italian study on 729 consecutive cases.

BACKGROUND: Studies specifically conducted to assess gender differences in genital lichen sclerosus (GLS) are not available. This multicenter study aimed to identify possible gender-related differences on GLS clinical features, history and course, through collecting data from a large mixed-sex sample of patients. METHODS: This was a cross-sectional study on 729 subjects (53.8% females, 46.2% males) affected with GLS, consecutively observed within a network of 15 Italian dermatology units. The following information was specifically collected: clinical features and severity of symptoms related to GLS, extragenital involvement, previous therapies, diagnostic suspicion at referral, type of referring physicians, development of genital squamous-cell carcinoma (SCC). RESULTS: Females complained of symptoms more frequent and severe than men; pallor and scarring-sclerosis-atrophy were the most frequent features without gender differences; itching-related signs were more frequent in females than in males as well as extragenital involvement; prior to receiving a definitive diagnosis, females received treatment more frequently than males; 40% of patients were referred with a misdiagnosis; the highest rate of correct suspected diagnosis at referral came from dermatologists than from other physicians; duration of the disease was found to predispose to SCC development. CONCLUSIONS: Our findings highlighted several gender differences on clinical presentation and symptom profile of GLS. In spite of some characteristic features, misdiagnosis at referrals was frequent.

Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels?

Hypothyroidism is associated with the risk of development of the metabolic syndrome (MS) and hypercholesterolemia. Direct evidence that hypothyroidism might be associated with advanced chronic liver disease via nonalcoholic steatohepatitis (NASH) is limited. We studied the relationship between thyroid hormones, thyroid stimulating hormone (TSH), cholesterol, and NASH. In consecutive euthyroid patients with biopsy-proven nonalcoholic fatty liver disease, TSH and thyroid hormone (FT3 and FT4) concentrations were compared in 25 patients with steatosis and 44 non-cirrhotic NASH patients featuring concurrent ballooning, lobular inflammation and steatosis. The MS was diagnosed according to ATP III criteria. A meta-analysis of previously published studies was performed to evaluate whether NASH, compared to simple steatosis, is associated with lower cholesterol levels. At univariate analysis, compared to those with steatosis, patients with NASH have a wider waist, elevated levels of BMI, ALT, AST, fasting insulin, HOMA-IR, ferritin, TSH and a lower serum cholesterol. At stepwise multivariable logistic regression analysis, the independent predictors of NASH are high HOMA and TSH and lower total cholesterol (Model 1); MS and high TSH (Model 2). At meta-analysis, serum total cholesterol levels are significantly lower in predominantly non-cirrhotic NASH than in simple steatosis. This study provides cross-sectional and meta-analytic evidence that, in euthyroid patients, high-though-normal TSH values are independently associated with NASH. Further work is needed to ascertain the role, if any, of lower cholesterol serum levels in assisting in the diagnosis of NASH.

O6-methylguanine-DNA methyltransferase promoter hypermethylation in colorectal carcinogenesis.

Epigenetic alterations have been reported in colorectal neoplasia which can either complement or in some cases be predisposed to genetic alterations such as K-ras mutations. We examined the promoter methylation status of the CDKN2A and O6-methylguanine-DNA methyltransferase (MGMT) genes, after sodium bisulfite conversion and DNA amplification with methylation specific PCR. Moreover, we searched for G to A transitions in codons 12 and 13 of the K-ras oncogene in normal colorectal mucosae, aberrant crypt foci (ACF, early premalignant lesions) and carcinomas. CDKN2A hypermethylation was an infrequent event in ACF (2 of 26, 7.7%). On the contrary, MGMT hypermethylation was found in the normal mucosae (3 of the 12 samples, 25%), in 14 of the 26 ACF (53.8%) and in 7 of the 9 (77.8%) carcinomas examined. K-ras mutations were evident in 6 ACF (23%) and in 3 carcinomas (33.3%), mostly associated with MGMT promoter hypermethylation. These findings strongly support the hypothesis that epigenetic mechanisms play an important role in the early steps of colorectal carcinogenesis.

Fatty liver, carotid disease and gallstones: a study of age-related associations.

AIM: To evaluate carotid intima-media thickening (IMT) and plaques, gallstone disease (GD) and fatty liver (FL) as a function of age. METHODS: In 449 subjects, FL and carotid disease were assessed ultrasonographically. In a subgroup of 65/449 patients with non-alcoholic fatty liver disease (NAFLD), carotid disease, GD and associated factors were determined. RESULTS: FL of unspecified etiology was more common in younger and GD in older individuals. FL subjects had an increased prevalence of IMT and a decreased prevalence of plaques and manifested carotid disease earlier. Plaques were more common in subjects with GD. Age was an independent predictor of carotid disease outcome and FL was a protective factor for plaques. In NAFLD, there was an inverse correlation between body weight and age and the latter independently predicted carotid findings. CONCLUSION: Cardiovascular risk in patients with FL and NAFLD needs to be assessed as a function of age and body weight.

Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates.

Eighty-four consecutive subjects with nonalcoholic fatty liver disease (NAFLD) were tested for non-organ-specific autoantibodies (NOSA) by indirect immunoflorescence. Indices of insulin resistance and biochemical and anthropometric parameters were assessed. The overall prevalence of anti-nuclear-antibodies (ANA), smooth muscle antibodies (SMA) and anti-mitochondrial-antibodies (AMA) was 35.7% (30/84), 18 subjects (21.4%) being positive for ANA, 4 (4.7%) for SMA, 6 for ANA and SMA, and 2 for AMA. NOSA-positive subjects were older (P < 0.01) and mostly females (63.3%). No significant difference was found in the age-corrected parameters studied, except for copper and ceruloplasmin, which was more elevated in NOSA-positive patients. The subset of high titer (>1:100) ANA-positive patients had significantly (P < 0.05) greater insulin resistance than ANA-negative patients. In contrast, SMA-positive patients had higher gammaglobulin and significantly lower insulin resistance as compared to high-titer ANA-positive patients. In 3 NOSA-positive but not in NOSA-negative patients, liver biopsy disclosed features of overlapping NASH with autoimmune hepatitis, partially responding to diet combined with steroid treatment. In conclusion, NOSA positivity in NAFLD is more prevalent than in the general population. High-titre ANA but not SMA positivity is associated with insulin resistance.