An increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors.

BACKGROUND: Concerns exist about a risk of non-melanoma skin cancer (NMSC) in psoriasis patients and rheumatoid arthritis (RA) patients treated with TNF-inhibitors. However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that these NMSC can be explained by previous therapies instead of by TNF-inhibitor therapy. OBJECTIVE: To investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and RA patients on TNF-inhibitors. METHODS: Time until first NMSC and the rate of NMSC were compared between psoriasis and RA patients from the same region treated with TNF-inhibitors and followed up for at least one year in prospective cohort studies, by using Cox regression and Poisson regression. Both analyses were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies). RESULTS: The NMSC risk was significantly higher in the psoriasis group [fully adjusted HR 6.0 (1.6-22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to RA. By Poisson regression, psoriasis patients had a 5.5 (2.2-13.4 95%CI) higher rate of NMSC. CONCLUSION: The time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in psoriasis compared with RA. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

Drug survival is not significantly different between biologics in patients with psoriasis vulgaris: a single-centre database analysis.

BACKGROUND: Drug survival depends on several factors such as dosing, effectiveness, quality-of-life improvement and safety, and could be seen as an overall marker for treatment success. Such data for biologics in psoriasis treatment are sparse. OBJECTIVES: To determine differences in drug survival between different biologics for psoriasis. METHODS: Drug survival, dosing, Psoriasis Area and Severity Index (PASI) and Skindex-29 at weeks 12 and 52, and adverse events of patients with psoriasis treated with a biologic registered in the local database of the Academic Medical Center, Amsterdam, were analysed. Patients were divided into those naive or non-naive for treatment episodes with biologics. RESULTS: Drug survival did not differ significantly for naive treatment episodes between the biologics (etanercept 85% to 64%, adalimumab 77% to 77%, infliximab 75% to 75% for year 1-4), or for non-naive treatment episodes (etanercept 86% to 42%, adalimumab 84% to 56%, infliximab 68% to 43% for year 1-4; ustekinumab 84% to 57% for year 1-3). The naive group showed better drug survival and PASI 75 response at week 12, although the difference was not significant. A similar improvement of mean ∆PASI and mean ∆Skindex-29 was observed at weeks 12 and 52 for all biologics for both groups, although no significant difference was seen between groups. Treatment termination was due mainly to nonresponse for all biologics. CONCLUSIONS: There was no significant difference in drug survival, mean ∆PASI or Skindex-29 response at weeks 12 or 52 between the biologics or between the naive and non-naive groups. Treatment termination was due mostly to nonresponse. Sequential treatment with the available biologics can be effective.

National consensus on biologic dose reduction in psoriasis: a modified eDelphi procedure.

BACKGROUND: Dose reduction of biologics for psoriasis is applied in daily practice, although guidelines are lacking. Striving for clear criteria is important, as it leads to a consistent application of dose reduction. OBJECTIVE: To achieve consensus on criteria for biologic dose reduction in psoriasis patients with stable and low disease activity. METHODS: An online Delphi procedure (eDelphi) was conducted. Dutch dermatologists were invited to participate in a maximum of 3 voting rounds. Proposed statements were selected based on literature review and included criteria for the application of dose reduction and dosing schedules. Biologic dose reduction was defined as 'application of injection interval prolongation'. Proposed statements were rated using a 9-point Likert scale; consensus was reached when ≥70% of all voters rated 'agree' (7-9) and <15% rated 'disagree' (1-3). RESULTS: A total of 27 dermatologists participated and reached a consensus on 15 recommendations over 2 voting rounds. Agreed statements included criteria for dose reduction eligibility, criteria for dose reduction (dis)continuation, and dosing schedules for adalimumab, etanercept, and ustekinumab. Based on the eDelphi outcomes, an algorithm fit for implementation in current practice was developed. CONCLUSIONS: Recommendations of this national consensus process can guide clinicians, and consequently their patients, toward consistent application of biologic dose reduction.

Susceptibility of hepatitis B virus to lamivudine restored by resistance to adefovir.

Serial monotherapy and add-on regimes for treatment of chronic hepatitis B virus (HBV) infection may induce the accumulation of viral resistance mutations in patients, reducing the options for ongoing viral suppression. The induction of antiviral resistance by serial application of polymerase inhibitors does not necessarily imply that the subsequent combined use of the drugs will fail. Some HIV strains resistant to one polymerase inhibitor show increased susceptibility to another polymerase inhibitor. After failure of sequential lamivudine and adefovir monotherapy, two patients with hepatitis B changed to treatment with lamivudine plus adefovir and had renewed suppression of HBV. To study the mutational history of resistant HBV subpopulations in the two patients, a part of the HBV polymerase gene was amplified, cloned, sequenced, and analyzed for the presence of mutations, in sequential plasma samples. In both patients serial monotherapy caused the replacement in all HBV clones of wild-type virus by classical lamivudine resistant mutants (L180M and M204V/I), which were replaced subsequently by adefovir resistant mutants (A181V and N236T). When finally lamivudine was added to adefovir, the A181V adefovir mutation persisted in all clones and lamivudine-related mutations did not reappear. During 18 months of combination therapy, HBV-DNA levels decreased 10,000, respectively, 1,000-fold, despite the earlier resistance to lamivudine and adefovir. Although clinically insufficient, this effect indicates that HBV polymerase resistance mutations may be antagonistic, which is relevant if chronic HBV infection is to be treated by a combination of polymerase inhibitors.

Validation of a sensitive and specific real-time PCR for detection and quantitation of hepatitis B virus covalently closed circular DNA in plasma of chronic hepatitis B patients.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) serves as a template for viral replication and plays a role in persistence of HBV infection. The origin and significance of cccDNA in plasma however, is not well understood. A sensitive, specific, and reproducible real-time PCR for detection and quantitation of cccDNA in plasma of chronic hepatitis B patients was developed and validated. Four HBV DNA reference panels, and 96 plasma samples of chronic hepatitis B patients were analyzed. Results were compared with total HBV DNA levels, individual ALT levels and the Histology Activity Index (HAI). This cccDNA assay had a lower limit of detection at 15 copies/PCR, a lower limit of quantitation at 91 copies/PCR and a correlation coefficient (R) of 0.98 (P < 0.0001). cccDNA was detected in two of four international panels. Significant correlation was found between cccDNA and total HBV DNA levels in both panels (R = 0.96, and R = 0.43) and in samples of the chronic hepatitis B patients (R = 0.88, P < 0.0001). In 57% of these samples cccDNA was detectable. Mean level of cccDNA was 0.16% of total HBV load. Plasma cccDNA levels were higher in HBeAg positive samples than in HBeAg negative samples (4.91 log copies/ml vs. 3.88 log copies/ml, P < 0.0001). Levels of total HBV DNA and HBV genotype did not influence cccDNA detection. ALT levels and HAI-score were not correlated with plasma cccDNA levels. These findings suggest that cccDNA levels in plasma are not the result of increased hepatocyte degeneration, but indicate that other mechanisms might be responsible.

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

BACKGROUND: The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. METHODS: This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. DISCUSSION: OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. TRIAL REGISTRATION: NTR4499 . Registered on 7 April 2014.

Hysterectomy: what do women need and want to know?

OBJECTIVE: The purpose of this article is to describe women's experiences of hysterectomy and to identify their fears, concerns, and met as well as unmet health care needs. DESIGN: Narrative data of women's hysterectomy experiences were collected via a written survey. SETTING: Data were collected from women living in southeastern Wisconsin. PARTICIPANTS: Participants were 102 women who had undergone hysterectomy within the previous 2 years. The mean age of the women was 43 and mean time since hysterectomy was 13 months. Eighty percent of the women had undergone both hysterectomy and oophorectomy, and 78% were taking hormone replacement therapy. MAIN OUTCOME MEASURES: A questionnaire of women's hysterectomy needs and a demographic questionnaire were used to collect data via mail. The data from three open-ended questions were content analyzed. RESULTS: Seven themes about women's experiences of hysterectomy were identified: (a) positive aspects, (b) hormone replacement therapy, (c) insufficient information, (d) changes in sexual feelings and functioning, (e) emotional support, (f) psychologic sequelae, and (g) feelings of loss. CONCLUSIONS: Women wanted treatment choices, a part in decision-making, accurate and useful information at an appropriate time, provider support, and access to professional and lay support systems. The essentials for hysterectomy care are outlined and include the characteristics of care that women desire, the informational content that women want, health care systems that support patient satisfaction, and the outcomes women want.

Validation of a sensitive and specific real-time PCR for detection and quantitation of hepatitis B virus covalently closed circular DNA in plasma of chronic hepatitis B patients.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) serves as a template for viral replication and plays a role in persistence of HBV infection. The origin and significance of cccDNA in plasma, however, are not well understood. A sensitive, specific, and reproducible real-time PCR for detection and quantitation of cccDNA in plasma of chronic hepatitis B patients was developed and validated. Four HBV DNA reference panels and 96 plasma samples of chronic hepatitis B patients are analyzed. Results are compared with total HBV DNA levels. This cccDNA assay had a lower limit of detection at 15 copies/PCR, a lower limit of quantitation at 91 copies/PCR, and a correlation coefficient (R) of 0.98 (p < 0.0001). HBV cccDNA can be detected in two of four international panels. Significant correlation is found between cccDNA and total HBV DNA levels in both panels (R = 0.96 and R = 0.43) and in samples of the chronic hepatitis B patients (R = 0.88, p < 0.0001). In 57 % of these samples cccDNA can be detected. Mean level of cccDNA is 0.16 % of total HBV load. Plasma HBV cccDNA levels are higher in HBeAg-positive samples than in HBeAg-negative samples (p < 0.0001). Total HBV DNA levels and HBV genotype do not influence cccDNA detection.