Martijn van Doorn

Type 2 iodothyronine deiodinase in skeletal muscle: Effects of hypothyroidism and fasting

CONTEXT The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production. OBJECTIVE We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia. DESIGN This was a prospective study. SETTING The study was conducted at a university hospital. PATIENTS We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T4( replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting. MEAN OUTCOME MEASURES D2 activity and D2 mRNA levels were measured in skeletal muscle samples. RESULTS No differences were observed in muscle D2 mRNA levels in DTC patients on and off T4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. CONCLUSION Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle.

Secukinumab shows significant efficacy in palmoplantar psoriasis: Results from GESTURE, a randomized controlled trial

Background: Plaque psoriasis affecting palms and soles is disabling and often resistant to treatment. Objective: Evaluate the efficacy and safety of secukinumab, an anti‐interleukin 17A antibody, in subjects with palmoplantar psoriasis. Methods: In this double‐blinded, randomized controlled trial, 205 subjects were randomized 1:1:1 to secukinumab 300 mg, 150 mg, or placebo. The primary endpoint was Palmoplantar Investigators Global Assessment (ppIGA) 0 (clear) or 1 (almost clear/minimal) response at week 16. Results: At week 16, the percentage of subjects who achieved clear or almost clear palms and soles (or ppIGA 0/1) with secukinumab 300 mg (33.3%) and 150 mg (22.1%) was superior to the percentage achieved with placebo (1.5%, P < .001). Palmoplantar Psoriasis Area and Severity Index (ppPASI) was significantly reduced with secukinumab 300 mg (−54.5%) and 150 mg (−35.3%) compared with placebo (−4.0%, P < .001). Dermatology Life Quality Index (DLQI) 0/1 responses from subjects in the secukinumab groups were also significantly higher compared with placebo at week 16 (P < .01) and pain and function of palms and soles was markedly improved with secukinumab as measured by the palmoplantar Quality‐of‐Life Instrument. Secukinumab 300 mg consistently showed the best outcomes. The safety profile was favorable and similar to previous studies. Limitations: Lack of active comparator. Conclusion: In GESTURE, the largest randomized controlled trial in palmoplantar psoriasis, secukinumab demonstrated the greatest efficacy to date for treating difficult‐to‐treat psoriasis.

Successful Treatment of Chronic Staphylococcus aureus-Related Dermatoses with the Topical Endolysin Staphefekt SA.100: A Report of 3 Cases

Staphylococcus aureus plays an important role in skin and soft tissue infections and contributes to the pathophysiology of complex skin disorders such as atopic dermatitis. Bacterial resistance against commonly used antibiotics has increased considerably in the last decades demanding alternative treatment approaches. We present 3 cases where patients with chronic and recurrent S. aureus-related dermatoses were successfully treated with Staphefekt SA.100. Staphefekt SA.100 is a recombinant phage endolysin for topical skin application that specifically targets both methicillin-sensitive and methicillin-resistant S. aureus. As a consequence of its specific mechanism of action, bacterial resistance is unlikely to develop. In our 3 cases, resistance induction was not observed. Our results indicate that targeted treatment with Staphefekt might be an attractive alternative for (long-term) classical antibiotic therapy, and confirmatory randomized controlled trials are warranted to evaluate its clinical efficacy and safety.

Monitoring antigen-specific biologics: current knowledge and future prospects.

Abstract: An increasing number of antigen-specific biologics have been introduced into clinical practice, and the ones that arrived first have already reached the end of their patented life span. Despite the use of these agents for over a decade, individualized dosing is not standard practice. Most patients are treated according to treatment protocols, with a fixed dose administered at fixed time intervals. Although the between-subject variability in the volume of distribution is small, there is a moderate to high between-subject variability in the clearance of these biologics. The formation of neutralizing antidrug antibodies (ADAs) further contributes to the variability in the pharmacokinetics and pharmacodynamics. After the development of assays to detect biologic drug serum concentrations and ADA titers, the first clinical studies in immune-mediated diseases such as rheumatology, gastroenterology, and dermatology have now shown clear concentration–effect relationships. By monitoring the serum trough concentrations of biologics, patients with high drug exposure could be identified and dose reductions in those patients may lead to improved safety and substantial cost savings. Low biologic drug serum concentrations may be due to the development of ADAs, and if these are detected, a switch to an alternative treatment is indicated. We envision a vast expansion of therapeutic drug monitoring to support the use of biologics, and we urge the International Association of Therapeutic Drug Monitoring and Clinical Toxicology to embark on initiatives to investigate the contribution of therapeutic drug monitoring to this field.

Injection site reactions after subcutaneous oligonucleotide therapy

Oligonucleotides (ONs) are short fragments of nucleic acids, currently being investigated as therapeutic agents. When administered subcutaneously (sc), ONs cause a specific local reaction originating around the injection site, such as erythema, itching, discomfort and pain, including more severe manifestations such as ulceration or necrosis. These injection site reactions (ISRs) are common, but rather poorly described in the literature. With this review, we aim to provide an overview on the extent of the problem of ISRs, based on reported incidence. A structured literature search was performed to identify reported incidence and clinical features of ISRs which yielded 70 manuscripts that contained information regarding ISRs. The data from literature was combined with data on file available at our institution. All sc administered ONs described in the literature lead to the occurrence of ISRs. The percentage of trial subjects that developed ISRs ranged from 22 to 100% depending on ON. The majority of ONs caused ISRs in more than 70% of the trial subjects. The severity of the observed reactions varied between different ONs. Occurrence rate as well as severity of ISRs increases with higher doses. For chemistry and target of the compounds, no clear association regarding ISR incidence or severity was identified. All ONs developed to date are associated with ISRs. Overcoming the problem of ISRs might add greatly to the potential success of sc‐administered ONs. Knowledge of these skin reactions and their specific immunostimulatory properties should be increased in order to obtain ONs that are more suitable for long‐term use and clinically applicable in a broader patient population.

Comparison of Three Assays to Quantify Infliximab, Adalimumab, and Etanercept Serum Concentrations

Background: To optimize treatment of inflammatory diseases, interest in the measurement of anti–tumor necrosis factor alpha (anti-TNF&agr;) serum drug concentrations is increasing. Preferably, assays for the detection of these drugs should be compared using the same reference material. In this study, 2 commercially available enzyme-linked immunosorbent assays (ELISAs) and a commercially available bioassay for the determination of anti-TNF&agr; drugs are compared. Methods: Serum samples from infliximab-, adalimumab-, and etanercept-treated patients, control samples from ustekinumab-treated patients, and healthy donors were obtained. ELISAs manufactured by Sanquin and Theradiag and the iLite reporter gene–based bioassay from Biomonitor were compared. Results: Sanquin, Theradiag, and iLite assays concordantly (100%) detected infliximab, adalimumab, and etanercept in the relevant patient groups. The Sanquin ELISAs specifically detected the anti-TNF&agr; drug they were designed for, whereas the Theradiag and iLite showed cross-reactivity with other anti-TNF&agr; drugs. Ustekinumab was not detected in any of the assays. Sanquin, Theradiag, and iLite exhibited linear quantitative correlation for all drug concentration assays. However, there were statistically significant quantitative differences in measured concentrations. Conclusions: All 3 commercially available assays seem suitable for therapeutic drug monitoring of anti-TNF&agr; drugs, allowing sensitive and comparable detection of infliximab, adalimumab, and etanercept concentrations, however with differences in specificity and recovery.

Treatment of port wine stains using Pulsed Dye Laser, Erbium YAG Laser, and topical rapamycin (sirolimus)—A randomized controlled trial

Pulsed Dye Laser (PDL) is currently the gold standard treatment for port wine stains (PWS), although the degree of lesion blanching is variable and often unpredictable. This appears to be due to reformation and reperfusion of blood vessels. Rapamycin has shown potential as an antiangiogenic agent and may prevent the revascularization after PDL treatment. The objective of this study was to evaluate the efficacy of adjuvant use of (commercially available) topical rapamycin after PDL treatment in patients with PWS.

Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study

Background: Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. Objective: To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. Methods: Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. Results: In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. Conclusion: Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability.

Allergic contact dermatitis caused by topical sirolimus used as an adjuvant for laser treatment of port wine stains.

Sirolimus (rapamycin) is a specific inhibitor of mammalian target of rapamycin, and, because of its antiangiogenic properties, its use as an adjuvant for the laser treatment of port wine stains (PWSs) has recently been suggested (1). We report a case of allergic contact dermatitis caused by sirolimus (Rapamune® 0.1% oral solution) that was used as an adjuvant topical treatment during laser treatment of a PWS.

Complement Activation in Inflammatory Skin Diseases

The complement system is a fundamental part of the innate immune system, playing a crucial role in host defense against various pathogens, such as bacteria, viruses, and fungi. Activation of complement results in production of several molecules mediating chemotaxis, opsonization, and mast cell degranulation, which can contribute to the elimination of pathogenic organisms and inflammation. Furthermore, the complement system also has regulating properties in inflammatory and immune responses. Complement activity in diseases is rather complex and may involve both aberrant expression of complement and genetic deficiencies of complement components or regulators. The skin represents an active immune organ with complex interactions between cellular components and various mediators. Complement involvement has been associated with several skin diseases, such as psoriasis, lupus erythematosus, cutaneous vasculitis, urticaria, and bullous dermatoses. Several triggers including auto-antibodies and micro-organisms can activate complement, while on the other hand complement deficiencies can contribute to impaired immune complex clearance, leading to disease. This review provides an overview of the role of complement in inflammatory skin diseases and discusses complement factors as potential new targets for therapeutic intervention.