[Alopecia areata universalis under treatment with sitagliptin : Possible immunological effect of dipeptidyl peptidase-4 inhibitors?] / Alopecia areata universalis nach Sitagliptin-Einnahme : Mögliche immunologische Wirkung von Dipeptidylpeptidase-4-Inhibitoren?

A 64-year old man developed alopecia universalis after one month of treatment with metformin and sitagliptin, a dipeptidyl peptidase­4 (DPP-4) inhibitor. Diabetes treatment was changed to another genericum of sitagliptin and dapagliflozin. Following our recommendation, sitagliptin was interrupted and monotherapy with dapagliflozin was continued. After 6 weeks, sitagliptin was reassumed due to unsatisfactory diabetes control. Alopecia did not improve. We suspect a connection between DPP­4 inhibition and development of alopecia due to its immunological potential. We assume that the treatment interruption might have been too short to induce regrowth of hair. DPP­4 may result in both inhibition and activation of the immune system.

[Possible effect of interleukin-17 blockade in pemphigus foliaceus and neutrophilic diseases]. / Mögliche Wirkung einer Interleukin-17-Blockade beim Pemphigus foliaceus und neutrophilen Erkrankungen.

The role of interleukin-17 (IL-17) in pemphigoid diseases is not fully understood. Both pemphigus vulgaris (PV) as well as pemphigus foliaceus (PF) show intralesional IL-17 positive cells. A patient with initially assumed coexisting PF and psoriasis pustulosa (PP) was treated with the anti-IL-17 antibody secukinumab. The clinical skin picture markedly improved and the level of anti-desmoglein-1 antibodies clearly decreased; however, with the prolongation of injection intervals of secukinumab, autoantibody levels started to rise again. A dose-dependent effect of secukinumab on autoantibody production in PF is suspected. Retrospectively, a neutrophilic PF can be discussed in the present case, where almost complete healing was achieved under IL-17 blockade treatment.

Suzuki-Miyaura Cross-Coupling Reactions of Highly Fluorinated Arylboronic Esters: Catalytic Studies and Stoichiometric Model Reactions on the Transmetallation Step.

Fluorinated 4-aryl phenylalanine amino acid derivatives (aryl=2-C5 NF4 , 4-C6 H4 SF5 , 2-C6 H4 SCF3 , C6 F5 ) were obtained in Suzuki-Miyaura cross-coupling reactions of phenylalanine precursors with highly fluorinated aryl boronic acid and esters in the presence of CsF. PdII complexes that possessed phenyl alanine derived ligands, such as trans-[PdBr{4-C6 H4 CH2 CH{NHC(O)CH3 }CO2 Et}(PiPr3 )2 ], were used as catalysts. Stoichiometric model reactions indicate the intermediate generation of the boronate Cs[BF(2-C5 NF4 )(pin)] (pin=pinacolato=O2 C2 Me4 ). The transmetallation step with Cs[BF(4-C6 H4 SF5 )(pin)], [NMe4 ][BF(2-C5 NF4 )(pin)] and/or the fluorido complex trans-[PdF{4-C6 H4 CH2 C{NHC(O)CH3 }(CO2 Et)2 }(PiPr3 )2 ] was investigated. A comparison of the reactions of trans-[PdX{4-C6 H4 CH2 C{NHC(O)CH3 }(CO2 Et)2 }(PiPr3 )2 ] (X=Br, F) with 2-Bpin-C5 NF4 or [NMe4 ][BF(2-C5 NF4 )(pin)] revealed the remarkable high reactivity of the fluorido complex towards 2-BpinC5 NF4 . Low-temperature NMR studies indicated the ionic species trans-[Pd{4-C6 H4 CH2 C{NHC(O)CH3 }(CO2 Et)2 }(PiPr3 )2 ][BF(2-C5 NF4 )(pin)] to be a highly reactive intermediate.

PREDICTORS OF QUALITY OF LIFE IN 165 PATIENTS WITH ACROMEGALY: RESULTS FROM A SINGLE-CENTER STUDY.

OBJECTIVE: Even if treated, acromegaly has a considerable impact on patient quality of life (QoL); despite this, the exact clinical determinants of QoL in acromegaly are unknown. This study retrospectively examines a cohort of treated patients with acromegaly, with the aim of identifying these determinants. METHODS: Retrospective survey analysis, with 165 patients included in the study. All patients completed a survey, which included demographic data and the clinical details of their disease, the Short Form-36 Health Survey (SF-36), the revised Beck Depression Inventory (BDI-II), and the Bern Embitterment Inventory (BEI). Stepwise regression was used to identify predictors of QoL. RESULTS: The strongest predictors of the physical component score of the SF-36 were (in order of declining strength of association): Delay between first presentation of the disease and diagnosis, body mass index (BMI), number of doctors visited before the diagnosis of acromegaly, and age at diagnosis. For the mental component score, the strongest predictors were: number of doctors visited, previous radiotherapy, and age at study entry; and, for the BDI-II score: number of doctors visited, previous radiotherapy, age at study entry, and employment status at the time of diagnosis. The following were predictors of the BEI score: number of doctors visited, and age at study entry. CONCLUSION: Diagnostic delay and lack of diagnostic acumen in medical care provision are strong predictors of poor QoL in patients with acromegaly. Other identified parameters are radiotherapy, age, BMI, and employment status. An efficient acromegaly service should address these aspects when devising disease management plans. ABBREVIATIONS: BDI-II = Beck Depression Inventory II BEI = Bern Embitterment Inventory BMI = body mass index IGF-1 = insulin-like growth factor 1 MCS = mental component summary (score) PCS = physical component summary (score) QoL = quality of life SDS = standard deviation score SF-36 = Short Form-36 Health Survey.

Diagnosis and management of acromegaly: the patient's perspective.

PURPOSE: Early diagnosis is a success factor for the prevention of long-term comorbidity and premature death in patients with acromegaly, but large-scale data on the diagnostic process and disease management are scarce. Therefore, we aimed to evaluate the diagnostic process, implementation of treatment and changes in life situation in patients with acromegaly, focusing on sex-specific differences. METHODS: Non-interventional patient-reported outcome study. 165 patients with clinically and biochemically proven acromegaly were questioned about the diagnostic process and utilization of health care by means of a self-developed standardized postal survey including questions on acromegaly symptoms experienced before diagnosis, number and specialty of consulted doctors, time to diagnosis and aftercare. RESULTS: The diagnostic process took 2.9 (SD 4.53) years, during which 3.4 (SD 2.99) physicians were consulted. Women waited longer [4.1 (SD 5.53) years] than men [1.6 (SD 2.69) years; p = 0.001] for the correct diagnosis, and consulted more doctors in the process [4.0 (SD 2.99) vs. 2.7 (SD 2.84) doctors, p < 0.001, respectively]. In 48.5 % of patients, acromegaly was diagnosed by an endocrinologist (men: 45.1 %; women: 52.4 %). Overall disease duration from symptom onset until last surgery was 5.5 (SD 6.85) years, with no sex differences. A change in employment status was the most commonly reported event after diagnosis and a quarter of the patients stated that the illness had changed their lives. CONCLUSIONS: Our findings confirm the urgent need to increase awareness of the clinical manifestation of acromegaly to facilitate an earlier diagnosis of the disease and to provide diagnostic equality across the sexes.

Modulation of Dietary Fatty Acids in an Open-Label Study Improves Psoriasis and Dampens the Inflammatory Activation Status.

Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients.

Biocatalytic Syntheses of Antiplatelet Metabolites of the Thienopyridines Clopidogrel and Prasugrel Using Fungal Peroxygenases.

Antithrombotic thienopyridines, such as clopidogrel and prasugrel, are prodrugs that undergo a metabolic two-step bioactivation for their pharmacological efficacy. In the first step, a thiolactone is formed, which is then converted by cytochrome P450-dependent oxidation via sulfenic acids to the active thiol metabolites. These metabolites are the active compounds that inhibit the platelet P2Y12 receptor and thereby prevent atherothrombotic events. Thus far, described biocatalytic and chemical synthesis approaches to obtain active thienopyridine metabolites are rather complex and suffer from low yields. In the present study, several unspecific peroxygenases (UPOs, EC 1.11.2.1) known to efficiently mimic P450 reactions in vitro-but requiring only hydroperoxide as oxidant-were tested for biocatalytic one-pot syntheses. In the course of the reaction optimization, various parameters such as pH and reductant, as well as organic solvent and amount were varied. The best results for the conversion of 1 mM thienopyridine were achieved using 2 U mL-1 of a UPO from agaric fungus Marasmius rotula (MroUPO) in a phosphate-buffered system (pH 7) containing 5 mM ascorbate, 2 mM h-1 H2O2 and 20% acetone. The preparation of the active metabolite of clopidogrel was successful via a two-step oxidation with an overall yield of 25%. In the case of prasugrel, a cascade of porcine liver esterase (PLE) and MroUPO was applied, resulting in a yield of 44%. The two metabolites were isolated with high purity, and their structures were confirmed by MS and MS2 spectrometry as well as NMR spectroscopy. The findings broaden the scope of UPO applications again and demonstrate that they can be effectively used for the selective synthesis of metabolites and late-state diversification of organic molecules, circumventing complex multistage chemical syntheses and providing sufficient material for structural elucidation, reference material, or cellular assays.

Reduced Serum Levels of Bone Formation Marker P1NP in Psoriasis.

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-α and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation-N-terminal propeptide of type I procollagen (P1NP) or bone resorption-C-terminal telopeptide of type I collagen (CTX-I)-were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring.

Immune-related pancreatitis associated with checkpoint blockade in melanoma.

Recognizing and treating rare checkpoint inhibitor related adverse events may be a clinical challenge in melanoma therapy. One of rather rare affected organs is the pancreas. Immune-related pancreatitis is difficult to recognize due to its variable clinical characteristics. Asymptomatic elevations of serum lipase and/or amylase during therapy with immune-checkpoint blockade impede the diagnostic process. We present a patient who developed an immune-related pancreatitis within the first 4 months of immunotherapy. Treatment with high dose systemic glucocorticosteroids with very slow tapering over a total period of 6.5 months was necessary to keep the patient symptom free as well as to maintain long-term normalization of serum lipase. Checkpoint blockade related pancreatitis may occur as acute or chronic disease and may lack any radiographic signs. As in our case, very slow tapering of initially high dose systemic glucocorticosteroids seems to be a crucial requirement for lasting recovery. Even after successful treatment, late-onset secondary pancreatic insufficiency may occur and patients have to be followed up at regular intervals. Restarting immunotherapy after resolution of immune-related pancreatitis is possible but needs careful risk-benefit consideration.

Oro-dental pathologies in acromegaly.

PURPOSE: Oro-dental pathologies (ODP) such as enlargement of the tongue, mandibular prognathism, and spaced teeth are characteristic features of acromegaly. Their frequency of occurrence during the course of the disease is largely unresolved. Purpose of this study was to assess ODP and oro-dental treatments in patients with acromegaly with regard to the length of the diagnostic process, tumor histology, and quality of life (QoL). METHODS: Single-center retrospective survey study using questionnaires on dental symptoms, diagnostic process, and treatment in patients with acromegaly operated on a growth hormone-secreting pituitary adenoma. The association between ODP and QoL was assessed using the Short-Form 36 (SF-36) Health Survey. RESULTS: 145/314 patients completed the questionnaires. 80.7% were affected by any ODP, most frequently enlargement of the tongue (57.9%), spaced teeth (42.8%), mandibular growth (24.1%), and mandibular prognathism (22.1%). ODP were significantly more frequent in patients with sparsely vs. densely granulated adenomas (p = 0.045). Early diagnosis within 2 years was associated with significantly fewer ODP than later diagnosis (68.5 vs. 87.2%, p = 0.009). Treatments included dental crowns (16.6%), dental bridges (12.4%), dental implants (9.7%), dental prostheses (3.4%), orthodontal (i.e., braces, 6.9%), and surgical correction of the teeth (2.1%). Physical QoL was significantly lower in patients with ODP than in those without (p = 0.014). CONCLUSION: In our large series of patients, four of five patients were affected by ODP at any time during the course of the disease. The results highlight the importance of early identification and treatment of oro-dental problems in patients with acromegaly as hallmarks of the disease.