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- Lavazais, S, et al.
(författare)
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IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases
- 2023
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 15:683, s. eabj3289-
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23–, IL-33–, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.
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| 4. |
- Pagnamenta, A. T., et al.
(författare)
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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 584-600
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.
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| 12. |
- Garzorz-Stark, N, et al.
(författare)
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IMPROVE 1.0: Individual Monitoring of Psoriasis Activity by Regular Online App Questionnaires and Outpatient Visits
- 2021
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Ingår i: Frontiers in medicine. - : Frontiers Media SA. - 2296-858X. ; 8, s. 648233-
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Tidskriftsartikel (refereegranskat)abstract
- Smartphone apps gain more and more importance in supporting management of chronic diseases. Psoriasis is a highly prevalent, lifelong chronic inflammatory skin disease with a high impact on patient's quality of life. Disease management includes regular topical and systemic treatment of skin lesions as well as co-treatment of metabolic and psychologic disorders. In this study, we investigated the potential of a new smartphone app (IMPROVE 1.0) for individual monitoring of disease activity and disease influencing factors. Twelve out of 50 psoriasis patients asked for study participation performed self-assessment of psoriasis severity, life quality, and stress scores using the app over a period of 1 year. Every 2 months, study participants were carefully examined by a dermatologist in order to control the quality of app-reported data. We found that psoriasis severity and life quality values as entered in the app closely correlate to physician's examination. Furthermore, we detected strong correlations of disease activity with life quality and psoriasis serum biomarker. Temporal relations between psoriasis aggravation and previous changes of lifestyle factors, such as increased stress levels, were observed in individual patients, indicating a high potential for preventive interventions in future psoriasis apps. The vast majority of study participants evaluated IMPROVE 1.0 app positively and wish to include the app into their daily life. Hence, we demonstrate that smartphone apps are a useful tool to raise self-awareness for the dimensions of complex diseases and fully integrate psoriasis patients into individual disease management. These data are important to develop more advanced digital tools supporting the management of chronic diseases in the future.
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| 13. |
- Hindelang, B, et al.
(författare)
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Enabling precision monitoring of psoriasis treatment by optoacoustic mesoscopy
- 2022
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 14:644, s. eabm8059-
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a widespread inflammatory skin disease affecting about 2% of the general population. Recently, treatments that specifically target key proinflammatory cytokines driving the disease have been developed to complement conventional therapies with unspecific antiproliferative or anti-inflammatory effects. Efficient monitoring of treatment efficacy in the context of precision medicine and the assessment of new therapeutics require accurate noninvasive readouts of disease progression. However, characterization of psoriasis treatment remains subjective based on visual and palpatory clinical assessment of features observed on the skin surface. We hypothesized that optoacoustic (photoacoustic) mesoscopy could offer label-free assessment of inflammation biomarkers, extracted from three-dimensional (3D) high-resolution images of the human skin, not attainable by other noninvasive methods. We developed a second-generation ultra-broadband optoacoustic mesoscopy system, featuring sub–10-μm resolution and advanced motion correction technology, and performed 80 longitudinal measurements of 20 psoriatic skin plaques in humans under conventional inpatient treatment or receiving biologics with concomitant topical corticosteroid treatment. Optoacoustic image analysis revealed inflammatory and morphological skin features that indicated treatment efficacy with sensitivity, accuracy, and precision that was not possible using clinical metrics. We identify 3D imaging biomarkers that reveal responses to treatment and offer the potential to facilitate disease and treatment characterization. Our findings suggest that optoacoustic mesoscopy may offer a method of choice for yielding both qualitative and quantitative evaluations of skin treatments that are inaccessible by other methods, potentially enabling optimized therapies and precision medicine in dermatology.
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| 15. |
- Lauffer, F, et al.
(författare)
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Cytokines of the IL-17 family in psoriasis
- 2020
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Ingår i: Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. - : Wiley. - 1610-0387. ; 18:7, s. 675-681
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Tidskriftsartikel (refereegranskat)
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| 20. |
- Rauch, L, et al.
(författare)
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Bisphosphonates for the Treatment of Calcinosis Cutis-A Retrospective Single-Center Study
- 2021
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- (1) Background: Calcinosis cutis is a frequent symptom of autoimmune connective tissue diseases leading to pain, transcutaneous expulsion of calcified material and bacterial superinfection. There is a high need for new therapeutic options as no standardized treatment algorithm is established. While case reports indicate beneficial effects of bisphosphonates, standardized evaluation of treatment effects is missing. (2) Methods: In this retrospective analysis we evaluate the effects of intravenous pamidronate, a second-generation bisphosphonate, in seven patients with calcinosis cutis using consecutive clinical pictures, radiological examinations and patient’s subjective evaluation. (3) Results: 5/6 patients reported a reduction of pain, improvement of general condition and cessation of calcinosis progression. Regression of skin lesions was detectable in clinical pictures of 2/6 patients, while 1/6 patients had stable disease. Radiological examination revealed improvement or stable disease in 3/5 patients. Fever was the most common side effect. One out of seven patients developed osteonecrosis of the jaw. (4) Conclusions: Bisphosphonates appear to have beneficial effects in a subgroup of calcinosis cutis patients. While patient’s subjective evaluation was mainly positive, objective assessments showed improvement in approximately half of the cases. With regard to potential severe side effects, a careful risk-benefit evaluation is necessary before treatment initiation.
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| 22. |
- Seiringer, P, et al.
(författare)
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Tofacitinib in Hypertrophic Lichen Planus
- 2020
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Ingår i: Acta dermato-venereologica. - : Medical Journals Sweden AB. - 1651-2057. ; 100:14, s. adv00220-
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Tidskriftsartikel (refereegranskat)
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