Tissue-specific personalized medicine: the next level of individualized treatment

Funding

R.J. Ludwig [email protected] Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin University of Lübeck Germany Deutsche Forschungsgemeinschaft: Research Training Group ‘Modulation of Autoimmunity’ GRK 1727 Clinical Research Unit ‘Pemphigoid Diseases’ KFO 303 Excellence Cluster ‘Precision Medicine in Chronic Inflammation’ EXC 2167 Funding sources: this work was supported by research grants from the Deutsche Forschungsgemeinschaft: Research Training Group ‘Modulation of Autoimmunity’ (GRK 1727), Clinical Research Unit ‘Pemphigoid Diseases’ (KFO 303) and the Excellence Cluster ‘Precision Medicine in Chronic Inflammation’ (EXC 2167). Conflicts of interest: R.J.L. has no current or past affiliations or other involvement in any organization or entity with a conflict of interest related to this commentary. However, in the past 3 years, the author has received research funding from Almirall, True North Therapeutics, UCB Pharma, ArgenX, TxCell, Topadur, Synthon, Incyte and Admirx and fees for consulting or speaking from ArgenX, Immunogenetics, Novartis and Lilly. Linked Article: Egu et al . Br J Dermatol 2020. DOI: 10.1111/bjd.18237 One good example is the selection of targeted treatments for patients with cancer, whereby treatments are prescribed based on the presence of certain molecular markers, such as BRAF inhibition in patients with metastatic melanoma carrying the V600E Despite the recent breakthrough advances in medicine, the diagnosis of chronic inflammatory disease is still based on patient history, disease symptoms and macroscopic inspection of the inflammatory reaction of the affected organs, which may be accompanied by laboratory findings. Furthermore, clinical disease scores describe the magnitude of functional abnormalities but they only indirectly mirror the local inflammation status. Hence, currently one major driver of innovation in medicine is use of multidimensional data for diagnostic as well as therapeutic decision making, termed personalized medicine. BRAF mutation. While in oncology personalized medicine approaches are becoming relatively well established, personalized treatment decisions have just begun to emerge in chronic inflammatory diseases. One such example is the article by Egu and colleagues in this issue of the Herein the authors first established a new model of mucosal pemphigus vulgaris (PV) and then contrasted the molecular pathways leading to blistering in this disease in skin and mucosa. PV is a prototypical, organ‐specific autoimmune disease of the skin, whereby autoantibodies against desmoglein (Dsg)3 (mucosal PV) or Dsg1 and Dsg3 (mucocutaneous PV) as well as those targeting desmocollin 3 cause intraepidermal blistering in the skin and/or the mucosa. BJD . (iv) pemphigus autoantibodies alter signalling pathways in keratinocytes, including the regulation of cell cohesion and turnover of desmosome components; i.e. p38 mitogen‐activated protein kinase (MAPK), protein kinase C, Src and epidermal growth factor receptor/extracellular signal‐related kinase. In PV, autoantibody‐induced blistering is induced by several mechanisms: (i) Dsg interactions may be reduced by the autoantibodies (steric hindrance); (ii) the autoantibodies (directly or indirectly) induce apoptotic pathways; the treatment of pemphigus remains challenging and overall quality of life is poor in patients affected by it. Hence, novel pemphigus therapeutics are urgently needed. Yet, current drug development programmes almost exclusively focus on inhibiting the half‐life of the IgG autoantibodies and on B/plasma cells. Targeting aberrant signalling pathways in the skin, could, in my opinion, be a very effective alternative therapeutic target because topical application of small molecule inhibitors is possible. Blockade of pemphigus autoantibody‐induced aberrant signalling in pemphigoid could lead to a rapid improvement of skin blistering, providing relief until B‐cell‐targeting treatments become effective. Despite recent advances, investigated the role of p38 MAPK in mucosal pemphigus. For this purpose, they established a human However, despite the fact that both the skin and mucosa are affected by pemphigus, most research in pemphigus is carried out using keratinocytes – hence, these insights are limited to the skin lesions of pemphigus. In this issue, Egu and colleagues, following their work on p38 MAPK in the skin, ex vivo mucosal cell culture system to evaluate the p38 MAPK dependency of mucosal blister formation. More specifically, human labial mucosa was injected with IgG from patients with mucosal‐dominant pemphigus in the presence or absence of p38 MAPK inhibitors. In line with previous observations using human skin, the injection of PV‐IgG induced intraepidermal blistering in the labial mucosa. However, and in contrast to ex vivo cultured human skin, blockade of p38 MAPK had no impact on PV‐IgG induced blistering in mucosal tissue. This study has two important implications. Firstly, relating to personalized medicine, the study highlights a tissue‐specific dependency of pathways in PV‐IgG‐induced blistering. These insights will be crucial for the development of small molecule inhibitors for the treatment of pemphigus. Secondly, the described human ex vivo mucosal cell culture system is an important addition to model systems duplicating pemphigus pathology.