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• W3048783314 abstract "To the Editor: I read with interest the article by Bettuzzi et al1Bettuzzi T. Frumholtz L. Jachiet M. et al.Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.J Am Acad Dermatol. 2020; 83: 1441-1444Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar on the use of sirolimus as a rescue therapy in combination with tumor necrosis factor alpha inhibitors (infliximab, adalimumab, certolizumab) in 9 patients with severe, refractory hidradenitis suppurativa (HS), based on the evidence for the upregulated mammalian target of rapamycin complex 1 (mTORC1) pathway in HS.1Bettuzzi T. Frumholtz L. Jachiet M. et al.Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.J Am Acad Dermatol. 2020; 83: 1441-1444Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar I have a few comments in relation to this study. In their study, Bettuzzi et al1Bettuzzi T. Frumholtz L. Jachiet M. et al.Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.J Am Acad Dermatol. 2020; 83: 1441-1444Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar did not report any adverse effect due to sirolimus except erysipelas in 1 patient.1Bettuzzi T. Frumholtz L. Jachiet M. et al.Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.J Am Acad Dermatol. 2020; 83: 1441-1444Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Sirolimus is known to cause serious adverse effects, like bone marrow suppression leading to thrombocytopenia and leukopenia, infections, and metabolic derangements like hyperlipidemia and hyperglycemia. Hyperlipidemia and hyperglycemia are important concerns in patients with HS because they are usually obese and have concomitant metabolic syndrome, and treatment with sirolimus will further compound this risk. The metabolic adverse effects of sirolimus are intriguing because overactivated mTORC1 is also considered responsible for insulin resistance and type 2 diabetes mellitus. To add to these, among cutaneous adverse effects, paradoxical occurrence of HS has been documented in 12% (10/80) of renal transplant recipients on sirolimus-based therapy for a mean duration of 18 months.2Mahe E. Morelon E. Lechaton S. et al.Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy.Transplantation. 2005; 79: 476-482Crossref PubMed Scopus (175) Google Scholar Second, Bettuzzi et al1Bettuzzi T. Frumholtz L. Jachiet M. et al.Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.J Am Acad Dermatol. 2020; 83: 1441-1444Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar used the HS–Physician's Global Assessment (HS-PGA) score to evaluate treatment response and even acknowledged it as one of the limitations of their study.1Bettuzzi T. Frumholtz L. Jachiet M. et al.Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa.J Am Acad Dermatol. 2020; 83: 1441-1444Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar I highlight here that the Hidradenitis Suppurativa Clinical Response (HiSCR) is a novel objective tool that is more responsive to change as a treatment outcome measure and may therefore be used in place of the HS–Physician's Global Assessment in clinical practice and research studies.3Kimball A.B. Sobell J.M. Zouboulis C.C. et al.HiSCR (Hidradenitis Suppurativa Clinical Response): a novel clinical endpoint to evaluate therapeutic outcomes in patients with hidradenitis suppurativa from the placebo-controlled portion of a phase 2 adalimumab study.J Eur Acad Dermatol Venereol. 2016; 30: 989-994Crossref PubMed Scopus (81) Google Scholar Finally, enhanced expression of T helper type (Th) 17 cells and interleukin (IL) 17 in lesional skin and increased serum levels of IL-17 have been reported in patients with HS, and this may explain the reported effectiveness of secukinumab as a targeted treatment option in cases of HS refractory to tumor necrosis factor alpha inhibitors. Interestingly, current evidence points to a link between the mTORC1 and Th17 pathways, which may suggest that sirolimus acts upstream in the pathway, attenuating IL-17 signaling.4Melnik B.C. John S.M. Chen W. et al.T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities.Br J Dermatol. 2018; 179: 260-272PubMed Google Scholar Enhanced mTORC1 activation in HS leads to increased expression of hypoxia inducible factor, which promotes transcriptional activation of RORγt signaling and, thus, differentiation of Th17 cells and expression of IL-17.4Melnik B.C. John S.M. Chen W. et al.T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities.Br J Dermatol. 2018; 179: 260-272PubMed Google Scholar Furthermore, increased toll-like receptor (TLR) expression on macrophages in the lesional skin of HS stimulates IL-23 production, which is of pivotal importance for differentiation of naive T cells into Th17 cells.4Melnik B.C. John S.M. Chen W. et al.T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities.Br J Dermatol. 2018; 179: 260-272PubMed Google Scholar There is increasing evidence to suggest that Notch signaling negatively regulates the TLR-activated innate immune response. However, in HS, the key pathomechanism is impaired Notch signaling that results in inadequate feedback suppression, leading to Th17-driven autoinflammation.4Melnik B.C. John S.M. Chen W. et al.T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities.Br J Dermatol. 2018; 179: 260-272PubMed Google Scholar Sirolimus has been shown to inhibit the TLR-4 pathway and IL-17 expression in early diabetic nephropathy in rats.5Yu R. Bo H. Villani V. et al.The inhibitory effect of rapamycin on toll like receptor 4 and interleukin 17 in the early stage of rat diabetic nephropathy.Kidney Blood Press Res. 2016; 41: 55-69Crossref PubMed Scopus (27) Google Scholar This cross-regulation of immune pathways underscores that the efficacy and adverse effects of sirolimus in HS need to be evaluated in blinded randomized controlled trials in a large cohort of patients. Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativaJournal of the American Academy of DermatologyVol. 83Issue 5PreviewTo the Editor: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily involving the pilosebaceous unit. Although the recent approval of adalimumab and the off-label use of infliximab widened the treatment armamentarium in moderate to severe HS, a significant proportion of severe HS cases still remain refractory to monotherapy with tumor necrosis factor (TNF) inhibitors.1,2 Evidence for upregulated mTORC1 pathway in HS lesions has raised the interest of mammalian target of rapamycin (mTOR) inhibitors in this disease. Full-Text PDF Reply to: Comment on “Sirolimus as combination rescue therapy with tumor necrosis alpha inhibitors for severe, refractory hidradenitis suppurativa”Journal of the American Academy of DermatologyVol. 84Issue 6PreviewTo the Editor: We read with interest the correspondence by Khullar1 about our article reporting the major efficacy of sirolimus in combination with tumor necrosis factor (TNF) inhibitors in a real-life series of patients with severe refractory hidradenitis suppurativa (HS).2 Full-Text PDF" @default.
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