2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:Ta5f,Necrobiosis lipoidica (NL) is a rare, chronic granulomatous skin disease for which no US Food and Drug Administration (FDA)-approved treatments exist. PCS499, an oral deuterated pentoxifylline analog, may offer therapeutic benefit. To evaluate the safety and exploratory efficacy of PCS499 in adults with biopsy-confirmed NL. A phase 2, open-label nonrandomized clinical trial (from January 2019-February 2020) with a 6-month treatment period with an optional 6-month extension was conducted at the University of Pennsylvania and University of Pittsburgh dermatology research centers. Adults aged 18 to 80 years with biopsy-confirmed NL were eligible. Inclusion required a reference lesion of 10 cm2 or larger and Investigator Global Assessment (IGA) of NL activity score of 2 or greater (scale 0-5). Key exclusions were recent corticosteroid, immunosuppressant, biologic, phototherapy, or pentoxifylline-class use; significant comorbidities; and pregnancy or lactation. Data were analyzed in May 2025. PCS499, 900 mg, orally twice daily for 6 months, with optional 6-month extension. Safety was assessed through adverse event (AE) monitoring, laboratory testing, and electrocardiograms. Exploratory efficacy end points included changes from baseline in IGA, Physician Global Assessments and Patient Global Assessments (PGA, PtGA), NL Color and Ulcer Scale (NLCUS), Dermatology Life Quality Index (DLQI), and Skindex-29 scores. Twelve participants were enrolled (median [range] age, 41 [19-66] years; all female individuals; 10 [83%] with diabetes; mean [SD] disease duration, 12.7 [9.3] years), and 10 completed treatment. The most common AE was mild gastrointestinal symptoms (33%). No serious AEs or clinically significant laboratory abnormalities occurred. Participants with ulcerated NL (n = 2 [17%]) achieved complete ulcer closure by day 85 and day 351 without recurrence. Six participants (50%) achieved clear or almost clear IGA status (median [range] time, 111 [54-166] days). Significant improvements were observed in IGA activity (median [IQR] change, -1.5 [-2.0 to 0.0]; P = .03), PGA (median [IQR] change, -1.3 [-2.8 to -0.9]; P = .04), NLCUS inflammation/color (median [IQR] change, -1.0 [-1.8 to 0.0]; P = .02), and induration (median [IQR] change, -1.0 [-2.0 to 0.0]; P = .04), and Skindex-29 function scores (median [IQR] change, -14.6 [-27.1 to 3.1]; P = .05). This nonrandomized clinical trial found that PCS499 was safe and well tolerated, with evidence of clinical and quality-of-life improvement, particularly in ulcerated NL; however, larger trials are warranted. ClinicalTrials.gov Identifier: NCT03698864.31:T123c, Importance Necrobiosis lipoidica (NL) is a rare, chronic granulomatous skin disease for which no US Food and Drug Administration (FDA)–approved treatments exist. PCS499, an oral deuterated pentoxifylline analog, may offer therapeutic benefit. Objective To evaluate the safety and exploratory efficacy of PCS499 in adults with biopsy-confirmed NL. Design, Setting, and Participants A phase 2, open-label nonrandomized clinical trial (from January 2019-February 2020) with a 6-month treatment period with an optional 6-month extension was conducted at the University of Pennsylvania and University of Pittsburgh dermatology research centers. Adults aged 18 to 80 years with biopsy-confirmed NL were eligible. Inclusion required a reference lesion of 10 cm 2 or larger and Investigator Global Assessment (IGA) of NL activity score of 2 or greater (scale 0-5). Key exclusions were recent corticosteroid, immunosuppressant, biologic, phototherapy, or pentoxifylline-class use; significant comorbidities; and pregnancy or lactation. Data were analyzed in May 2025. Intervention PCS499, 900 mg, orally twice daily for 6 months, with optional 6-month extension. Main Outcomes and Measures Safety was assessed through adverse event (AE) monitoring, laboratory testing, and electrocardiograms. Exploratory efficacy end points included changes from baseline in IGA, Physician Global Assessments and Patient Global Assessments (PGA, PtGA), NL Color and Ulcer Scale (NLCUS), Dermatology Life Quality Index (DLQI), and Skindex-29 scores. Results Twelve participants were enrolled (median [range] age, 41 [19-66] years; all female individuals; 10 [83%] with diabetes; mean [SD] disease duration, 12.7 [9.3] years), and 10 completed treatment. The most common AE was mild gastrointestinal symptoms (33%). No serious AEs or clinically significant laboratory abnormalities occurred. Participants with ulcerated NL (n = 2 [17%]) achieved complete ulcer closure by day 85 and day 351 without recurrence. Six participants (50%) achieved clear or almost clear IGA status (median [range] time, 111 [54-166] days). Significant improvements were observed in IGA activity (median [IQR] change, −1.5 [−2.0 to 0.0]; P = .03), PGA (median [IQR] change, −1.3 [−2.8 to −0.9]; P = .04), NLCUS inflammation/color (median [IQR] change, −1.0 [−1.8 to 0.0]; P = .02), and induration (median [IQR] change, −1.0 [−2.0 to 0.0]; P = .04), and Skindex-29 function scores (median [IQR] change, −14.6 [−27.1 to 3.1]; P = .05). Conclusions and Relevance This nonrandomized clinical trial found that PCS499 was safe and well tolerated, with evidence of clinical and quality-of-life improvement, particularly in ulcerated NL; however, larger trials are warranted. Trial Registration ClinicalTrials.gov Identifier: NCT03698864 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Phase 2 Open-Label Nonrandomized Clinical Trial: study design Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Phase 2 Open-Label Nonrandomized Clinical Trial (study design). Clinician-written summaries and actionable practice insights. 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The most common AE was mild gastrointestinal symptoms (33%). No serious AEs or clinically significant laboratory abnormalities occurred. Participants with ulcerated NL (n = 2 [17%]) achieved complete ulcer closure by day 85 and day 351 without recurrence. Six participants (50%) achieved clear or almost clear IGA status (median [range] time, 111 [54-166] days). Significant improvements were observed in IGA activity (median [IQR] change, -1.5 [-2.0 to 0.0]; P = .03), PGA (median [IQR] change, -1.3 [-2.8 to -0.9]; P = .04), NLCUS inflammation/color (median [IQR] change, -1.0 [-1.8 to 0.0]; P = .02), and induration (median [IQR] change, -1.0 [-2.0 to 0.0]; P = .04), and Skindex-29 function scores (median [IQR] change, -14.6 [-27.1 to 3.1]; P = .05).","abstract":"$30","keywords":[],"pubmed_id":"42054009","conclusions":"","publication_date":"2026-04-29T00:00:00"},"crossref":{"DOI":"10.1001/jamadermatol.2026.0863","URL":"https://doi.org/10.1001/jamadermatol.2026.0863","ISSN":["2168-6068"],"link":[{"URL":"https://jamanetwork.com/journals/jamadermatology/articlepdf/2848176/jamadermatology_rubenstein_2026_br_260004_1777042050.63363.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Deuterated Pentoxifylline Analog in the 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Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania"},{"name":"Now with Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill"}]},{"given":"Misha","family":"Rosenbach","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia"}]}],"issued":{"date-parts":[[2026,4,29]]},"member":"10","prefix":"10.1001","source":"Crossref","volume":null,"created":{"date-time":"2026-04-29T15:30:24Z","timestamp":1777476624000,"date-parts":[[2026,4,29]]},"indexed":{"date-time":"2026-05-02T23:51:51Z","timestamp":1777765911467,"date-parts":[[2026,5,2]]},"subject":[],"abstract":"$31","language":"en","relation":{},"resource":{"primary":{"URL":"https://jamanetwork.com/journals/jamadermatology/fullarticle/2848176"}},"subtitle":["A Nonrandomized Clinical 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Dermatol","doi-asserted-by":"publisher"},{"DOI":"10.1007/BF03348204","key":"dbr260004r7","year":"2003","issue":"10","author":"Basaria","volume":"26","first-page":"1037","unstructured":null,"article-title":"Necrobiosis lipoidica diabeticorum: response to pentoxiphylline.","journal-title":"J Endocrinol Invest","doi-asserted-by":"publisher"},{"DOI":"10.1016/j.ejphar.2006.02.017","key":"dbr260004r8","year":"2006","issue":"1-3","author":"Fantin","volume":"535","first-page":"301","unstructured":null,"article-title":"Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties.","journal-title":"Eur J Pharmacol","doi-asserted-by":"publisher"},{"DOI":"10.1177/1060028018797110","key":"dbr260004r10","year":"2019","issue":"2","author":"Russak","volume":"53","first-page":"211","unstructured":null,"article-title":"Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals.","journal-title":"Ann 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quality of life in patients with dermatological conditions.","journal-title":"Br J Dermatol","doi-asserted-by":"publisher"},{"DOI":"10.1111/ddg.15137","key":"dbr260004r15","year":"2023","issue":"10","author":"Schiefer-Niederkorn","volume":"21","first-page":"1120","unstructured":null,"article-title":"Necrobiosis lipoidica in childhood: a review of literature with emphasis on therapy.","journal-title":"J Dtsch Dermatol Ges","doi-asserted-by":"publisher"},{"DOI":null,"key":"dbr260004r4","year":"2008","issue":null,"author":"Kalus","volume":null,"first-page":"1467","unstructured":null,"article-title":null,"journal-title":null,"doi-asserted-by":null},{"DOI":null,"key":"dbr260004r9","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"Pentoxifylline? FDA. U.S. National Library of Medicine. Accessed January 21, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd840a2c-2a0e-4b2b-84ff-a0406bb6fa37","article-title":null,"journal-title":null,"doi-asserted-by":null},{"DOI":null,"key":"dbr260004r11","year":null,"issue":null,"author":null,"volume":null,"first-page":null,"unstructured":"National Library of Medicine. A Phase 2 Study of PCS499 for the Treatment of Ulcerated and Nonulcerated Necrobiosis Lipoidica. Updated November 2, 2018. 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Both participants with ulcerated NL achieved complete ulcer closure (by day 85 and day 351) without recurrence. Significant improvements were seen in IGA activity (median change −1.5, P=.03), PGA (median change −1.3, P=.04), NLCUS inflammation/color (P=.02), induration (P=.04), and Skindex-29 function scores (P=.05). The most common adverse event was mild GI symptoms (33%); no serious adverse events occurred.","limitations":"Very small sample (n=12), all female, no control arm — results may not generalize to males or broader populations. Open-label design without randomization limits causal inference. Single-disease subgroup findings (ulcerated NL, n=2) are difficult to interpret at this scale.","practice_takeaway":"For patients with refractory NL — especially ulcerated cases — PCS499 showed a favorable safety profile and meaningful clinical response in this small pilot trial. 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