Dermatología en Costa Rica: NECROBIOSIS LIPOIDICA IN A WINK

By Warren R. Heymann, MD, FAAD
May 3, 2023
Vol. 5, No. 18

Ninety years have transpired since Urbach coined the term necrobiosis lipoidica diabeticorum (NLD) for the granulomatous disorder first described by Oppenheim in 1929 as dermatitis atrophicans lipoidica diabetica. (1) Early authors observed sclerotic plaques with erythematous, violaceous borders, yellowish centers, and telangiectasias, predominantly on the lower extremities. Although subsequent case reports of NLD were published, in 1960, Rollins and Winkelmann recognized that many patients with NLD are not diabetic; the authors defined the clinical and histological differences between the two groups. (2) Their observation spearheaded the change to refer to the disorder as necrobiosis lipoidica (NL) instead of NLD. This commentary focuses on newer literature about NL.

NL is observed mostly in female patients, representing up to 75% of all cases. The disorder is characteristically observed in middle age, with an earlier average age of onset in diabetic patients (25 years) compared to nondiabetic individuals (46 years). (3,4) There have been multiple reports in the pediatric literature, an example being a 13-year-old girl with type I diabetes presenting with a morphologically characteristic lesion in an uncommon location (her left arm). (4) Lesions classically involve the pretibial region, usually commencing as small, firm red-brown papules that enlarge, becoming centrally atrophic. Lesions may Koebnerize. Uncommonly, lesions may affect other sites such as the arms, face, and scalp. (1) In a literature review encompassing 81 NL patients, the incidence of ulceration was found to occur between 15-35% of cases. Diabetes was observed in 65.4% and hypertension in 11%. (5) In a cross-sectional analysis of 236 patients with NL, associations with diabetes, obesity, hypertension, hyperlipidemia, and thyroid disease were confirmed. (6) Other reported associations include inflammatory bowel disease (Crohn and ulcerative colitis), rheumatoid arthritis, and sarcoidosis. (1)

The complications of NL are secondary infection, scarring, and the development of cutaneous malignancies. In their retrospective review of 328 cases of NL at the Mayo Clinic, Harvey et al identified 6 cutaneous cancers within NL lesions: 6 were squamous cell carcinoma (SCC), 1 basal cell carcinoma, and 1 melanoma. All malignancies were in ulcerated NL; the authors surmise that the ulceration itself may be predispose lesions toward malignancy, akin to patients with ulcerative lichen planus and lichen sclerosus. (7) In this context, it must be recognized that distinguishing pseudocarcinomatous hyperplasia from true SCC is challenging and requires careful clinicopathologic correlation. (8)

Tian and Coulson eloquently summarize the management of NL: "Smoking cessation and avoiding trauma to the affected shins are key factors to avoid transformation from an unsightly plaque into a painful, recalcitrant ulcer. The progression of new lesions may be halted by intralesional or occluded potent topical corticosteroids applied to the margins of the lesions. Topical tacrolimus can also be effective. Once atrophy has developed, there is little that will reverse this, although topical retinoids may be tried. Telangiectasia is often marked and has been treated with pulsed dye laser. Extensive lesions may justify trials of nicotinamide or prednisolone.Antiplatelet therapy in the form of aspirin or dipyridamole has its enthusiasts, though responses are inconclusive. Phototherapies such as topical psoralen and ultraviolet (UV) A (PUVA) and UVA-1, as well as photodynamic therapy,have received recent interest and may arrest progression and improve the appearance. A variety of systemic antiinflammatory and immunosuppressive agents have been tried with some success, including mycophenolate mofetil, fumaric acid esters, ciclosporin, antimalarials, thalidomide, and pentoxifylline. Biologics, especially anti-TNFs (adalimumab, infliximab, and etanercept), and more recently ustekinumab, have also been proposed. Platelet-rich plasma has some evidence of efficacy. The chronically ulcerated lesion is a challenge; antibiotics deal with secondary infection, appropriate dressings may be required, and growth factors such as becaplermin and granulocyte–macrophage colony-stimulating factor (GM-CSF) may accelerate healing. Because diabetics may have coexisting large vessel atherosclerosis that may contribute to ulceration, non-invasive arterial studies or angiography needs to be considered if clinically indicated. Excision and grafting including punch grafting may transform the patient's quality of life and improve cosmesis. Work with the diabetologist to optimize diabetic control." (9) Given the accumulating evidence for benefit of JAK inhibitors in granulomatous disorders, the initial report of tofacitinib efficacy in a recalcitrant case of ulcerated NL (10) is a likely prelude to many future reports of other JAK inhibitors for treating NL.

The etiology of NL remains an enigma. The association of NL with diabetes points toward microangiopathy. Glucose transporter 1 is expressed in fibroblasts of sclerotic collagen; abnormal collagen fibrils with increased cross-linking could be etiologic. The pathogenic contributions of impaired neutrophilic migration, tumor necrosis factor-alpha, and deposition of other immunoreactants require further definition. (1,3)

The classical histological appearance of NL demonstrates a "layer cake" of horizontal granulomatous dermatitis with dermal fibrosis admixed with necrobiosis and lymphoplasmacytic infiltration. In their study, Rollins and Winkelmann demonstrated that NL in diabetic versus nondiabetics is different — with the classical appearance in the former and epithelioid granulomatous appearance resembling sarcoidosis in the latter. (2) This observation has been confirmed (again from the Mayo Clinic) by Johnson et al, in a retrospective histological review of 97 NL patients, finding a statistically significant difference with naked (sarcoidal/tuberculoid) granulomas being more frequently observed in nondiabetic NL patients (22.7%) compared to diabetic NL patients (3.2%). (11)

This commentary was written on Father's Day 2022. I never met Richard K. Winkelmann, MD, PhD, but anyone practicing dermatology and dermatopathology has been influenced by this founding father of the American Society of Dermatopathology. I encourage you to read the enlightening tribute to him by Perniciaro in which he notes that Dr. Winkelmann insisted that colleagues, friends, and family address him as "Wink." (12) I dedicate this commentary to Wink, who has indirectly taught me so much throughout my career.

Point to Remember: Necrobiosis lipoidica is usually associated with diabetes, but may also be accompanied by thyroid disease, hypertension, hyperlipidemia, and other disorders. JAK inhibitors are on the horizon in treating the granulomatous component of the disorder.

Our expert's viewpoint

Aaron R. Mangold, MD, FAAD
Associate Professor of Dermatology, Mayo Clinic
Scottsdale, Arizona

Necrobiosis lipoidica (NL) is a chronic granulomatous disease often associated with ulceration, pain, and scarring. Although up to half of cases are associated with poorly controlled diabetes, average HbA1c of 8.6%, the underlying metabolic and inflammatory drivers remain unclear. Newer gene expression data in both NL as well as other granulomatous diseases found a key role of immune pathways and pathogenic, interferon gamma secreting T-cells as well as metabolically active macrophages. Our team's recent phase 2 trial using topical ruxolitinib in NL has confirmed the key role of interferon signaling as well as the therapeutic potential with an overall response rate of 82%.

There are limited clinical practice guidelines for the management of NL and it is challenging to draw conclusions on evidence-based treatment recommendations. In those with diabetes, improved glucose control may reduce the risk of developing comorbidities and improve lesions of NL. Additional management of chronic wounds as well as venous insufficiency may be beneficial. For indurated, tender plaque of NL, topical, intralesional, and systemic anti-inflammatories can be effective. Although there are no comparative studies, biologics (95%), classic immunosuppressants (89%), and topical therapies (79%) seems to be the most effective treatments followed by light-based modalities including ultraviolet A (54%) and photodynamic therapies (80%).

Lepe K, Riley CA, Salazar FJ. Necrobiosis Lipoidica. 2021 Aug 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29083569
ROLLINS TG, WINKELMANN RK. Necrobiosis lipoidica granulomatosis. Necrobiosis lipoidica diabeticorum in the nondiabetic. Arch Dermatol. 1960 Oct;82:537-43. doi: 10.1001/archderm.1960.01580040055010. PMID: 13742950.
Berman HS, Shabihkhani M, Hogeling M. Pediatric necrobiosis lipoidica: case report and review of the literature. Dermatol Online J. 2021 Jul 15;27(7). doi: 10.5070/D327754363. PMID: 34391328.
Alhameedy MM. Necrobiosis Lipoidica: Atypical Presentation in a Diabetic Girl. Case Rep Dermatol. 2021 Nov 30;13(3):547-552. doi: 10.1159/000520588. PMID: 35082617; PMCID: PMC8739632.
Di Bartolomeo L, Macca L, Motolese A, Guarneri C, Guarneri F. Ulcerative necrobiosis lipoidica: case report of an atypical presentation and literature review. Eur Rev Med Pharmacol Sci. 2021 Oct;25(19):6047-6050. doi: 10.26355/eurrev_202110_26882. PMID: 34661264.
Hashemi DA, Brown-Joel ZO, Tkachenko E, Nelson CA, Noe MH, Imadojemu S, Vleugels RA, Mostaghimi A, Wanat KA, Rosenbach M. Clinical Features and Comorbidities of Patients With Necrobiosis Lipoidica With or Without Diabetes. JAMA Dermatol. 2019 Apr 1;155(4):455-459. doi: 10.1001/jamadermatol.2018.5635. PMID: 30785603; PMCID: PMC6523472.
Harvey JA, Severson KJ, Brumfiel CM, Patel MH, Butterfield RJ, Nelson SA, Sekulic A, Pittelkow MR, Mangold AR. Necrobiosis lipoidica-associated cutaneous malignancy. J Am Acad Dermatol. 2022 Jun;86(6):1428-1429. doi: 10.1016/j.jaad.2021.06.848. Epub 2021 Jun 18. PMID: 34153393.
Xie CB, Ring N, Damsky W, McNiff JM, Olino K, Odell I. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica treated with radical resection and split-thickness skin graft. JAAD Case Rep. 2021 Nov 17;19:90-93. doi: 10.1016/j.jdcr.2021.11.005. PMID: 35024397; PMCID: PMC8724883.
Tian TM, Coulson IH. Necrobiosis Lipoidica, in Lebwohl MG, Heymann WR, Coulson IM, Murrell DF, Treatment of Skin Disease, Sixth Edition, Elsevier, 2022. Accessed online June 19th, 2022.
Janßen S, Jansen TM. Ulcerated necrobiosis lipoidica successfully treated with tofacitinib. Int J Dermatol. 2022 Jun;61(6):739-741. doi: 10.1111/ijd.15960. Epub 2021 Nov 16. PMID: 34783006.
Johnson E, Patel MH, Brumfiel CM, Severson KJ, Bhullar P, Boudreaux B, Butterfield RJ, DiCaudo DJ, Nelson SA, Pittelkow MR, Mangold AR. Histopathologic features of necrobiosis lipoidica. J Cutan Pathol. 2022 Apr 11. doi: 10.1111/cup.14238. Epub ahead of print. PMID: 35403265.
Perniciaro C. Richard K. "Wink" Winkelmann, MD, PhD (July 12, 1925 to August 16, 2012). Am J Dermatopathol 2013; 35: 281-282.

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