Necrobiosis lipoidica arising in a port wine stain treated with topical ruxolitinib

Case description

A 44-year-old woman with no known history of diabetes or medical comorbidities presented to the dermatology clinic in November 2019 with a 2-year history of progressively worsening bilateral pretibial lesions. The lesions initially appeared as bruise-like discolorations that gradually enlarged and darkened. The patient denied recent medication use.

Upon examination, the patient exhibited well-demarcated, shiny, atrophic, waxy, reddish-brown plaques on the bilateral pretibial regions. Surrounding these plaques were asymptomatic, prominent red-purple, blanchable vascular-appearing patches, which have been present since birth (Figure 1). A punch biopsy was performed on one of the atrophic plaques. A histological examination revealed a thin flattened epidermis, a broad zone of necrobiosis in the mid-to-lower dermis, and chronic infiltrate including plasma cells, confirming the diagnosis of NL (Figure 2).

Figure 1:

The patient’s right leg (A) reveals erythematous, atrophic plaques with yellowish discoloration overlying a background of well-demarcated, violaceous, vascular-appearing patches. The left leg (B) has similar plaques. Arrows indicate areas of atrophic plaques with yellow discoloration located within the port-wine stain (PWS) lesion.

Figure 2:

Histopathology at (A) 40x, (B) 100x, (C) 200x, and (D) 400x, respectively, revealed a thin flattened epidermis, a broad zone of necrobiosis in the mid-to-lower dermis, and chronic infiltrate including plasma cells (yellow oval in Figure 2D indicates plasma cells).

After her condition failed to respond to clobetasol ointment, tacrolimus ointment, and pulsed dye laser, the patient was initiated on topical ruxolitinib, a JAK inhibitor, as monotherapy. At the 1-month follow-up, lesions were noted to be less indurated and raised, and after 3 years of treatment, the lesions appeared to be less acutely inflamed with noticeable scarring and hyperpigmentation (Figure 3). The lesions remained asymptomatic throughout treatment.

Figure 3:

(A, B) Lesions are less indurated and inflamed after 3 years of treatment with ruxolitinib. (B) There is noticeable post-inflammatory hyperpigmentation and scarring on the lower leg.

Discussion

We present a case of NL arising within a PWS. NL is a rare granulomatous disorder often associated with diabetes mellitus [1] NL classically presents on the bilateral shins as yellow-brown plaques, often accompanied by telangiectasias, central atrophy, and induration. Complications include painful ulcerations and more rarely malignant transformation [2], 3]. Although the etiology of this condition remains unknown, the leading theory suggests that microangiopathy, caused by glycoprotein deposition in the vasculature, leads to blood vessel thickening [1]. Hypoxia is also believed to play a role.[1]

Diagnosis can be made by clinical examination; however, a biopsy may be needed to distinguish NL from differential diagnoses, such as sarcoidosis, pretibial myxedema, and erythema nodosum. A histological examination typically reveals palisading necrobiotic granulomas arranged in a layered fashion admixed with collagen degeneration in the dermis and subcutaneous tissue [4]. Lymphocytic infiltrate and septal panniculitis is also seen. In individuals with diabetes, vascular changes are prominent, including thickened blood vessel walls and endothelial swelling, a finding shared with diabetic microangiopathy.⁴

NL treatment often requires a multimodal approach due to the lack of standardized guidelines and inconsistent results among treatments. The first-line management includes topical or intralesional corticosteroids. Other reported therapies include tumor necrosis factor (TNF) inhibitors, calcineurin inhibitors, biologics, photochemotherapy, pentoxifylline, interleukin (IL)-17 inhibitors, photodynamic therapy, or surgery.[5]

There have been promising results regarding the use of JAK inhibitors for granulomatous disorders, and more specifically, in the management of NL [3], [6], [7], [8], [9]. Various studies have found elevated JAK/signal transducer and activator of transcription proteins (STAT)-related cytokines in patients with NL, providing a possible mechanistic explanation for the use of JAK inhibitors for this condition [3], [5], [6], [7, 10]. Nugent et al. [11] reported a case of NL that improved with topical ruxolitinib and pentoxifylline. To our knowledge, this is the first case of concomitant NL and PWS treated with topical ruxolitinib monotherapy. Emerging trials aim to clarify the role of topical JAK inhibitors in NL, with a focus on ruxolitinib.

The present patient is unique in having NL within a coexisting PWS. Inflammation and endothelial dysfunction play a significant role in the pathogenesis of these conditions. PWS, a congenital vascular malformation, is defined by incomplete differentiation of endothelial cells resulting in the formation of defective capillaries [12]. The dysregulation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways is thought to play a significant role in the pathogenesis of these vascular lesions [13]. Vural et al. [12] reported the overexpression of vascular endothelial growth factor in PWS lesions compared to controls, suggesting that PWS lesions may progress by vascular hyperplasia and hypertrophy. NL is primarily driven by inflammation and microvascular damage. Slowik-Kwiatkowska et al [14] reported elevated TNF-alpha levels in patients with NL compared to controls, suggesting the impact that this inflammatory mechanism has on angiogenesis. Because the MAPK, PI3K, and TNF-alpha pathways are closely related inflammatory pathways, it raises questions about whether shared pathophysiological mechanisms in these conditions may have contributed to their simultaneous presence. However, it is important to note that the vast majority of NL cases occur in individuals without PWS, making a causal relationship unlikely in most patients. Further investigation is needed to determine whether such overlap reflects shared mechanisms or mere coincidence.

Conclusions

In conclusion, the diagnosis of NL within a PWS is unique and raises questions about whether the interplay of microvascular dysfunction, inflammation, and extracellular matrix involvement may explain their coexistence. Targeting JAK pathways presents a promising therapeutic avenue for inflammatory conditions. This case underscores the need for further research into the roles of cytokines, growth factors, and immune responses in vascular malformations and inflammatory dermatoses, which could lead to more tailored and effective treatments.