American Journal of Clinical Dermatology (2023) 24:275–286

https://doi.org/10.1007/s40257-022-00753-5

REVIEW ARTICLE

Stasis Dermatitis: An Overview of Its Clinical Presentation,

Pathogenesis, and Management
Gil Yosipovitch1 · Susan T. Nedorost2 · Jonathan I. Silverberg3 · Adam J. Friedman4 · Juliana M. Canosa5   · Amy Cha6

Accepted: 20 December 2022 / Published online: 17 February 2023

© The Author(s) 2023

Abstract
Stasis dermatitis is a chronic inflammatory skin disease of the lower extremities. It typically occurs in older individuals and
is the cutaneous manifestation of venous hypertension caused by venous reflux. Such retrograde venous blood flow is the
result of incompetent venous valves, valve destruction, or venous obstruction. Stasis dermatitis is eczematous. The associ-
ated impairment of venous valves may cause swelling of the legs, leading to serious conditions including venous ulcerations.
Diagnosis can be challenging because of its clinical resemblance to other skin conditions and poor clinical recognition by
physicians. The cornerstones of stasis dermatitis treatment are compression therapy to ameliorate pain and swelling, topi-
cal treatments to alleviate secondary skin changes, and interventional treatment options to correct the underlying causes of
venous reflux. Given the central role of inflammation of the lower extremities in driving the cutaneous changes characteristic
of stasis dermatitis, new therapeutic approaches that target the inflammation are under clinical evaluation in patients with
stasis dermatitis.

Plain Language Summary

Stasis dermatitis is a skin disease that can affect a person for a long time. It affects the legs of older people who have a disease
called chronic venous insufficiency. This is when a person’s veins have difficulty sending blood from their limbs back to their
heart. Stasis dermatitis is caused by increased pressure inside a person’s veins. Its signs and symptoms are skin discoloration,
itch, dryness, and scaling and can be similar to the signs and symptoms of cellulitis and allergic contact dermatitis. Cellulitis
is a common skin infection caused by bacteria. Cellulitis causes redness, swelling, and pain. Allergic contact dermatitis is an
itchy skin rash caused by contact with something that irritates the skin. Stasis dermatitis is usually diagnosed after a health-
care provider has looked at person’s skin and their medical history. Treatment for stasis dermatitis should treat the chronic
venous insufficiency that causes the disease. It should also treat the skin lesions caused by stasis dermatitis. One way to treat
stasis dermatitis is to reduce pain and swelling. This is done by applying pressure with compression stockings or bandages.
Minor surgery can treat the venous insufficiency that causes stasis dermatitis. No treatments have been approved for the skin
symptoms associated with stasis dermatitis. New ways to treat such symptoms need to be developed.

Key Points 

* Juliana M. Canosa Stasis dermatitis is caused by venous hypertension.

juliana.machadocanosa@pfizer.com
Treatment often involves the use of compression therapy
1
Miami Itch Center, Miller School of Medicine, University and minor surgical procedures.
of Miami, Miami, FL, USA
2
No treatments are approved for the management of the
University Hospitals of Cleveland, Cleveland, OH, USA
skin changes associated with stasis dermatitis, although
3
The George Washington University School of Medicine topical corticosteroids are frequently used.
and Health Sciences, Washington, DC, USA
4
GW Medical Faculty Associates, NW, Washington, DC, USA
5
Pfizer Brasil Ltda., São Paulo, SP, Brazil
6
Pfizer Inc., New York, NY, USA

Vol.:(0123456789)

276 G. Yosipovitch et al.

1 Introduction was identified in 1.4% of 773 individuals aged ≥ 15 years

who had varicose veins [12]. In another study, SD was
Statis dermatitis (SD), also known as venous eczema, found in 6.2% of 4099 individuals aged ≥ 65 years [13].
stasis eczema, venous SD, or gravitational dermatitis, Similar studies have found an SD prevalence of 5.9% in
is a chronic inflammatory skin disease driven by under- 68 individuals with a mean age of 74 years (range 50–91),
lying chronic venous insufficiency that typically affects increasing to 6.9% in 584 individuals with a mean age of
the lower extremities of older individuals [1, 2]. In SD, 80 years (range 55–106) [2]. With the increasing age of the
alterations in the function of the deep venous plexus US population, rising rates of obesity, and more sedentary
at the lower extremities cause blood to backflow to the lifestyles, the prevalence of chronic venous insufficiency
superficial venous system, leading to venous hyperten- (and, consequently, SD) is expected to increase.
sion, cutaneous inflammation, and a range of potential Venous ulcerations of the lower extremities are a signifi-
complications, including venous ulcers [3]. This review cant complication in patients with advanced venous insuf-
describes the incidence, clinical presentation, diagnosis, ficiency. Although compression therapy remains the most
pathogenesis, and treatment of SD. Literature was selected frequently used treatment for venous ulcerations, with the
via a high-level PubMed search using keywords related to healing of ulcers reported in approximately 70% of treat-
SD, such as “stasis dermatitis,” “stasis ulcers,” “venous ment-adherent patients, a significant portion of patients do
ulcers,” “venous hypertension,” “venous stasis dermatitis,” not fully respond to this treatment [14]. Compression stock-
“venous eczema,” “chronic venous insufficiency,” “chronic ings may be too painful for patients with stasis ulcers to
venous disease,” and “chronic venous insufficiency.” don, so surgical treatments may be necessary (see Sect. 7
on treatments). After healing, the 5-year frequency for the
recurrence of venous ulcerations ranges between 26 and
51%, with the exact value depending on the initial degree of
2 Epidemiology ulceration [15]. Moreover, healing does not guarantee the
full restoration of proper function in patients, nor the resolu-
Chronic venous disease, including chronic venous insuf- tion of discomfort or pain.
ficiency, is a common disease that increases with age and
is more prevalent in women [4, 5]. Estimates for the preva-
lence of chronic venous insufficiency vary widely, high- 3 Clinical Presentation
lighting a knowledge gap in the extant epidemiological
data, with the observed numbers often depending on the SD, as a cutaneous manifestation of chronic venous insuf-
clinical characteristics and lifestyles of the populations ficiency caused by retrograde venous blood flow, is classified
examined. Geographically, the highest reported prevalence as C4 (changes in skin and subcutaneous tissue secondary
of chronic venous insufficiency is across Western coun- to chronic venous disease) on the Clinical-Etiology-Anat-
tries, ranging from < 1 to 40% in women and from < 1 omy-Pathophysiology (CEAP) classification of venous dis-
to 17% in men [1, 6]. A Saudi Arabian study estimated orders [1, 16]. This is an internationally accepted standard
the overall prevalence of chronic venous insufficiency as for describing patients with chronic venous disorders based
about 45.6% [7]. A Scottish study found the age-adjusted on the clinical manifestations, the current understanding of
prevalence of chronic venous insufficiency to be 9% in disease etiology, the involved anatomy, and the underlying
men and 7% in women, with the prevalence increasing venous pathology [16]. The typical clinical presentation
with age [8]. In a cross-sectional study of chronic venous involves poorly demarcated erythematous and eczema-
insufficiency in patients in 24 cities in Italy, only 22.7% tous patches and plaques of the lower extremities, with
of approximately 5200 adult participants demonstrated no the medial malleolus region being the most frequently and
visible signs of the disease [9]. It is estimated that between severely involved [1, 2]. The eczematous nature of SD is
2 and 6 million individuals in the United States have represented by scaling, erythema, and xerosis of the skin.
advanced forms of chronic venous insufficiency, including These skin changes may extend to the foot as well as to the
swelling and skin changes, with about 500,000 individu- knee. Characteristic symptoms include pruritus (itch) on the
als displaying painful venous ulcers [10]. Approximately medial ankle (which can extend to the shin), pain, lesional
37–44% of individuals with leg ulcers had been diagnosed inflammation, scaling, and skin color changes and thicken-
with SD [11]. SD is an advanced cutaneous presentation ing [1, 3]. Itch is the most troublesome symptom, impact-
of chronic venous insufficiency that is more common in ing patient quality of life (QOL) and leading to scratching
older patients; age is positively correlated with the num- that can aggravate wounds and increase risk of skin infec-
ber of insufficient venous segments [2]. In one study, SD tion. Chronic scratching due to itching can also result in
Stasis Dermatitis: A Review 277

oozing and erythema (Fig. 2) [2]. Patients with SD may also

develop acroangiodermatitis (pseudo–Kaposi sarcoma), and
a biopsy may be required to differentiate it from Kaposi sar-
coma [1, 2, 20].
It is clinically important to differentiate between acute
and chronic SD. Acute SD is often observed with acute or
worsening edema and is characterized by substantial ery-
thema, bullae, weeping, and vesicles (referred to as a flare).
Both chronic and acute SD are often misdiagnosed as bilat-
eral cellulitis. Chronic SD often presents with poorly demar-
cated hyperpigmentation and erythema that is linked with
chronic edema and underlying inflammation of the lower
extremities. Patients with chronic SD can develop acute
flares that are clinically shown as worsening of the eczema,
Fig. 1  Stasis dermatitis with hyperpigmentation. Figure used with with signs of inflammation, such as pain and swelling. The
permission from https://​www.​scien​cepho​to.​com
lipodermatosclerosis that is observed in chronic SD is a
severe fibrosing panniculitis of the subcutaneous tissue and
may lead to an “inverted champagne bottle” appearance of
the lipodermatosclerosis of the leg. In acute SD settings,
lipodermatosclerosis may present with painful subcutaneous
plaques or nodules [1, 3].

4 Burden of Disease

Chronic venous disease, including SD, is associated with

pain and a reduced QOL, including limitations in physical
function, sleep, and mobility. Reductions in physical func-
tioning and mobility can limit the patient’s ability to apply
topical medications or to put on or take off compression
Fig. 2  Stasis dermatitis with leg ulcers. Figure used with permission stockings, thereby worsening the situation. Patients with SD
from https://​www.​scien​cepho​to.​com
also report social isolation and depression [4, 14]. Emotional
and social well-being can be impacted by the cosmetic skin
skin thickening and lichenification [1, 17]. Brown speckles changes (including hyperpigmentation and scaling) typi-
(hyperpigmentation), the result of hemosiderin deposition, cally observed [2, 21]. Post-inflammatory hyperpigmenta-
which is the byproduct of hemoglobin from extravasated tion can persist even after other signs and symptoms have
erythrocytes, also represents a classic chronic sign (Fig. 1). resolved with therapy [2]. A study of 2404 patients using
SD may be associated with other typical presentations of the generic Medical Outcomes Study 36-Item Short-Form
chronic venous disease, including cramps, leg aching/pain, General Health Survey questionnaire identified a significant
itching, swelling, and lipodermatosclerosis [2]. Due to the correlation between the severity of venous disease and the
disruption of the epidermal barrier, secondary infections decline in the affected patient’s QOL [21]. Similarly, a cor-
may also occur, leading to superficial infections such as relation was found between CEAP class and QOL using a
impetiginization, cellulitis, and erysipelas. Both cellulitis disease-specific questionnaire [22]. A study examining QOL
and erysipelas are skin infections caused by bacteria with in patients with advanced venous insufficiency found that
the main difference being the depth of infection—erysipelas patients suffered from severe pain and discomfort, with
are more superficial, markedly affecting the face and lower patients’ overall level of independence being lower than that
limbs, while cellulitis reaches the deeper dermis and subcu- of healthy individuals [14]. As previously noted, pruritus
taneous fat layers, markedly affecting the palm of the hands is one of the troublesome symptoms reported in SD. In a
and the lower limbs [1, 18, 19]. Importantly, if the underly- survey involving an elderly population, SD was the most
ing venous alterations remain untreated, the venous disease commonly reported dermatitis to cause itch [23]. Patients
patient may develop chronic venous ulcerations along with with pruritus of the lower extremities exhibited lower

278 G. Yosipovitch et al.

health-related QOL and higher leg pain ratings than those such as a sedentary lifestyle and obesity can be addressed,
without pruritus [24]. Compounding this issue, the itch in potentially resulting in disease improvement.
SD can be refractory to conventional therapies [17]. SD is typically diagnosed by clinical evaluation of the
Chronic venous diseases, including SD, directly impact affected skin and medical history [1, 28]. If the initial diag-
healthcare resources and are associated with a loss of annual nosis is inconclusive, duplex ultrasounds can be used to
workdays and an increase in overall treatment costs. In detect the direction of blood flow, assess venous reflux, and
the United States, treatment costs of venous diseases are identify potential venous obstructions. Widespread use of
between US$2.5 and US$3 billion, with a loss of 2 million duplex ultrasound is supported by its accuracy, non-invasive-
workdays per year [25]. Overall, chronic venous diseases ness, and cost-effectiveness [1, 30]. Computed tomography
account for 1–3% of the total healthcare budgets in nations and magnetic resonance imaging can also be used to detect
with developed healthcare systems [4], although there is obstructions in proximal veins and surrounding structures
not a robust body of literature that describes the economic [2]. A diagnosis of SD can be confirmed through biopsy
impact of SD. Moreover, chronic venous insufficiency in and demonstration of classic histological features of SD,
general is often underdiagnosed and undertreated for pro- including hemosiderin-laden macrophages, dermal fibrosis,
longed periods of time, and the low recognition of SD within extravasated erythrocytes, perivascular lymphocytic infiltra-
the healthcare system and a lack of dermatology services tion, and the proliferation of dilated blood vessels in the pap-
in many hospitals, emergency rooms, and urgent care set- illary dermis [1]. Biopsies are generally avoided because the
tings further compounds the burden on the patient [26, 27]. impaired blood flow in the affected areas of skin can result
Several healthcare specialists (including general physicians, in poor healing and development of ulcers [1, 28].
dermatologists, geriatricians, vascular surgeons, and wound Several cutaneous disorders can present similarly to SD,
care specialists) may be involved in the initial interaction leading to delayed or inaccurate diagnosis and subsequent
with and subsequent care of the patient. disease mismanagement and the associated impact on patient
anxiety and healthcare costs. Indeed, over 10% of the diag-
noses of cellulitis are incorrect, with SD being the most
5 Diagnosis and Histopathology common misdiagnosed condition. Cellulitis is associated
with previous trauma or a disrupted epithelial barrier in the
Several risk factors were established with the development affected region, marked by unilateral erythematous plaque
of venous insufficiency leading to SD, including older age, along with tenderness, swelling, and warmth [1]. Cellulitis
female sex, pregnancy, obesity, prolonged sitting or standing, is often accompanied by a variety of systemic symptoms,
heart failure, and family history of venous disease (Table 1) including mild leukocytosis, fever, and, less commonly,
[1, 28]. The association with pregnancy and obesity is due to regional lymphadenopathy and/or ascending lymphangitis
extra stress placed on the patient’s lower extremities [1, 3]. [1, 31]. Indications of cellulitis also include a history of
Patients who are unable to move may experience leg edema acute progression and improvement with antibiotics [2].
caused by venous stasis that is due to immobility itself and However, SD is often bilateral, not associated with signifi-
not to anatomical venous complications [29]. Risk factors cant tenderness, and chronic and frequently occurs with pit-
ting edema [31]. However, unilateral presentations of SD
may be observed when the venous insufficiency is limited to
one extremity [1]. Due to the many similarities between cel-
Table 1  Established risk factors for developing stasis dermatitis
lulitis and SD, patients with SD are often treated for recur-
Risk factors rent cellulitis. Given that cellulitis is potentially a medical
Older age (usually > 50 years)
emergency, a misdiagnosis can result in unnecessary hospi-
Female sex talization and exposure to antibiotics. Not surprisingly, early
Pregnancy consultation with a dermatologist was shown to improve the
Obesity accuracy of diagnosis of inflammatory skin diseases in hos-
Prolonged periods of sitting or standing
High blood pressure
pitalized patients [1, 32].
Heart failure Allergic contact dermatitis is also a risk factor in patients
Kidney failure with a longer history of SD and ulcerations and is often
Chronic edema mistaken for SD [1, 31, 33]. Due to the breakdown of the
History of cellulitis
Varicose veins
epidermal barrier in patients with SD and frequent and
History of blood clots in the legs (e.g., deep vein thrombosis) extended use of topical treatments containing sensitizing
Leg vein surgeries ingredients, allergic contact dermatitis may present on a
Leg injuries background of SD, further complicating the diagnosis. Patch
Family history of venous disease
testing is often needed to confirm allergic contact dermatitis
Stasis Dermatitis: A Review 279

[1, 2]. A patient’s history, including their previous applica- In terms of both the pathogenesis of SD and develop-
tion of products, stockings, and dressings, is essential when ing effective therapies, it is important to understand that
determining which allergens to patch test [1]. Autoeczema- inflammation causes the skin changes characteristic of SD
tization, also known as an id reaction, which is the acute [2, 4]. The accumulation of leukocytes in the microcircula-
onset of a highly erythematous, pruritic, morbilliform, or tion of extremities with venous hypertension was reported
papulovesicular eruption due to an exposure to a stimulus, in the 1980s, and such leukocyte trapping is now considered
commonly occurs with SD [1, 34]. typical of the early stages of chronic venous insufficiency,
Pigmented purpuric dermatoses (PPDs) and exercise- particularly in SD [40, 41]. Studies demonstrated that the
induced vasculitis may also resemble SD due to their main passively dependent blood in the feet of individuals with
clinical feature of punctate petechiae secondary to the chronic venous diseases has low levels of leukocytes, sug-
extravasated erythrocytes [1, 35]. Like SD, PPDs are lim- gesting leukocyte accumulation in regions of high venous
ited to the lower limbs bilaterally and are often chronic with pressure, leading to the observed inflammatory response
recurrent exacerbations. Hemosiderin deposition is found [41, 42]. Here, leukocytes attach to the endothelium of
in the superficial dermis in PPDs, with the deposition being vein walls and valve leaflets, causing the necrosis and/or
deeper in SD [1, 2]. Other SD mimickers include atopic apoptosis of the endothelium, fibroblasts, smooth muscle
dermatitis (AD), diabetic dermopathy, and xerotic eczema cells, and parenchymal cells of the venous wall. This causes
[1, 36]. Being familiar with the appearance of such condi- weakening and destruction of the venous walls and valve
tions, as well as pursuing the correct diagnostic workup that leaflets, leading to the observed venous changes in SD
includes both the history and the clinical presentation, is [43, 44]. Increased numbers of T lymphocytes, macrophages,
important to correctly diagnose cutaneous disorders asso- and mast cells were also observed in skin biopsies of the
ciated with the inflammation of lower extremities [1, 28]. lower legs of individuals with chronic venous insufficiency,
Moreover, general physicians may not recognize venous further supporting the association of inflammatory media-
disorders or appreciate their seriousness and, consequently, tors with cutaneous damage [2, 43]. In SD, venous hyper-
may not refer the patient to a specialist [37]. tension promotes the cellular accumulation of inflammatory
cells, such as macrophages, as well as the extravasation of
erythrocytes at the affected areas. Erythrocyte extravasation
6 Pathogenesis is followed by hemoglobin decomposition, which results in
the excessive buildup of iron that is stored at the affected
Venous reflux that drives venous hypertension can be the tissues as hemosiderin. Further macrophage accumulation
result of incompetent venous valves, obstruction to venous is induced by the buildup of hemosiderin and hemoglobin.
flow, or failure of the lower extremity muscle pump and may Such macrophages, alongside other cells, promote inflam-
occur in the superficial or deep venous systems [1, 4]. In a mation and induce several histological features seen in SD,
study of patients with chronic venous disease, primary val- including epidermal spongiotic changes and capillary pro-
vular incompetence was present in 70–80% of cases; valvu- liferation [17].
lar incompetence was due to trauma or deep vein thrombo- It was also demonstrated that expression of intercellular
sis in 18–25% of cases [4]. In chronic venous insufficiency, adhesion molecule-1 and vascular cell adhesion molecule-1
increased venous hypertension initiates changes in the local on microvascular endothelial cells, and their ligands lym-
subcutaneous tissue and skin, including activation of the phocyte function-associated antigen-1 and very late anti-
endothelial cells, extravasation of red blood cells and mac- gen-4 on leukocytes, is upregulated in the early stages of
romolecules, diapedesis of leukocytes, and inflammatory chronic venous insufficiency, including SD. This process
changes that are often noted at and above the ankles [38]. remains upregulated as SD progresses. This would facili-
There is an accumulation of clinical evidence to support the tate the transmigration of leukocytes into nearby tissues.
concept that venous hypertension causes SD. One study that Epidermal basal keratinocytes were also found to express
examined 360 lower limbs indicated a positive correlation elevated levels of intercellular adhesion molecule-1 and vas-
between increased ambulatory venous pressure and severe cular cell adhesion molecule-1 in SD, potentially promoting
skin damage [39]. In another study, venous hypertension was skin tissue damage through a perpetuated and upregulated
found to be the only plausible cause of SD in patients with influx of activated leukocytes and eventually leading to skin
superficial venous insufficiency, with negative patch testing ulcerations [45].
and without insufficiency of the deep veins. Interestingly, in Studies also demonstrated the role of matrix metallo-
this second study, surgical intervention targeting the venous proteinases (MMPs) in remodeling lesional skin in SD via
pressure resulted in the complete and rapid resolution of SD degradation of extracellular matrix proteins and impair-
for all patients who underwent surgery [40]. ment of healing. In a study that examined skin samples from

280 G. Yosipovitch et al.

immune cells (e.g., T cells, eosinophils, mast cells, and

basophils). IL-31 has been implicated in the induction of
pruritus in several diseases, including AD, psoriasis, prurigo
nodularis, and cutaneous T cell lymphoma. A recent study
by Hashimoto et al. has demonstrated the potential involve-
ment of dermal IL-31 from macrophages in inducing SD-
associated pruritus. The majority of IL-31–expressing cells
in SD are C­ D68+ macrophages. Such ­CD68+ macrophages,
which coexpress CD163 (a macrophage-specific membrane
marker), are classified as M2 macrophages. The number of
­IL31+CD68+ macrophages was higher in patients with SD
with severe pruritus compared to SD without severe pruritus.
The number of ­IL31+CD68+ macrophages was positively
correlated with the number of substance P ­ + cells, dermal
+
C-C chemokine receptor type ­4 T helper type 2 cells, and
basophils and the dermal deposition of hemosiderin and
Fig. 3  Protein expression of MMPs and their TIMPs in extracts of periostin [17].
skin samples from patients with stasis dermatitis. Data were taken
from Western blots with monoclonal antibodies against MMP-1,
MMP-2, MMP-13, TIMP-1, and TIMP-2 in stasis dermatitis and con-
trol skin lesions. Densitometric evaluations of immunoreactive blots 7 Treatments
for MMP-1, MMP-2, MMP-13, TIMP-1, TIMP-2 from stasis derma-
titis (black bars) and healthy skin (white bars) are shown. Data are The goals of current treatment options in patients with SD
mean ±SEM; n = 10 for stasis dermatitis and n = 4 for control. The include addressing the clinical impact of the underlying
significance of difference was determined by an unpaired Student t
test and is indicated in each mapped group. Figure used with permis- venous insufficiency, edema, and inflammation (itch and
sion from Herouy et al. [46] J Dermatol Sciences, 2001. MMP matrix pain), improving skin lesions, and healing ulcers (Table 2).
metalloproteinase, ns not significant, SEM standard error of the mean, Initial options for the treatment of SD include exercise,
TIMP tissue inhibitor of metalloproteinase. *p < 0.05 walking, and leg elevation, although such approaches are
generally effective only for mild cases of SD [1, 2]. The
19 patients with SD, elevated levels of MMP-1, MMP-2, and cornerstone of treatment for SD remains compression ther-
MMP-13 were found, with diminished levels of tissue inhibi- apy through bandages or stockings, using a high pressure of
tor of metalloproteinases (TIMP)-1 and TIMP-2, compared about 60 mmHg or a median pressure of about 30 mmHg
to healthy control samples (Figs. 3, 4). Such overexpression [48], respectively, to reduce the ambulatory venous pressure
and production of MMP-1, MMP-2, and MMP-13, with- and resultant hypertension. Although compression was dem-
out the inhibitory effects of TIMP-1 and TIMP-2, may be onstrated to alleviate swelling, pain, and stasis skin changes
the result of cytokine-mediated induction [46]. Increased in patients with SD, this approach often fails due to nonad-
expression of MMPs and other proteinases by the vessel wall herence or loss of stocking elasticity after repeated use [1, 2,
promotes further degradation of the vascular extracellular 49–52]. Indeed, only about 50–60% of patients comply with
matrix, resulting in abnormal vascular permeability as well compression therapy, with bandages being more challenging
as edema [1]. Moreover, the release of ferritin and ferric ion to apply correctly (versus stockings) without professional
from extravasated erythrocytes may result in oxidative stress guidance [2, 50, 53]. In addition, the synthetic rubber in
and additional MMP activation, promoting skin tissue dam- compression stockings can result in allergic contact derma-
age, ulcer formation, and delaying healing [2, 4, 47]. MMPs titis of the lower extremities, further impacting treatment
as well as other forms of inflammation may also cause skin adherence [54]. Topical dressings, such as the Unna boot,
hyperpigmentation in SD [2]. which is a bandage that contains moist zinc oxide, can also
Very little is known regarding the pathophysiological be utilized. Such dressings serve as non-elastic compressions
mechanisms of SD-linked pruritus. Pruritus is either hista- that contain a topical treatment for SD. The Unna boot can
minergic or nonhistaminergic. SD-related pruritus is likely also be combined with other treatments, including topical
nonhistaminergic because antihistamines do not improve corticosteroids. Use of the Unna boot alleviates various SD
SD-associated pruritus. Such nonhistaminergic pruritus symptoms, including cutaneous inflammation, pruritus, and
involves various mediators, including cytokines/chemokines eczema [1]. One study found the use of the Unna boot over
(e.g., interleukin [IL]-31), amines, neuropeptides and their a topical ointment to be more efficacious than Unna boot
receptors, proteases and their receptors, ion channels, and compression alone [55].
Stasis Dermatitis: A Review 281

Fig. 4  Immunohistochemical detection of MMP-1, MMP-2, and one patient are shown. The experiment was repeated with comparable
MMP-13 in lesions of stasis dermatitis. Increased immunoreactive results (n = 2 for stasis dermatitis; n = 2 for control). Figure used
staining was observed in skin from stasis dermatitis lesions for a with permission from Herouy et al. [46] J Dermatol Sciences, 2001.
MMP-1, b MMP-2, and c MMP-13. Representative photographs from MMP matrix metalloproteinase

Although no drugs are currently approved for the treat- healing rate of venous ulcers [61]. Pentoxifylline is an
ment of SD symptoms, several topical options are used to inhibitor of platelet aggregation that reduces blood vis-
relieve the symptoms associated with SD. Skin care treat- cosity, thereby improving microcirculation. Pentoxifylline
ments for SD include non-soap cleansers, barrier prepara- has been shown to be effective for the treatment of venous
tions, and bland emollients [2]. Moisturization through the ulcers when added to compression therapy [62]. Edema
liberal application of emollients is recommended to address may be reduced through the use of venoactive drugs,
the skin dryness that is associated with the concomitant which reduce capillary permeability, increase venous tone,
xerosis [56]. High- or mid-potency topical corticosteroids decrease blood viscosity and improve lymphatic drainage
can also be used intermittently to relieve pruritus, although [2]. Escin, a horse chestnut seed extract that stimulates
prolonged use may lead to cutaneous atrophy and systemic F-series prostaglandins, is used to improve symptoms of
side effects [1, 57]. Topical calcineurin inhibitors are also an chronic venous insufficiency on a short-term basis [63].
option given their effectiveness in other steroid-responsive Another venoactive drug, micronized purified flavonoid
dermatoses. Although topical tacrolimus (used off-label) has fraction, was shown to be more potent than other venoac-
been shown to be effective for the treatment of SD, topical tive drugs at reducing ankle edema [64].
calcineurin inhibitors are associated with a burning sensa- Hydroxyethylrutosides can also be utilized to relieve
tion upon application and require patient education due to symptoms of chronic venous insufficiency, including pain,
a box warning for an increased risk of lymphoma [57–59]. cramps, and a feeling of heaviness in the legs. Hydroxy-
Cutaneous hyperpigmentation often persists even if the ethylrutosides is a standardized mixture of semisynthetic
chronic venous insufficiency is treated; although responses flavonoids that is derived through hydroxylation of the natu-
are often poor, noncoherent intense pulsed light or laser ral substance rutin. The benefits of hydroxyethylrutosides
treatments do represent an approach to removing hyperpig- for chronic venous insufficiency may be due to their abil-
mentation [60]. ity to inhibit capillary filtration via reducing microvascu-
Multiple oral treatments have shown promise in improv- lar permeability, leading to reduced edema and improved
ing some of the symptoms experienced by patients with microcirculation. However, a meta-analysis that assessed the
SD. Oral pentoxifylline is often used with or without com- effectiveness of hydroxyethylrutosides for chronic venous
pression therapy to reduce leg pain and to increase the insufficiency found only modest improvements in several

282

Table 2  Summary of the treatments used for stasis dermatitis

Edema Feeling of Hyper- Inflammation Leg cramps Pain Prevent Promote Pruritus Xerosis
heaviness in pigmen- ulcer recur- healing of
legs tation rence ulcers

Nonpharmacological: exercise, walking, leg elevation, stockings, band- X X X X

ages, topical dressings (Unna boot)
Non-soap cleansers, barrier preparations, bland emollients X
Moisturizers X
Topical high- and mid-potency corticosteroids X
Topical calcineurin inhibitors (topical tacrolimus [off-label]) X
Antihistamines X
Pulsed light treatments X
Oral pentoxifylline X X X
Topical pentoxifylline and phlebotonics X X
Venoactive medications (escin, micronized purified flavonoid fraction), X
calcium channel blocker (amlodipine), angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers
Hydroxyethylrutosides X X X
Ultrasound-guided foam sclerotherapy, endovenous thermal ablation, X X
ambulatory phlebectomy
Topical phosphodiesterase 4 inhibitors (crisaborole [off-label]) X X
Oral analgesics (anti-inflammatory medications, acetaminophen, meta- X X
mizole)
Topical anesthetic creams (prilocaine and lidocaine) X
Antibiotics and antiseptics X
G. Yosipovitch et al.
Stasis Dermatitis: A Review 283

associated symptoms; all analyzed trials were of limited modality for long-term treatment for venous ulcers, or the
quality [65]. Secondary bacterial infections, if present, can use of dressings. Compression therapy reduces pain and
be treated with appropriate oral antibiotics [1]. Antihis- edema, improves venous reflux, enhances ulcer healing, and
tamines have been used in an attempt to relieve pruritus, prevents ulcer recurrence. Stockings or bandages can also be
but responses were poor; such results are not unexpected used. The use of various layers is more effective than single
because the pruritus associated with SD is not driven by the layers, with elastic systems being more efficacious than non-
histamine pathway, as noted earlier [1, 17]. elastic ones [74]. In patients with healed ulcers, compression
Calcium channel blocker (CCB)-related edema is com- stockings help reduce the risk of ulcer recurrence by about
mon in clinical practice and is due to a decrease in arteriolar half [75]. Topical dressings are recommended to promote
resistance, which increases the hydrostatic pressure in the moist wound healing and cover ulcers, although no dressing
precapillary circulation, causing fluid shifts into the inter- has been shown to be superior [62, 74]. The most commonly
stitial compartment. Antihypertensive medications, such as used drugs are oral analgesics (such as anti-inflammatory
amlodipine, are CCBs that increase capillary permeability drugs, acetaminophen and metamizole) and topical anes-
[66]. When used as monotherapy, such CCBs are associ- thetic creams (such as prilocaine and lidocaine). Topical
ated with a substantial risk of developing peripheral edema, medications, which include pentoxifylline and phleboton-
which is the most common reason for their discontinuation ics, can be applied as monotherapies or in combination with
[67]. Discontinuing the CCB or switching to an alternative compression therapy [37, 74, 76]. Antibiotics and antiseptics
antihypertensive therapy, such as angiotensin-converting can be used to slow bacterial colonization in venous ulcers,
enzyme inhibitors or angiotensin-receptor blockers, may thereby improving wound healing; however, a review of sys-
reduce the associated peripheral edema [66]. temic and topical antibiotics and antiseptics for venous ulcer
Interventional options that aim to treat the underlying treatment found no correlation between the routine use of
venous reflux are also available. Classic open surgical tech- oral antibiotics and ulcer healing [62, 77]. Surgical options,
niques have been replaced with minimally invasive proce- which include endovenous ablation and skin grafting, can
dures, such as ultrasound-guided foam sclerotherapy, end- also be utilized to promote healing and prevent ulcer recur-
ovenous thermal ablation, and ambulatory phlebectomy. rence [74]. A large review study that evaluated 832 patients
Compared with conventional techniques, minimally inva- with advanced chronic venous insufficiency (CEAP clinical
sive procedures are less painful, are associated with a lower scores of 4–6) found that surgical intervention resulted in an
number of complications, are more cost-effective, and have ulcer healing rate of 92%, with recurrence rates as low as 4%
quicker recovery times [2, 38, 68–70]. [78]. Surgical options have also been studied in comparison
Given the central role in the pathogenesis of SD, inflam- to non-surgical compression therapy where surgery reduced
mation represents a logical focus for the development of ulcer recurrence compared to non-surgical treatment after
new therapeutic options. Phosphodiesterase 4 is an intra- 4 years (31% vs 56%, respectively) [79]. In patients with
cellular nonreceptor enzyme that modulates inflammation, recurring ulcers, the addition of ablative superficial surgery
and patients with inflammatory diseases (AD, discoid lupus to standard treatment may be an option [79]. Besides the
erythematosus, and psoriasis) show elevated expressions addition of surgery for recurring ulcers, standard treatment
of phosphodiesterase 4 compared to healthy individuals with compression therapy remains the first-line treatment of
[57, 71]. Moreover, targeting phosphodiesterase 4 was veri- choice for patients with venous ulcers [80].
fied as an effective therapeutic strategy for several inflam-
matory conditions, including psoriasis and AD [71]. Crisab-
orole, a topical phosphodiesterase 4 inhibitor approved 8 Conclusion
for the treatment of AD in multiple countries, underwent
evaluation in the completed phase 2 trial (NCT04091087) SD represents the cutaneous manifestation of venous hyper-
in adults with SD [72, 73]. Crisaborole is rapidly metabo- tension caused by venous reflux and most commonly occurs
lized to inactive metabolites that have no effect on cytokine in the lower extremities of elderly individuals. Cutaneous
release or phosphodiesterase 4 activity, limiting systemic changes associated with SD are driven by inflammation.
exposure and reducing the risk of adverse effects. A topi- The typical clinical presentation involves erythematous and
cal phosphodiesterase inhibitor could lead to the targeted eczematous patches and plaques. Itch is one of the most
inhibition of inflammation observed in skin diseases while troublesome symptoms and often leads to scratching that
avoiding unwanted side effects [57]. can aggravate wounds and increase the risk of skin infection.
In the case of venous ulcers, treatment options include SD may also progress to chronic venous ulcerations with
management, mechanical modalities, wound therapy, medi- oozing and erythema. Accordingly, prompt diagnosis and
cations, and/or surgery. Management options include the treatment are essential to preventing serious complications.
use of compression therapy, which is the standard treatment However, diagnosis is challenging due to the resemblance

284 G. Yosipovitch et al.

of SD to other skin conditions. The cornerstone of treatment material. If material is not included in the article's Creative Commons
includes compression therapy to ameliorate pain and swell- licence and your intended use is not permitted by statutory regula-
tion or exceeds the permitted use, you will need to obtain permission
ing, together with topical treatments to alleviate secondary directly from the copyright holder. To view a copy of this licence, visit
skin changes and associated signs and symptoms. No treat- http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc/4.​0/.
ments are currently approved for alleviating the symptoms
associated with SD; new therapeutic approaches that target
inflammation in SD are thereby needed.

Acknowledgements  Editorial/medical writing support under the guid-

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