Dermatol Ther (Heidelb) (2023) 13:935–950

https://doi.org/10.1007/s13555-023-00908-0

REVIEW

Narrative Review of the Pathogenesis of Stasis

Dermatitis: An Inflammatory Skin Manifestation
of Venous Hypertension
Jonathan Silverberg . J. Mark Jackson . Robert S. Kirsner .
Roni Adiri . Gary Friedman . Xing-Hua Gao . Steven D. Billings .
Urs Kerkmann

Received: November 23, 2022 / Accepted: February 17, 2023 / Published online: March 22, 2023
Ó The Author(s) 2023

ABSTRACT secondary to incompetent venous valves, valve

destruction, or obstruction of the venous sys-
Introduction: Stasis dermatitis (SD), also tem. Many of the common symptoms associ-
known as venous dermatitis, is a form of ated with SD are caused by inflammatory
inflammatory dermatitis of the lower extremi- processes.
ties that typically occurs in older individuals Methods: This review summarizes the patho-
and represents a cutaneous manifestation of genesis and key role of inflammation in SD by
venous hypertension. Venous hypertension reviewing inflammatory biomarkers associated
(also known as sustained ambulatory venous with SD. The literature was selected though a
pressure) is most often due to retrograde blood high-level PubMed search focusing on keywords
flow, which occurs due to calf muscle pump relating to inflammation associated with SD.
failure. This failure is most commonly Results: Venous reflux at the lower extremities
causes venous hypertension, which leads to

J. Silverberg X.-H. Gao

The George Washington University School of Department of Dermatology, The First Hospital of
Medicine & Health Sciences, 2300 I St NW, China Medical University, 110001 Shenyang, China
Washington, DC 20052, USA
S. D. Billings
J. M. Jackson Department of Pathology, Cleveland Clinic, 9500
Division of Dermatology, University of Louisville, Euclid Ave, Cleveland, OH 44195, USA
501 S 2nd St, Louisville, KY 40202, USA
U. Kerkmann
R. S. Kirsner Pfizer Pharma GmbH, Linkstraße 10, Postfach
Dr. Phillip Frost Department of Dermatology and 610194 10922, 10785 Berlin, Germany
Cutaneous Surgery, University of Miami Miller
School of Medicine, 1295 NW 14th St, Miami, FL
33125, USA

R. Adiri (&)
Pfizer Pharmaceuticals Israel Ltd., 9 Shenkar St,
4672509 Herzliya Pituach, Israel
e-mail: Roni.Adiri@pfizer.com

G. Friedman
Pfizer Inc., 500 Arcola Rd, Collegeville, PA 19426,
USA
936 Dermatol Ther (Heidelb) (2023) 13:935–950

chronic venous insufficiency. High venous pressure in leg veins. Several molecules are
pressure due to venous hypertension promotes associated with the inflammation observed in
the local accumulation and extravasation of stasis dermatitis, including white blood cells,
inflammatory cells across the vascular matrix metalloproteinases, phosphodi-
endothelium. Leukocyte trapping in the esterase 4, and interleukin-31. Treatment for
microcirculation and perivascular space is asso- stasis dermatitis should focus both on the
ciated with trophic skin changes. Cell adhesion underlying chronic venous insufficiency and
molecules are linked with the perpetuated the associated skin issues. Identifying inflam-
influx of activated leukocytes into inflamma- matory markers and pathways could help treat
tory sites. Here, inflammatory cells may influ- the signs and symptoms associated with stasis
ence the remodeling of the extracellular matrix dermatitis, including the skin symptoms.
by inducing the secretion of proteinases such as
matrix metalloproteinases (MMPs). The
increased expression of MMPs is associated with Keywords: Stasis dermatitis; Venous dermati-
the formation of venous leg ulcers and lesions. tis; Inflammation; Venous hypertension;
Phosphodiesterase 4 activity has also been Pathogenesis
shown to be elevated in individuals with
inflammatory dermatoses compared to healthy
individuals. Key Summary Points
Discussion: Because inflammation is a key dri-
ver of the signs and symptoms of SD, several of Stasis dermatitis is caused by venous
the highlighted biomarkers of inflammation hypertension due to venous reflux.
represent potential opportunities to target and If undiagnosed or left untreated, stasis
interrupt molecular pathways of cutaneous dermatitis may be a precursor to venous
inflammation and, therefore, remediate the ulcers.
signs and symptoms of SD.
Conclusion: Understanding the pathogenesis Chronic inflammation represents the
of SD may help clinicians identify drivers of most likely link between the venous
inflammation to use as potential targets for the hypertension and cutaneous changes
development of new treatment options. observed in stasis dermatitis.
Interrupting the molecular pathways that
sustain cutaneous inflammation may
remediate the signs and symptoms of
PLAIN LANGUAGE SUMMARY stasis dermatitis.

Stasis dermatitis is a skin disease that affects the

legs, most often of older people, with chronic
venous insufficiency. Chronic venous insuffi-
ciency is when veins cannot return blood from
the legs back to the heart. This leads to high INTRODUCTION
blood pressure in veins and causes blood in
those veins to flow backwards. If stasis der- Venous reflux at the lower extremities causes
matitis is left untreated, complications, includ- venous hypertension (also known as sustained
ing skin ulcers, can result. Other skin symptoms ambulatory venous pressure), which leads to
of stasis dermatitis include itchiness, scaling, chronic venous insufficiency. Stasis dermatitis
and discoloration. Such skin symptoms can (SD), also known as venous dermatitis, is an
have a negative effect on a person’s quality of inflammatory dermatitis of the lower extremi-
life. Inflammation that lasts a long time is likely ties that predominantly affects older individuals
the main link between the skin changes seen in with underlying chronic venous insufficiency
people with stasis dermatitis and the increased [1, 2]. SD typically presents as bilateral
Dermatol Ther (Heidelb) (2023) 13:935–950 937

erythematous and eczematous patches and injection drug use, calf muscle injury, and a
plaques of the lower extremities [3]. Estimates history of deep venous thrombosis [1, 8, 10, 11].
of the prevalence of chronic venous insuffi- SD is more common in patients who are obese
ciency vary widely depending on the charac- and/or pregnant, especially those who are
teristics of the populations examined. multigravida, because of the extra stress that is
Approximately 2–6 million individuals in the placed on the veins of their lower extremities
USA have advanced forms of chronic venous [12]. Immobile patients may also develop SD
insufficiency [2, 4]. In one study, SD was due to the reduced tone and contractility of the
observed in 1.4% of individuals with varicose musculature at their lower extremities rather
veins aged 15 years or more [5]. SD is more than anatomical complications of the venous
prevalent in older individuals and was found in system. Failure to activate the calf muscle pump
6.2% of individuals aged 65 years or more [6]. because of angle joint issues or muscle disease
Results from similar studies indicated that SD can also lead to SD, even in the absence of
was found in 5.9% of individuals with a mean venous changes [10, 11, 13].
age of 74 years (range 50–91 years) and in 6.9% SD is an indication of underlying vascular
of those with a mean age of 80 years (range pathology and, if undiagnosed or left untreated,
55–106 years) [2]. is a precursor to venous ulcers [1, 2]. As was
Early symptoms and signs of SD include found in one study, 37–44% of patients with leg
pruritic, scaly, irritated, and discolored skin, ulcers were diagnosed with SD [14]. Approxi-
especially in areas of the lower leg where vari- mately 2.2 million individuals in Europe and
cose veins are present; additional symptoms more than 6 million individuals in the USA
and signs include aching and heaviness in one experience venous leg ulcers [15]. Venous ulcers
or both legs as well as swelling of the ankle and can occur as either a single or multiple ulcers
the lower leg [7]. The histologic epidermal and are often located over the medial malleolus
changes linked to SD include hyperkeratosis, (Fig. 1). Untreated SD can present with oozing
parakeratosis, acanthosis, and spongiosis. The and red, eroded, and/or scaly patches and pla-
histologic dermal changes associated with SD ques. Other skin changes may coexist. Contact
include extravasated erythrocytes, dermal dermatitis and autoeczematization due to SD
fibrosis, perivascular lymphocytic infiltration, can also arise [1]. Patients may also develop
hemosiderin-laden macrophages, and prolifera- acroangiodermatitis [2, 16]. Additional presen-
tion of dilated small blood vessels with rela- tations of the legs in patients with SD include
tively thick walls in the papillary dermis [2]. SD swelling, itching, tingling, leg aching, restless
is typically diagnosed on the basis of clinical legs, cramps, and lipodermatosclerosis [2].
findings and medical history [1, 8]. Lipodermatosclerosis is an indurated plaque in
Several cutaneous disorders present similarly the medial malleolus that can be exquisitely
to SD, leading to misdiagnosis and misman- painful in its acute form, with the chronic form
agement. More than 10% of cellulitis diagnoses presenting with skin induration and hyperpig-
are incorrect, with SD being the disease most mentation of the legs [17–19]. Secondary
frequently mistaken for cellulitis. Allergic forms infections may also occur because of the dis-
of contact dermatitis are also often mistaken for ruption of the epidermal barrier. Allergic con-
SD. Moreover, allergic contact dermatitis may tact dermatitis in SD may be caused by allergen
present simultaneously with SD, especially in penetration through the deteriorated epidermal
patients with venous ulcers [1, 9]. SD can also barrier as well as contact with potential aller-
resemble pigmented purpuric dermatoses, lym- gens that are applied during treatment.
phedema, and sometimes neoplasms [1–3]. Autoeczematization, also referred to as an ‘‘id
Several risk factors are associated with SD, reaction,’’ is the onset of a widespread, highly
including female sex, pregnancy, older age, pruritic, erythematous, morbilliform or
obesity, prolonged immobility, family history papulovesicular eruption in response to stimuli.
of venous disease, chronic edema, heart failure, The eruption often occurs at a distant location
previous lower extremity trauma/surgery, from the stimulus. Such stimuli could be due to
938 Dermatol Ther (Heidelb) (2023) 13:935–950

[1, 2, 13, 20–22]. However, compression therapy

often fails because of the gradual loss of elas-
ticity of the device or as a result of patient
nonadherence with a treatment plan [1, 23]. It
has been reported that only 50–60% of patients
with SD adhere to compression therapy [24].
Skincare treatments such as bland emollients
are often used to alleviate the secondary skin
changes associated with SD, including scaliness
and pruritus [2]. High- or mid-potency topical
corticosteroids can be intermittently used to
reduce pruritus and inflammation in SD. The
prolonged use of corticosteroids should be
avoided because they may lead to cutaneous
Fig. 1 Venous ulcers located over the medial malleolus.
Note the presence of hyperpigmentation. Reprinted with atrophy and systemic side effects, potentially
permission from Ref. [68], with permission from Isabel C. increasing the risk of ulcer formation [1, 25–28].
Valencia et al., 2001, Chronic venous insufficiency and Topical calcineurin inhibitors can also be used
venous leg ulceration for the management of SD; however, their use
has been associated with burning upon appli-
cation and requires patient awareness of
a chronic inflammation from SD, contact der- potential and theoretical long-term complica-
matitis, or infections [1]. tions (e.g., increased risk of elevated serum
An improved understanding of the patho- creatinine, hyperlipidemia, malignancy, and
genesis of SD could help in the development diabetes mellitus) [25–27, 29–32]. Venous
and utilization of more targeted and efficacious interventions are also available to treat the
treatments. Accordingly, this review summa- underlying venous reflux. Interventional radi-
rizes the pathogenesis and role of inflammation ology and surgical interventions may lead to the
in SD. The PubMed literature search focused on resolution of SD. However, the recurrence of
keywords related to the inflammation associ- SD-related complications remains a problem
ated with SD, including stasis dermatitis, vari- regardless of the treatment used [1, 33]. There is
cose ulcers, venous stasis ulcers, stasis ulcers, therefore a need for novel therapies that can
venous ulcers, venous hypertension, varicose elicit anti-inflammatory effects and target the
veins, venous eczema, venous stasis dermatitis, cutaneous manifestations of SD with optimized
collagenases, dermatitis, inflammation, matrix risk–benefit profiles. However, research regard-
metalloproteinases, and venous insufficiency. ing novel treatment options for SD is lacking
When indicated, venous intervention may [2]. Nevertheless, because inflammation plays a
remediate the underlying venous reflux associ- vital role in SD pathogenesis, several novel
ated with SD. When interventions are not fea- therapies that target inflammatory pathways
sible or fail, multiple long-term pharmaceutical could be promising. Such therapies include
and medical device options are available to treat Janus kinase (JAK) inhibitors, phosphodi-
the various dermatological symptoms associ- esterase 4 (PDE4) inhibitors, and immunosup-
ated with SD [1]. Non-invasive therapeutic pressive therapies. A number of
approaches include leg elevation and walking immunosuppressive therapies with anti-
[1]; however, such treatments were only shown inflammatory properties, including azathio-
to improve mild cases [2]. The initial treatment prine, cyclosporin, and mycophenolate mofetil,
recommendation for SD is compression therapy could also be potentially utilized in the treat-
in the form of compression bandages or stock- ment of SD [34–36]. Topical PDE4 inhibitors,
ings, which exert pressure to reduce ambulatory such as crisaborole, could target the inflamma-
venous pressures, alleviating SD symptoms such tion observed in SD while reducing unwanted
as swelling and stasis skin changes side effects that are associated with systemic
Dermatol Ther (Heidelb) (2023) 13:935–950 939

treatments [25]. Studies regarding the evalua- blood flow is induced by incompetent venous
tion of JAK inhibitors targeting receptor-associ- valves and venous flow obstruction as part of
ated kinases, such as delgocitinib, are also calf muscle pump failure at the lower extremi-
anticipated for SD [34]. ties [2, 40]. Such venous reflux can occur at the
This article is based on previously conducted superficial venous system, the deep venous
studies and scientific literature and does not system, or both [40]. When valve failure occurs
contain any new studies with human partici- at the superficial and perforating veins, venous
pants or animals performed by any of the pressure in the veins and venules of the skin
authors. No ethics approval was necessary for and subcutaneous tissues remains high during
this review. ambulation, whereas it typically diminishes in
Prompt treatment and diagnosis of SD could normal legs. Increased venous pressure may
ameliorate potential future complications, such lead to the reversal of blood flow. Sustained
as ulcers [2]. General practitioners may not elevated venous pressure leads to the margina-
recognize the severity of venous disorders such tion and extravasation of cells from the blood
as SD and thereby may not refer their patients vessels and into the surrounding tissues. Such
to the appropriate specialists. Overall, the blood flow patterns lead to the restructuring of
misdiagnosis of SD is partially due to the lack of the superficial veins and venules, which are less
dermatology services in healthcare settings supported from a mechanical perspective than
[37, 38]. However, dermatologic consultation is deep veins. Associated alterations include valve
often not considered by inpatient providers cusp perforation, elongation, tearing, and dis-
when treating patients with lower extremity appearance [41]. In one study that included
inflammation. The introduction of educational patients with venous disease, primary valvular
campaigns regarding SD for general practition- incompetence was found in approximately
ers could promote the development of ‘‘cham- 70–80% of cases; such valvular incompetence
pions of care’’ in healthcare settings who are was due to trauma or deep vein thrombosis in
able to promptly initiate the appropriate diag- 18–25% of cases [40].
nosis and treatment of the disease. One study Venous hypertension is associated with ele-
found that the average patient with SD was seen vated and unstable venous pressure values; such
by about 6.9 doctors throughout the course of venous pressure is mainly driven by two com-
their treatment. However, the high number of ponents: a hydrostatic and a hydrodynamic
consulted physicians in SD was mainly due to component. The hydrostatic component is
the patients’ lack of adherence to treatment determined by the weight of the blood in the
[38]. Accordingly, highlighting the importance venous system, whereas the hydrodynamic
of treatment adherence to patients could also component is determined by the pressure gen-
improve disease outcome in SD. erated by leg skeletal muscle contractions and
the pressure in the capillary network. While a
person is standing, the hydrostatic component
PATHOGENESIS OF STASIS and the capillary flow determine the venous
DERMATITIS pressure in the legs, reaching values of 80–-
90 mmHg. During ambulation, skeletal muscle
Venous Hypertension contractions increase the pressure observed in
the deep leg veins, causing venous blood to
SD is a cutaneous manifestation of venous return to the heart under normal physiologic
hypertension that is the result of underlying conditions. Accordingly, competent venous
chronic venous insufficiency [1, 2]. Chronic valves ensure the blood’s flow towards the
venous insufficiency of the lower extremities heart, reducing venous pressure in the legs by
ranges from asymptomatic to severely symp- emptying the superficial and deep venous sys-
tomatic [39]. Chronic venous insufficiency has tems and, hence, lowering the local venous
been clinically linked to sustained ambulatory pressure to less than 30 mmHg [2, 40, 41]. In the
venous pressures, whereby retrograde venous absence of competent valves, the reduction in
940 Dermatol Ther (Heidelb) (2023) 13:935–950

the venous pressure at the lower extremities cells, has been replaced by the understanding
that is brought upon by leg movement is that inflammation plays a key role in the
attenuated. If the perforator venous valves of observed cutaneous changes. Indeed, chronic
the deep venous system are incompetent, inflammation represents the most likely link
increased venous pressure is observed during between venous hypertension and cutaneous
standing as well as during calf muscle contrac- changes, as suggested by the correlation
tions, which leads to the reflux of blood into the between such hypertension and inflammation
superficial venous system and into the micro- [2, 40]. A major driver in the progression of
circulation in the skin. This results in an overall uncontrolled inflammation in chronic venous
and continuous high-pressure system. Accord- insufficiency is the extravasation of leukocytes
ingly, the vessel walls of the superficial and deep across the vascular endothelium. Such extra-
venous systems are distorted, leading to a vasated leukocytes infiltrate nearby tissues,
chronic cycle of worsening valvular incompe- secrete high levels of inflammatory mediators,
tence and venous hypertension [1, 40]. Chronic and recruit inflammatory cells, thereby perpet-
elevation of venous pressure is linked to uating the inflammatory response. Moreover,
inflammatory reactions in the venous valves, high venous pressure due to venous hyperten-
eventually leading to venous reflux and dys- sion promotes the local accumulation of
function as well as the elevation of upstream inflammatory cells, such as macrophages and
venous pressure [41]. Impaired venous valves T cells [2, 44]. Thomas et al. [45] found that
limit the return of blood to the heart, which leukocytes repeatedly accumulate in the
leads to backward venous flow, venous hyper- microcirculation and perivascular space of
tension, and venous stasis [2]. In one study that extremities with venous hypertension. Such
included 360 patients with SD, it was demon- leukocyte trapping is commonly seen during
strated that increases in ambulatory venous the earlier stages of chronic venous insuffi-
pressure are associated with severe skin damage, ciency, particularly in cases of SD [43]. A parallel
including ulceration [42]. In another study of study that examined the lower extremities of
patients that had negative patch testing and patients with chronic venous insufficiency
negative deep venous insufficiency, venous found that leukocytes and membrane adhesion
hypertension was found to be the most proba- molecules were more common on proximal
ble cause of SD, thus demonstrating that venous venous valve surfaces and venous walls than on
hypertension alone can cause SD in the lower distal venous regions. Chronic venous reflux is
extremities [2, 43]. In the same study, successful associated with increases in leukocyte–
classical vein surgery that targeted superficial endothelial cell interactions as well as an
venous reflux, including saphenectomy of increase in the number of activated leukocytes.
incompetent superficial vein segments and Unsteady stress alterations on the vein walls as
ligation of proximal point of reflux, led to the well as venous distensions may lead to the
complete resolution of SD symptoms in treated activation of polymorphonuclear cells, macro-
patients. Here, the lower leg dermatitis healed phages, and endothelial cells [41]. Indeed,
rapidly, completely, and without recurrence for increased numbers of macrophages, mast cells,
an observation period of 1 year [43]. and T lymphocytes were observed in the skin
biopsies of lower extremities in individuals with
Stasis Dermatitis is an Inflammatory chronic venous insufficiency [46]. As a result,
Disease leukocytes become attached to the endothelium
of the vein walls and valve leaflets, leading to
Leukocytes and Cell Adhesion Molecules the necrosis and/or apoptosis of the endothe-
The initial theory that the cutaneous changes in lium, fibroblasts, smooth muscle cells, and the
SD were driven by fibrin cuffs encasing dermal parenchymal cells of the venous wall. These
capillaries, thereby impeding the diffusion of changes may promote weakening and destruc-
oxygen from the vasculature and into epidermal tion of the venous wall structures and valve
leaflets, resulting in the clinically observable
Dermatol Ther (Heidelb) (2023) 13:935–950 941

venous changes [41]. The trophic skin changes during the early stages of chronic venous
seen in patients with venous hypertension may insufficiency, including SD, and remain upreg-
be due to the repeated accumulation of leuko- ulated throughout latter stages (Fig. 2) [42, 43].
cytes in the microcirculation and the perivas- The highly expressed CAMs potentially pro-
cular space [45]. Studies have shown that blood mote skin tissue damage via the facilitation of
of the lower extremities in individuals with an upregulated and perpetuated influx of acti-
chronic venous disease is low in leukocytes, vated leukocytes into the inflammatory sites
which suggests that leukocytes accumulate in [49]. Indeed, the aforementioned CAMs were
regions of high venous pressure, leading to an found to be highly expressed on tissue-invading
inflammatory response [45–47]. Sustained high leukocytes and vascular endothelium at the
venous pressure also promotes the extravasa- edges of leg ulcers [50]. Such inflammatory
tion of erythrocytes at the affected regions changes lead to the release of several mediators,
[2, 44]. The extravasation of the erythrocytes is such as proteolytic enzymes, including collage-
followed by the decomposition of hemoglobin, nase and elastase, chemotactic factors, free
resulting in the excessive buildup of iron, which radicals, and cytokines, which leads to an
is stored at the affected tissue as hemosiderin increase in vascular permeability [51].
and causes local hyperpigmentation. Further
macrophage accumulation is induced by the Matrix Metalloproteinases
buildup of the hemoglobin and hemosiderin; Matrix metalloproteinases (MMPs) are prote-
such macrophages alongside other cells pro- olytic enzymes that are associated with vascular
mote inflammation (especially the accumula- disease and cardiovascular remodeling, as well
tion of inflammatory macrophages) and induce as the turnover of elastin, collagen, and other
the various histological features associated with proteins of the extracellular matrix. The results
SD, including vascular proliferation and epi- of studies regarding ulcer fluid environments
dermal spongiotic changes [44, 48]. The suggest a potential association between the
observed inflammatory response leads to local activity of MMPs and the development of
tissue damage [49]. venous leg ulcers and skin lesions. Imbalances
The invasion of tissues by inflammatory cells between the expression and activity of MMPs
is dependent on the transmigration of cells and endogenous tissue inhibitors of MMPs
across the microvascular endothelium. This (TIMPs) may cause pathological alterations of
complex process of transmigration is mediated the vein walls and valves, leading to the symp-
by cell adhesion molecules (CAMs). CAMs are toms associated with chronic venous diseases.
expressed on the microvascular endothelial Increases in venous hydrostatic pressure may
cells, whereas their receptors are found on the lead to endothelial cell injury and increased
surface of leukocytes. The adhesion of leuko- cellular permeability, resulting in the infiltra-
cytes onto the endothelium is a multistep pro- tion of leukocytes and vascular inflammation
cess [1, 2, 42]. The first step is the reversible into the surrounding dermis. This then leads to
binding of the endothelial cell selectin mole- loss of wall integrity, tissue fibrosis, valve
cules, such as P-selectin and E-selectin, onto the degradation, and vein damage that is charac-
sialyl Lewis X ligands on leukocytes. Leukocytes teristic of the late stages of chronic venous
then firmly adhere onto the endothelial cells, insufficiency [52].
which is required for the transmigration of Activated endothelial and inflammatory cells
leukocytes onto nearby tissues. This adhesion is can degrade components of the extracellular
mediated by intercellular adhesion molecule 1 matrix, including collagen, elastin, laminin,
(ICAM-1) and vascular cell adhesion molecule 1 and fibronectin, through the release of oxygen
(VCAM-1), found on endothelial cells, and their free radicals and MMPs [42, 53]. Several MMPs
ligands lymphocyte function-associated anti- were linked to the degradation of structure-
gen 1 (LFA-1) and very late antigen 4 (VLA-4), maintaining collagen macromolecules, with
which are found on leukocytes. ICAM-1, MMP-1, -2, and -13 degrading type I, IV, and V
VCAM-1, LFA-1, and VLA-4 are upregulated collagens as well as elastin. These MMPs are
942 Dermatol Ther (Heidelb) (2023) 13:935–950
 Dermatol Ther (Heidelb) (2023) 13:935–950 943

b Fig. 2 ICAM-1, VCAM-1, LFA-1, and VLA-4 are MMPs are associated with the degradation of
upregulated in stasis dermatitis and remain upregulated extracellular matrix proteins, potentially lead-
in lipodermatosclerosis. Samples were obtained from ing to the remodeling of lesional skin and
healthy individuals (A–D), patients with stasis dermatitis impaired healing in SD [54]. MMP-1, -2, and -13
(E–H), and patients with lipodermatosclerosis (I–L). may induce a number of histological features
Cryosections of all skin samples were immunohistochem- observed in SD, including spongiosis, alteration
ically stained with monoclonal antibodies against ICAM-1, of papillary structures, and proliferation of
VCAM-1, LFA-1, and VLA-4. The bar indicates a length small blood vessels in the papillary dermis [2].
of 150 lm. Reprinted with permission from Ref. [34],
Alterations in MMP-2 activity, in conjunction
with permission from Acta Dermato-Venereologica. ICAM-
with events mediated via TGFb1 (such as the
1 intercellular adhesion molecule 1, VCAM-1 vascular cell
differentiation of fibroblasts into myofibrob-
adhesion molecule 1, LFA-1 lymphocyte function-associ-
lasts), were found to lead to the degradation of
ated antigen 1, VLA-4 very late antigen 4
epidermal basement membrane collagen and
the loss of epidermal integrity, creating an
environment that is susceptible to the forma-
secreted by inflammatory cells such as neu- tion of venous ulcers (Figs. 3, 4) [53].
trophils, eosinophils, and macrophages. MMP-
1, -2, and -13 are associated with the patho- Phosphodiesterase 4
genesis of several skin disorders, including basal PDE4 is a cyclic adenosine monophosphate
cell carcinoma, immune-bullous diseases, and (cAMP)-specific intracellular nonreceptor
granuloma annulare [2, 54]. Inflammatory cells enzyme that regulates various fundamental
influence the remodeling of the extracellular functions, including inflammatory responses, as
matrix by producing MMPs and by secreting well as epithelial and endothelial barrier stabil-
cytokines that induce MMP gene expression, ity [25, 56, 57]. Patients with inflammatory
including tumor necrosis factor-a, interleukin diseases show elevated levels and activity of
(IL)-1, and transforming growth factor-b1 PDE4 compared with healthy individuals. As
(TGFb1) [54]. The increased expression of MMPs has been shown in studies, the overexpression
and other proteinases by the vessel wall breaks and overactivity of PDE4 leads to increases in
down the vascular extracellular matrix, leading the production of inflammatory cytokines
to vascular permeability and edema [1]. Extra- (Fig. 5), causing skin inflammation and disease
vasated erythrocytes release ferritin and ferric exacerbation in patients with atopic dermatitis.
ion, which may result in oxidative stress and The inhibition of PDE4 elevates intracellular
the activation of additional MMPs; this process cAMP levels, thereby modulating the inflam-
delays healing via promoting skin tissue dam- matory response and maintaining the immune
age and ulcer formation [2, 40, 55]. Hyperpig- balance. Targeting PDE4 has been shown to be
mentation of the skin, which is observed in SD, an effective strategy for several inflammatory
is due to hemosiderin deposition from extra- conditions, including psoriasis, atopic dermati-
vasated erythrocytes, activation of MMPs, and tis, chronic obstructive pulmonary disease,
inflammatory mediators [1, 2]. The activity of asthma, inflammatory bowel diseases, rheuma-
MMPs is tightly regulated by their inhibitors, toid arthritis, lupus, and neuroinflammation
TIMPs, with alterations in the balance between [56]. Accordingly, the inhibition of PDE4 may
MMPs and TIMPs contributing to the patho- decrease the production of inflammatory
logical changes observed in venous diseases cytokines, thereby limiting associated skin
[52]. In one study, elevated levels of MMP-1, -2, inflammation and disease exacerbation in SD
and -13, as well as lower levels of TIMP-1 and -2, [58, 59]. Emerging therapies for the treatment
were present in the skin samples of patients of secondary skin changes associated with SD
with SD compared with healthy individuals. such as skin inflammation could involve the
Such overexpression of MMP-1, -2, and -13 application of nonsteroidal topical ointments,
without the inhibitory effects of TIMP-1 and -2 such as crisaborole. Crisaborole is a topical
may be due to cytokine-mediated induction. PDE4 inhibitor that has been approved for the
944 Dermatol Ther (Heidelb) (2023) 13:935–950

Fig. 3 The possible roles of MMPs and TGFb1 in the metalloproteinase, TGFb1 transforming growth factor-b1,
formation of venous ulcers. Reproduced from Ref. [38], TIMP-1 tissue inhibitor of metalloproteinase-1
with permission from Elsevier. MMP matrix

Fig. 4 Pathophysiology of stasis dermatitis. MMP matrix metalloproteinase

Dermatol Ther (Heidelb) (2023) 13:935–950 945

Fig. 5 The cAMP cascades involved in PDE4 inhibition. protein, Epac 1/2 exchange protein directly activated by
Reproduced from Ref. [48], with permission from MDPI cAMP 1 and 2, NF-jB nuclear factor kappa light chain
(Basel, Switzerland). 50 AMP 5-adenosine monophosphate, enhancer of activated B cells, PDE4 phosphodiesterase 4,
AC adenylyl cyclase, ATF-1 cAMP-dependent activating PDE4-I phosphodiesterase 4 inhibitor, PKA protein
transcription factor 1, ATP adenosine triphosphate, Bcl-6 kinase A, Popeye Popeye domain family, Rac1 Ras-related
B cell lymphoma 6 protein, cAMP 30 ,50 -cyclic adenosine C3 botulinum toxin substrate 1, Rap 1 Ras-related
monophosphate, CREB cAMP response element binding protein 1, RhoA Ras homolog family member A

treatment of mild-to-moderate AD in multiple associated with exacerbating pruritus in various

countries and was recently investigated in a diseases, including psoriasis, atopic dermatitis,
phase 2 study for SD treatment (NCT04091087) prurigo nodularis, and cutaneous T-cell lym-
[60, 61]. phoma [63–65]. Increased IL-31 expression is
found in the skin of patients with atopic der-
Interleukin-31 matitis, prompting the release of inflammatory
Patients with SD often report having pruritus, mediators and lowering the expression of
which impairs quality of life and induces fur- molecules associated with maintaining the skin
ther cutaneous irritation and breakdown due to barrier [66]. The correlation between pruritus
excessive scratching [1, 44]. Indeed, SD was the and IL-31 was highlighted in a study in which
most frequently reported type of dermatitis to serum levels of IL-31 were found to be signifi-
cause itch complaints in one study involving cantly higher in patients with chronic pruritus
older adults [62]. Constant scratching aggra- of unknown origin compared with those in
vates wounds and increases the chances of healthy individuals [67].
developing skin infections; it may also result in A recent study has implicated dermal IL-31
skin thickening and lichenification [1, 44]. The from macrophages in inducing itch in SD [44].
pathogenesis of SD-linked pruritus is incom- The majority of IL-31-expressing cells in SD are
pletely understood; however, it is likely non- CD68? macrophages. The number of
histaminergic because it is not remediated by IL-31?CD68? macrophages is significantly
use of antihistamines. Nonhistaminergic itch higher in patients with SD with severe pruritus
involves several itch mediators, such as cytoki- compared with those with SD without severe
nes/chemokines (e.g., IL-31), proteases and pruritus. These CD68? macrophages, which also
their receptors, amines, neuropeptides and their coexpress CD163 (a macrophage-specific mem-
receptors (e.g., substance P and its receptor brane marker), are classified as M2 macrophages
neurokinin-1 receptor), ion channels, and (Fig. 6) [66]. The number of IL-31?CD68? mac-
immune cells (e.g., mast cells, T cells, eosino- rophages is positively correlated with the
phils, and basophils) [44]. IL-31 is a T-helper number of dermal C–C chemokine receptor
type (Th)2-related pruritogenic cytokine that type 4? Th2 cells, basophils, and substance P?
has recently been implicated as a potential tar- cells, as well as dermal deposition of hemosi-
get for skin conditions involving itch. IL-31 is derin and periostin. Moreover, the number of
946 Dermatol Ther (Heidelb) (2023) 13:935–950

Fig. 6 CD68? macrophages express IL-31 and are CD68?/CD163? cells was greater in SD lesions and
correlated with pruritus in SD. Images of healthy skin correlated with pruritus. *P \ 0.05 (unpaired t test).
and SD lesions with the quantification of staining are Vertical bars indicate standard deviation. Dotted lines
shown. a Epidermal expression of IL-31 was not higher in indicate the dermo-epidermal junction. The bar indicates
SD lesions. The number of CD68? macrophages and IL- 100 lm. Reproduced from Ref. [29], with permission from
31? cells was greater in SD lesions. b Most IL31? cells Elsevier. AU arbitrary unit, CD cluster of differentiation,
expressed CD68. The number of CD68?/IL31? cells was DAPI 40 ,6-diamidino-2-phenylindole, IL-31 interleukin-
greater in SD lesions and was correlated with pruritus. c In 31, NS not significant, SD stasis dermatitis, w/ with, w/o
SD with severe pruritus, CD68? macrophages expressed without
CD163 (an M2 macrophage marker). The number of

IL-17? cells is also higher in SD lesions, which is promotes M2 macrophage skewing, with M2
consistent with Th17 immunity predominating macrophages promoting Th17 cell expansion
in SD. The number of IL-17? cells is correlated [44].
with the number of IL-31?CD68? cells but not
with the presence of pruritus. IL-17 likely
Dermatol Ther (Heidelb) (2023) 13:935–950 947

CONCLUSIONS Robert Scott Kirsner, Roni Adiri, Gary Friedman,

Xinghua Gao, Steven D. Billings, Urs
SD is a cutaneous manifestation of venous Kerkmann.
hypertension that is commonly seen in older
patients with underlying venous insufficiency, Disclosures. Jonathan Silverberg served as
wherein retrograde venous blood flow is an investigator for Celgene, Eli Lilly and Com-
induced by incompetent venous valves, venous pany, F. Hoffmann-LaRoche, Menlo Therapeu-
flow obstruction, or muscle pump failure at the tics, Realm Therapeutics, Regeneron, and
lower extremities. Treatments for SD focus pri- Sanofi; as a consultant for Pfizer Inc., AbbVie,
marily on identifying and eliminating primary Anacor, AnaptysBio, Arena Pharmaceuticals,
causes of venous hypertension and insufficiency Dermavant, Dermira, Eli Lilly and Company,
when feasible and, secondarily, on manage- Galderma, GlaxoSmithKline, Glenmark, Incyte,
ment of associated skin changes as well as Kiniksa Pharmaceuticals, LEO Pharma, Menlo
preventing potential complications. Under- Therapeutics, Novartis, Realm Therapeutics,
standing the pathogenesis of SD may help Regeneron, and Sanofi; and as a speaker for
clinicians effectively diagnose and treat SD. Regeneron and Sanofi. J. Mark Jackson has
Several of the highlighted biomarkers of received research, honoraria, consulting or
inflammation represent potential opportunities speaking fees from AbbVie, Arcutis, Dermavant,
to individually or jointly interrupt molecular Evommune, Janssen, Lilly, Novartis, Pfizer Inc.,
pathways which sustain cutaneous inflamma- and UCB. Robert S. Kirsner served as a consul-
tion and, therefore, remediate the signs and tant for Pfizer Inc. Roni Adiri is an employee
symptoms of SD that diminish quality of life in and shareholder of Pfizer Pharmaceuticals Israel
patients with SD. Ltd. Gary Friedman is an employee and share-
holder of Pfizer Inc. Urs Kerkmann is an
employee and shareholder of Pfizer Pharma
GmbH. Xing-Hua Gao reports the following:
ACKNOWLEDGEMENTS personal fees from Novartis, Pfizer, Astellas,
Meda Pharma S.p.A., a Viatris company, Sanofi,
Lilly, Bayer, LEO, GSK, Pierre Fabre, and Jans-
Funding. This review, as well as the journal’s
sen, outside the submitted work. Steven D.
Rapid Service Fee, was funded by Pfizer Inc.,
Billings reports no relevant disclosures.
New York, NY, USA.
Compliance with Ethics Guidelines. This
Medical Writing and Editorial Assis-
article is based on previously conducted studies
tance. Editorial/medical writing support under
and scientific literature and does not contain
the guidance of authors was provided by Mark
any new studies with human participants or
Bloom, PhD, at ApotheCom, Yardley, PA, USA,
animals performed by any of the authors. No
and was funded by Pfizer Inc., New York, NY,
ethics approval was necessary for this review.
USA, in accordance with Good Publication
Practice (GPP 2022) guidelines (Ann Intern Med. Data Availability. Data sharing is not
2022; https://doi.org/10.7326/M22-1460). applicable to this article as no data sets were
generated or analyzed during the current study.
Authorship. All named authors meet the
International Committee of Medical Journal Open Access. This article is licensed under a
Editors (ICMJE) criteria for authorship for this Creative Commons Attribution-Non-
article, take responsibility for the integrity of Commercial 4.0 International License, which
the work as a whole, and have given their permits any non-commercial use, sharing,
approval for this version to be published. adaptation, distribution and reproduction in
any medium or format, as long as you give
Author Contributions. Writing—review and
appropriate credit to the original author(s) and
editing: Jonathan Silverberg, J. Mark Jackson,
948 Dermatol Ther (Heidelb) (2023) 13:935–950

the source, provide a link to the Creative a diagnosis of stasis dermatitis referred for patch
Commons licence, and indicate if changes were testing, North American contact dermatitis group
data, 2001–2016. Arch Derm Res. 2022;314(9):
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