C u t a n e o u s S a rc o i d o s i s

Mariam Abdelghaffar, BHSca, Erica Hwang, BSb, William Damsky, MD, PhDb,c,*

KEYWORDS
 Cutaneous sarcoidosis  Erythema nodosum  Lupus pernio  Darier-Roussy  Angiolupoid

KEY POINTS
 About 20% to 35% of patients with sarcoidosis may show cutaneous involvement.
 Skin lesions of sarcoidosis may represent either specific skin involvement by sarcoidal granulomas
or nonspecific reactive lesions.
 Common specific skin lesions include lupus pernio, dermally based papules and plaques, and sub-
cutaneous nodules. The most widely recognized nonspecific cutaneous manifestation is erythema
nodosum.
 Cutaneous manifestations of sarcoidosis can have a significantly negative influence on patients’
quality of life, may lead to scarring and dyspigmentation, and may be a motivation for patients to
pursue treatment.
 Treatment strategy depends on the severity and distribution of skin lesions and should incorporate
patient preference and treatment considerations for other organs that may be involved.

INTRODUCTION BURDEN OF CUTANEOUS DISEASE

Sarcoidosis is a multisystem disease that most The burden of inflammatory skin diseases on quality
commonly affects the lungs, lymphatic system, of life (QoL) has been extensively documented.5–8
eyes, and skin but any organ may be involved. It This encompasses the psychological, social, and
has been estimated that 20% to 35% of patients emotional consequences of skin diseases on
with sarcoidosis have cutaneous involvement.1,2 patients’ health and wellness. Studies have demon-
Cutaneous sarcoidosis (CS) most commonly pre- strated that patients with skin diseases are more
sents as pink-red to red-brown papules and pla- likely to have depression, suffer from social isolation
ques (raised lesions) that commonly affect the or loneliness, and have a lower QoL.5–8 Further-
head and neck. However, CS is often referred to more, inflammation in cutaneous diseases such
as a great mimicker in dermatology, meaning as psoriasis can have direct consequences on
several other lesion morphologies are possible health by effects of chronic inflammation on the
and a high index of suspicion must be maintained. vasculature, thereby increasing cardiovascular
These varied cutaneous presentations will be risk. This concept is not as well studied in other in-
reviewed herein. Dermatologic evaluation can pro- flammatory skin diseases including CS, however,
vide strong evidence to support a suspected diag- and merits further investigation.9
nosis of sarcoidosis due to the skin being readily The consequences on QoL specific to CS have
accessible for assessment and biopsy.3,4 We will not been well described. Compared with other
also review disease immunopathogenesis and inflammatory skin disorders, CS more commonly in-
how this relates to current and emerging treatment volves the face, a particularly cosmetically sensitive
approaches. area. In addition to active inflammatory lesions, CS
chestmed.theclinics.com

a
School of Medicine, Royal College of Surgeons in Ireland, Smurfit Building, Beaumont Hospital, Dublin 9,
Ireland; b Department of Dermatology, Yale School of Medicine, 333 Cedar Street, LCI 501 PO Box 208059,
New Haven, CT 06520, USA; c Department of Pathology, Yale School of Medicine, 310 Cedar Street, LH 108,
PO Box 208023, New Haven, CT 06520, USA
* Corresponding author. Department of Dermatology, Yale School of Medicine, 333 Cedar St LCI 501 PO Box
208059, New Haven, CT.
E-mail address: william.damsky@yale.edu

Clin Chest Med 45 (2024) 71–89

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72 Abdelghaffar et al

may also result in postinflammatory dyspigmenta- initially had only cutaneous lesions later developed
tion (hyperpigmentation and/or hypopigmentation) systemic involvement, emphasizing the impor-
and scarring, especially in individuals with darker tance of ongoing screening.10
skin types (Fig. 1). This may be difficult or impos- Lesion morphology in sarcoidosis may vary but
sible for patients to conceal and may make things the most common presentation is of dermally based
like going out in public a challenge. In our experi- papules and plaques (raised lesions). Common and
ence, skin involvement may be the patient’s primary uncommon presentations of CS will be reviewed in
motivating factor for seeking treatment of their the following section. Hair and nails may also be
sarcoidosis. Yet, the effects of CS on QoL and affected, necessitating a comprehensive mucocu-
how they might be mitigated by successful treat- taneous examination when evaluating for CS
ment are not well documented in the medical litera- (Table 2). Classically, skin lesions of sarcoidosis
ture. In our experience, acknowledging how difficult have been divided into 2 categories: specific lesions
CS may be for patients and giving them the oppor- and nonspecific lesions. Specific lesions reveal
tunity to openly discuss its effects on their lives can noncaseating granulomas (the histologic hallmark
make patients feel heard and may improve compli- of sarcoidosis) when biopsied, whereas nonspecific
ance with treatment recommendations for their lesions are thought to be a reactive phenomenon,
sarcoidosis more generally. Shared decision- show different histopathology, and may be seen in
making around therapeutic selection and discus- settings other than sarcoidosis.1,2,11 The most
sing the likelihood it will help their CS is also key. commonly recognized nonspecific skin lesion is
erythema nodosum (EN; Table 3).1,11
CLINICAL PRESENTATION
Common Morphologies of Specific Cutaneous
The relationship between cutaneous and systemic Involvement
sarcoidosis is not well understood. Why some pa-
tients develop cutaneous involvement, whereas Papules
others do not is not fully clear. Although lupus per- A common cutaneous morphology in sarcoidosis is
nio and angiolupoid presentations (see later dis- papules, which are small, raised lesions less than
cussion, Table 1) may be associated with more 1 cm in diameter (Fig. 2).2 They are characterized
chronic disease, the severity of cutaneous involve- as having a pink-red to red-brown color. Erythema
ment in general does not usually correlate with the may be more difficult to appreciate in patients with
severity or extent of extracutaneous disease. In darker skin tones. As a dermally based inflamma-
fact, most patients with severe systemic sarcoid- tory process, classic sarcoidosis lesions do not
osis have no skin involvement at all. have scale, which reflects epidermal inflammation
In some patients, skin involvement may be the when present. However, in clinical practice, lesions
presenting sign of disease. In other patients, cuta- may have some scale and so its presence does not
neous involvement may develop synchronously necessarily exclude sarcoidosis (Fig. 3). Papule-
with or after internal organ involvement. The eval- predominant morphology has been described as
uation and monitoring of patients with CS is out- more common in self-resolving presentations of
lined in Box 1. A study by Mana and colleagues sarcoidosis.12,13 Lesions may be present on the-
noted that approximately 30% of patients who face (often peri-orificial), neck, extremities, and/or
trunk. Papular sarcoidosis may resolve without
scarring.

Plaques
Plaques are larger raised lesions that are 1 cm or
larger in diameter. They commonly co-occur with
papules and are thought to be similar pathophy-
siologically. These lesions may commonly involve
the face, trunk, extensor surfaces of the arms,
scalp, and/or extremities; however, any area of
the skin may be involved.2,14,15 Sarcoidosis pla-
ques (and papules) are frequently but not always
annular with raised, prominent edges (see
Fig. 3).14 Plaques, therefore, may be associated
Fig. 1. Atrophic scarring and dyspigmentation in a with chronic presentations of this disease and
Black woman with sarcoidosis. Dyspigmentation often resolve with scarring and/or hyperpigmenta-
refers to areas of both hyperpigmentation and tion.2 It is important to note that these secondary
hypopigmentation. changes may be equally bothersome to the patient

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 Cutaneous Sarcoidosis 73

Table 1
Commonly used sarcoidosis terms and definitions

Term Definition
Lofgren syndrome Lofgren syndrome presents with hilar lymphadenopathy, arthritis,
fever, and erythema nodosum.15,34 This syndrome is generally
considered an acute form of sarcoidosis with an excellent prognosis.
It is most common in Scandinavian countries
Melkersson-Rosenthal “Classic” Melkerson-Rosenthal presents with a triad of orofacial
syndrome swelling, facial weakness, and fissured tongue.33 However, most
patients do not have the full triad. Granulomatous cheilitis may be
used to describe swelling of lips in this setting and may be the only
sign present. Orofacial granulomatosis may be a more useful,
encompassing term. This constellation of symptoms may be seen in
the setting of sarcoidosis, Crohn disease, or may be idiopathic
Blau syndrome Blau syndrome classically presents with a triad of CS, arthritis, and
uveitis in young children.37 Also known as early-onset sarcoidosis,
this is caused by germline NOD2 mutation and is inherited in an
autosomal dominant fashion
Angiolupoid sarcoidosis Angiolupoid sarcoidosis refers to lesions of sarcoidosis that have
prominent overlying telangiectasia. This is most common on the
nose and central face in patients with lighter skin tones and is seen in
the setting of chronic disease26,27
Heerfordt-Waldenström A very rare presentation of sarcoidosis that shows parotid gland
syndrome enlargement, anterior uveitis, fever, and facial palsy.89,90 All features
may not be present, and these findings are not specific to
sarcoidosis. Signs of CS may also be present on examination and help
with the diagnosis
Darier-Roussy sarcoidosis Refers to specific involvement of the subcutaneous fat by sarcoidal
granulomas (see Table 3)14,15
Lupus pernio The most precise and preferred definition refers to papules of
sarcoidosis along the alar rims and/or columella of the nose. Lupus
pernio is associated with upper airway involvement. A less-specific
usage of this term in the literature is to refer to sarcoidosis of any
part of the central face
Miescher granuloma This histologic feature may be seen in erythema nodosum. It refers to
radially configured aggregates of histiocytes around a central cleft
and is typically present in inflamed septae of the subcutaneous fat,
when present.91 It should not be confused for the granulomas of
sarcoidosis
Schaumann bodies Although this histologic finding may be seen in sarcoidosis, it is neither
specific to sarcoidosis nor required for diagnosis. Schaumann bodies
are intracytoplasmic inclusions typically found within
multinucleated giant cells. They appear as concentric laminated
calcifications (purple on hematoxylin and eosin stain)40,41
Asteroid bodies Although this histologic finding may be seen in sarcoidosis, it is neither
specific to sarcoidosis nor required for diagnosis. Asteroid bodies are
intracytoplasmic inclusions typically found within multinucleated
giant cells. They appear as star-like bodies and are pink in color on
hematoxylin and eosin40,41

as the inflammatory lesions themselves, particu- Although ultimately a misnomer because there is
larly pigmentation changes in individuals with no direct relationship to lupus, this nomenclature
darker skin tones. has persisted. Lupus pernio refers to papules along
the alar rims and/or columella of the nose
Lupus pernio (Fig. 4).2,15 Similarly to papules in other areas of
In 1889, Ernest Besnier was the first to describe CS the skin, lesions are often pink-red in color in pa-
in a patient with what was called “lupus pernio.”2 tients with lighter skin tones and more brown in

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74 Abdelghaffar et al

Box 1
Initial evaluation and monitoring recommendations for patients with cutaneous sarcoidosis without
known sarcoidosis in other organs

Evaluation of patients with a new diagnosis of CS for systemic involvement

History
 Including occupational/environmental exposures
 Comprehensive ROS
Physical examination
Pulmonary evaluation
 At least a screening chest radiographa
 Pulmonary function testsb
 Referral to pulmonology
Cardiac evaluation
 At least a screening EKG
 If ROS positive for history of presyncope, syncope, episodic dizziness, or palpitations urgent referral to
cardiology is mandatory
Ophthalmologic evaluation
 Consider ophthalmology referralc
Other organs
 Consider referral to other specialists depending on ROS and laboratory workup
 Communicate with the primary care provider
Laboratory testing
 Complete blood count
 Comprehensive metabolic panel (liver function tests and basic metabolic panel)
 QuantiFERON
 Thyroid stimulating hormone level
 Vitamin D: 25-hydroxyvitamin D, 1,25-hydroxyvitamin D
 Disease biomarker (soluble IL-2R [CD25]d level and/or ACE level)
Monitoring of patients with known CS for progression to systemic involvement
 Annual complete physical examination, ROSe
 Annual complete blood count (CBC) and comprehensive metabolic panele,f,g
 Consider rechecking disease biomarker if change in symptoms
 Consider re-referral to specialist (or discuss with PCP) if change in symptoms
a
If positive pulmonary ROS (case-by-case basis) consider starting with high-resolution chest CT
b
We typically will refer to pulmonology to perform and interpret this testing
c
Some experts recommend referrals for all patients with CS, others on a case-by-case basis depending on
ROS. Referral for baseline examination in patients embarking on hydroxychloroquine therapy in partic-
ular, regardless of ROS, is likely judicious.
d
Although not elevated in all patients with CS/sarcoidosis we find this useful for following disease ac-
tivity and response of systemic disease to therapy
e
Therapeutics may require more frequent follow-up and laboratory evaluation
f
Further diagnostic workup guided by physical examination and ROS
g
Consider annual EKG
Abbreviations: ROS, review of systems, EKG, electrocardiogram.

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 Cutaneous Sarcoidosis 75

Table 2
Elements of a comprehensive mucocutaneous examination in patients with diagnosed or suspected
cutaneous sarcoidosis

Site Example of Clinical Features

Hair Sarcoid alopecia is an inflammatory and scarring process. Look for
inflammatory papules, papules, and/or nodules with overlying loss of hair
(and eventually the follicular ostea (or openings) will disappear). This
typically occurs in a patchy, asymmetric as opposed to diffuse, symmetric
pattern
Face Nose: look for papules along the alar rims and/or columella of the nose (lupus
pernio)
Eyes: lacrimal gland hypertrophy may be present and helps support the
clinical impression of sarcoidosis
Tear trough and nasofacial sulcus: sarcoidosis lesions in these areas may be
associated with ocular involvement
Neurologic: assess for facial asymmetry (Melkersson-Rosenthal and
Heerfordt-Waldenström syndromes)
Oropharynx Oral manifestations are nonspecific but may include fissured tongue,
orolabial swelling, or mucosal cobblestoning
Complete cutaneous Be sure to look everywhere as CS lesions may be very localized. For example,
examination they rarely may be limited to the genitalia
Tattoos Visually inspect and palpate tattoos for papules and subcutaneous nodules.
If present, biopsy may be required to establish the diagnosis. Specific ink
colors such as red and yellow may be preferentially involved with visible
papules
Scars Visually inspect and palpate scars for papules and subcutaneous nodules. If
present, biopsy may be required to establish the diagnosis
Digits and nails Nail alterations seen in sarcoidosis include nail plate dystrophy. Dactylitis may
or may not be present. Distal digital involvement is associated with
underlying bony abnormalities. Evaluate for digital clubbing

patients with darker skin tones. A deep violaceous airway involvement with sarcoidosis.16 Patients
color may sometimes develop and is evocative of presenting with lupus pernio frequently have
the original “pernio” nomenclature. Patients with involvement of other areas on their face and tend
lupus pernio have a higher likelihood of upper toward more chronic disease. Facial involvement,

Table 3
Features that may help distinguish erythema nodosum and subcutaneous sarcoidosis

Erythema Nodosum (non-specific) Subcutaneous Sarcoidosis (specific)

Color Pink-red Flesh colored to light pink
Symptoms Painful, tender Usually painless, nontender
Size Larger lesions common, May have mix of small and
lesions <1 cm uncommon large lesions
Number of lesions May be relatively few May be numerous
Motility and demarcation Nonmobile, poorly demarcated May be mobile, may be
sharply demarcated
Distribution Symmetrically on anterior shins Extremities (most commonly the
arms) and sometimes trunk,
may be asymmetric, can occur
anywhere on skin
Histologic findings Septal panniculitis and may have Epithelioid granulomas within
focal granuloma formation subcutaneous fat  deep
(Meischer granuloma) dermis
Diagnostic of sarcoidosis No Yes

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76 Abdelghaffar et al

Fig. 2. Papules of sarcoidosis in a Black patient (A) and White patient (B). In B, some papules coalesce into small
plaques. (William D. James, Dirk Elston, James R. Treat, Misha A. Rosenbach. Andrews’ Diseases of the Skin. Edi-
tion 13, Figure 31.9; Elsevier 2019.)

specifically lupus pernio, has the potential for a summarized in Table 4 but ultimately evaluation
devastating impact on patients’ QoL; however, by an experienced dermatologist and a sufficiently
studies quantifying these effects have not been deep biopsy are often required. Whereas subcu-
performed and are needed.17 taneous sarcoidosis shows epithelioid granulomas
in the subcutaneous fat on histopathologic exam-
Subcutaneous sarcoidosis ination, EN instead shows septal predominant
Subcutaneous sarcoidosis, sometimes referred to panniculitis. The septal panniculitis in EN may be
as the Darier-Roussy subtype (see Table 1), typi- focally granulomatous in nature but this so-called
cally presents as subcutaneous nodules. Compared Miescher’s granuloma (see Table 1) of EN should
with the papules and plaques of sarcoidosis, nod- not be confused with sarcoidosis.
ules of subcutaneous sarcoidosis may have less
well-defined borders because the granulomatous Scar and tattoo sarcoidosis
inflammation is located deeper in the skin. For this CS is also known to exhibit tropism to tattoos and/
reason, inflammation may be less clinically apparent or scars. Involvement of tattoos is well docu-
(light pink to flesh-colored) (Fig. 5). Patients may or mented and was first reported in 1939.18 Specific
may not have more typical papules and plaques in ink colors, especially red and yellow, may be pref-
addition.14,15 Histologic evaluation of subcutaneous erentially involved and present as induration and/
lesions shows sarcoid granulomas based in the or visible papules (Fig. 6).19,20
subcutaneous fat (and may also involve the deep Scars involved by sarcoidosis may appear
dermis). erythematous and/or indurated (Fig. 7).17,21,22 Pa-
Subcutaneous sarcoidosis on the anterior lower tients presenting with concern for sarcoidosis
legs may be confused with EN. Clinical features should have their scars and tattoos examined
that may help distinguish between the 2 are (see Table 2). It is also important to consider the

Fig. 3. Plaque of sarcoidosis in a Black patient (A) and White patient (B). Annular lesions with a raised border are
common in sarcoidosis (as in A). Some scale may be present and does not exclude the possibility of CS (as in B).

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 Cutaneous Sarcoidosis 77

Involvement of the underlying bones is not uncom-

mon in this setting.23,24 Radiologically, sarcoidosis
dactylitis is characterized by trabecular changes
with a honeycomb appearance.24,25 Sarcoid dac-
tylitis is generally quite resistant to treatment and
is mostly seen with chronic forms of sarcoidosis.
Dystrophy of the nail plate may or may not be pre-
sent (see later discussion).

Angiolupoid Sarcoidosis
Angiolupoid sarcoidosis is also a less common
manifestation of the disease and typically affects
patients with lighter skin tones.26 Angiolupoid re-
fers to the involvement of the nose and central
face with prominent telangiectasia developing
over the inflammatory lesions (Fig. 9).26,27 Angiolu-
poid sarcoidosis is often seen in the setting of
chronic disease. The mechanism by which telangi-
ectasias form in this variant is unclear; however,
Fig. 4. Lupus pernio in a Black patient (A) and White one hypothesis involves the production of vascular
patient (B). Although inflammation is dermally based, endothelial growth factor and other angiogenic
slight scale may be present (as in B). (Jean Bolognia, factors by activated macrophages.28
Julie Schaffer, Karynne Duncan, Christine Ko. Derma-
tology Essentials. Edition 2, Figure e78.2; Elsevier
2021.) Other Uncommon Morphologies and Special
Sites

possibility of systemic involvement of sarcoidosis Several other cutaneous morphologies have been
even in patients presenting with cutaneous described in CS. These include hypopigmented,
involvement limited to scars and/or tattoos (see verrucous, ichthyosiform, psoriasiform, and ulcer-
Box 1).17,21,22 ative; however, they are fairly rare and will not be
discussed further other than to state that in order
to diagnose one of these other morphologies, a
Sarcoidal Dactylitis
biopsy demonstrating sarcoidal granulomas is
Dactylitis is the inflammation of one or more fin- required, and in some cases, sterile culture to
gers and/or toes (Fig. 8). Sarcoid dactylitis is a rule out an infectious process is necessary.29
rare manifestation that is observed in approxi- Close clinicopathologic correlation by an experi-
mately 0.2% of cases of sarcoidosis.23 enced dermatologist is helpful.

Fig. 5. Subcutaneous sarcoidosis (A, C) and EN (B, D) in patients with darker skin tones (A, B) and lighter skin
tones (C, D). In panel C, typical dermally based papules (pink) and subcutaneous lesions (circled areas) are
both present. Clinical features that may help distinguish subcutaneous sarcoidosis and EN are summarized in Ta-
ble 3. (Mariana Montoya Castilloa, Sebastián Herrera Uribeb, Juan David Berlinghieri Péreza. Löfgren syndrome
as an acute presentation of sarcoidoisis. 25:2; Figure 1, Elsevier 2018.)

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 78
Table 4
List of available therapies for cutaneous sarcoidosis, level of evidence, common adverse effects, and monitoring recommendations

Abdelghaffar et al
Medication Name Level of evidenceref Dosing Adverse Effects Monitoring
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Topical Therapy:
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Topical corticosteroids IIB92–94 Ultrapotent agents Skin atrophy, None

intermittently used twice hypopigmentation, striae,
daily, eg, 1 wk on, 1 wk off petechiae
Intralesional corticosteroids IA95,96 Triamcinolone 2.5–20 mg/mL Skin atrophy, None
every 2-3 months hypopigmentation, striae,
petechiae
Topical calcineurin III67,97,98 Twice daily BW: malignancy; also skin None
inhibitors (tacrolimus irritation, stinging
0.1% ointment,
pimecrolimus 1% cream)
Topical JAK inhibitor III28,70 Twice daily BW: serious infections, None
(compounded) mortality, malignancy,
major cardiovascular events,
thrombosis
Systemic Therapy:
Oral corticosteroidsa III17,99–101 0.1–0.5 mg/kg/d typically; Weight gain, hypertension, Blood pressure, glucose
higher doses may be needed diabetes, osteoporosis, monitoring, DEXA scan if
for internal organ mood disturbance, others long term
involvement
Corticotrophin repository III102 80 units/mL (5 mL) Weight gain, hypertension, Blood pressure, glucose
injectiona diabetes, osteoporosis, monitoring, DEXA scan if
mood disturbance, others long term
Doxycycline IIB77 100 mg twice daily Contraindicated in pregnancy, None
<8 yo; photosensitivity, GI
upset, esophagitis
Minocycline IIB76,77 100 mg twice daily Contraindicated in pregnancy, None
<8 yo; dizziness
Chloroquine IIB71 250–500 mg daily Retinopathy, QT EKG, fundus examination, CBC
prolongation, myopathy, and CMP every 3 mo
neuropathy
 Hydroxychloroquine IIB78,103 200 mg twice daily Retinopathy, QT EKG, fundus examination, CBC
prolongation, myopathy, and CMP every 3 mo
neuropathy
Methotrexate IIB103–105 10–25 mg po or intramuscular BW: adverse reactions, CBC, CMP every 3 mo
weekly hypersensitivity, embryo-
fetal toxicity; infection, GI
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fibrosis
Mycophenolate III106 500–1500 mg po twice daily BW: infections, malignancy, CBC, CMP every 3 mo
embryo-fetal toxicity; GI
upset, cytopenias
Thalidomide IIB81,107–109 100–200 mg once daily BW: contraindicated in CBC, CMP, and TSH every 3 mo;
pregnancy, thromboembolic monitor for neuropathy
events; peripheral
neuropathy,
hypothyroidism
Infliximab III17,80,83,84,110–112 3–10 mg/kg every 4–8 wk BW: serious infections, Hepatitis, HIV, and
malignancy; infusion tuberculosis (TB) screening
reaction, GI upset, infection at baseline; annual TB
screening
Adalimumab (and other III83,113,114 varies BW: serious infections, Hepatitis, HIV, and TB
subcutaneously malignancy screening at baseline;
administered TNF-alpha annual TB screening
inhibitors)
Tofacitinib (or other JAK III61,87,115,116 5–10 mg twice daily BW: serious infections, Hepatitis, HIV, and TB
inhibitors) (tofacitinib) mortality, malignancy, screening at baseline;
major cardiovascular events, annual TB screening; CBC,
thrombosis CMP, lipidsb every 3 mo

Cutaneous Sarcoidosis
Procedural Therapy:
Pulsed dye laser III117–119 6–14 J/cm2 (585–595 nm, 7– Purpura, bruising, None
12 mm) postinflammatory
hyperpigmentation

Abbreviation: BW, boxed warning; CMP, complete metabolic panel; DEXA, dual-energy X-ray absorptiometry; TSH, thyroid stimulating hormone.
a
FDA-approved therapy (for pulmonary sarcoidosis).
b
Monitored annually if stable after 3 mo of treatment.

79
80 Abdelghaffar et al

Fig. 6. Tattoo sarcoidosis in a Black patient (A) and White patient (B). Specific ink colors may be preferentially
involved. (Jean Bolognia, Julie Schaffer, Lorenzo Cerroni. Dermatology 2 volume set. Edition 4; Figure 93.2e.
Elsevier 2017.)

Involvement of Mucous Membranes, Hair, and Nail sarcoidosis is most commonly mistaken as
Nails tinea unguium. Definitive diagnosis requires a nail
matrix biopsy, which would be expected to
Patients with suspected sarcoidosis should also
demonstrate sarcoidal granulomas. Finally,
have careful examination of hair, nails, and mu-
mucosal changes may be present and are most
cous membranes because sarcoidosis may also
commonly characterized by localized swelling.32
manifest in these areas (see Table 2). Scalp
In Melkersson-Rosenthal syndrome, there is a
involvement may present as cicatricial (scarring)
triad of facial paralysis, swelling of the face and
alopecia, usually occurring on a background of
lips (usually upper lip), and the development of
more typical sarcoidal inflammatory lesions
folds and furrows in the tongue.33 Although not
(Fig. 10).30 Occasionally, sarcoidosis may present
specific, an assessment for lacrimal gland hyper-
as large solitary plaques of the scalp, which may
trophy is often performed. Heerfordt syndrome of
develop alopecia and even ulcerate. A biopsy is
sarcoidosis may present with facial palsy and pa-
required for the diagnosis of sarcoidal alopecia
rotid swelling (see Table 1).
and noncaseating granulomas are expected; other
processes may need to be excluded. Nonspecific
Sarcoidosis can also result in alterations to the Nonspecific cutaneous lesions seen in sarcoidosis
nail unit including nail dystrophy and subungual are thought to be reactive in nature and when a bi-
hyperkeratosis (see Fig. 8).31 This may occur in opsy is performed, sarcoidal granulomas are not
the setting of sarcoid dactylitis or in isolation. seen. The most common nonspecific cutaneous

Fig. 7. Involvement of scars in a Black patient (A) and White patient (B) with sarcoidosis. Involvement in a similar
area of the forehead is coincidental.

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 Cutaneous Sarcoidosis 81

Fig. 8. (A) Nail plate dystrophy and hyperpigmentation due to nail matrix involvement by sarcoidosis in a Black
patient. Dactylitis is absent. (B) Nail plate dystrophy in the setting of sarcoid dactylitis in a White patient. Nail
matrix biopsy in patient A showed sarcoid granulomas. Nail dystrophy in both patients improved with treatment
of sarcoidosis.

lesion seen with sarcoidosis is EN. EN is not (of many causes), is a poor prognostic factor
specific to sarcoidosis and is more commonly when present in sarcoidosis.35,36
observed in other settings. EN presents as painful,
pink-to-red subcutaneous nodules that are usually Cutaneous Sarcoidosis in Children
symmetrically distributed on the anterior shins.12
Sarcoidosis is very uncommon in pediatric pa-
In sarcoidosis, EN is most commonly seen in the
tients. When it does present in children, those
setting of Lofgren syndrome, which also includes
aged 9 to 15 years are more commonly infected.
hilar lymphadenopathy, arthritis, and fever (see
Blau syndrome is an early onset form of sarcoidosis
Table 1).13,34 This syndrome, which is typically
due to NOD2 mutation and usually presents with a
considered an acute form of sarcoidosis, has an
triad of CS (which may be the initial presentation),
excellent prognosis and often does not require
uveitis, and arthritis (see Table 1).37 Sarcoidosis
steroids.19,20,34
is very rare in children, and cutaneous granuloma-
Digital clubbing, which is thought to occur in the
tous inflammation in this population should raise
setting of clinically significant pulmonary disease
concern for alternate diagnoses such as immuno-
deficiency syndromes.38,39

Histopathological Features
When CS is suspected, punch biopsy of the cuta-
neous lesions is generally recommended so the
dermis and subcutaneous fat are sampled. Deep
sampling is especially important if subcutaneous
sarcoidosis is suspected.40
The hallmark of sarcoidosis is the presence of
noncaseating granulomas that are composed of
tightly aggregated epithelioid histiocytes (macro-
phages) (Fig. 11). In the skin, the associated lym-
phocytic infiltrate may be sparse, and the term
Fig. 9. Angiolupoid sarcoidosis in a White patient. “naked granulomas” has been used to describe
Prominent telangiectasis is present within inflamma- the histology of sarcoidosis in the skin for this
tory papules and plaques. reason.41,42 Multinucleated giant cells may or may

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82 Abdelghaffar et al

Fig. 10. (A) Multifocal plaques of cicatricial alopecia in a Black patient with extensive CS. (B) Large solitary plaque
of cicatricial alopecia in a White patient with CS; biopsy showed sarcoid granulomas.

not be present, and in some cases, they are prom- required as granulomatous inflammation may also
inent. Schaumann bodies and asteroid bodies are be seen in the setting of immunodeficiencies
also commonly described histologic phenomena; (including Rubella granulomas as may occur in pa-
however, they are neither specific to sarcoidosis tients with common variable immunodeficiency),
nor required to make the histologic diagnosis (see paraneoplastic syndromes, and with immunostimu-
Table 1). latory medications including recombinant interferon
Even with a typical histologic appearance, estab- alpha and cancer immunotherapies such anti-
lishing a diagnosis of sarcoidosis still requires clini- CTLA-4 and anti-PD1/PD-L1.
copathologic correlation. Other causes that can
lead to granulomatous inflammation histologically Molecular Pathogenesis of Cutaneous
should be considered and excluded: these include Sarcoidosis
foreign body reactions (evaluate for polarizable
foreign material) and infection (stain for microorgan- The pathogenesis of CS (and sarcoidosis in gen-
isms and possibly biopsy for sterile tissue culture eral) is not completely understood. Broadly,
depending on the clinical presentation). Polarizable inflammation in sarcoidosis is thought to result
foreign material has been described in 22% to 77% from a complex interplay among factors including
of CS biopsies and does not necessarily preclude a environmental and/or infectious antigens, nonor-
diagnosis of CS.42 Clinical correlation is also ganic material from the environment, genetics,
and the immune system. Possible infectious trig-
gers that have been proposed include Cutibacte-
rium acnes (formerly Propionibacterium acnes)
and Mycobacterium spp.43 Pesticides, herbicides,
bioaerosols, beryllium, aluminum, zirconium, agri-
cultural agents, and other environmental agents
have also been implicated.44 The role of genetics
is reinforced by observations such as monozygotic
twins of patients with sarcoidosis having an 80-
fold increased risk of developing sarcoidosis.45
Genome-wide susceptibility studies have also
identified new susceptibility loci.46–48
A truly infectious nature to sarcoidosis has largely
been disproven and patients improve with immuno-
suppression. Although CS may rarely respond to
treatment with oral antibiotics (see later discussion),
Fig. 11. Hematoxylin and eosin-stained section of CS.
most patients do not respond. Antibiotics are also
Larger pale cells (macrophages) form tight spheroid
aggregates (granulomas) in the dermis. Smaller generally not used to treat patients with extracuta-
darker cells (lymphocytes) are present but relatively neous sarcoidosis and so the true role, if any, of C.
sparse. (Jean Bolognia, Julie Schaffer, Lorenzo Cer- acnes in sarcoidosis pathogenesis remains unclear.
roni. Dermatology 2 volume set. Edition 4; Figure In terms of Mycobacteria, an active role for viable or-
93.6a. Elsevier 2017.) ganisms also seems unlikely given the negative

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 Cutaneous Sarcoidosis 83

results of the CLEAR trial,49 where patients with pul- single-cell RNA sequencing (scRNA-seq) and
monary sarcoidosis were treated with a potent anti- bulk RNA sequencing in CS, our group again found
mycobacterial regimen. Interestingly, CD41 T cells similar signals that centered on activation of Th1
from patients with Lofgren’s sarcoidosis were immunity with CD41 T cell-derived IFN-g appear-
recently shown to recognize an Aspergillus nidulans ing to drive classical macrophage activation. GM-
epitope.50 The broader implications of this compel- CSF, which has proinflammatory effects on
ling finding, particularly in chronic presentations of myeloid cells in the tissue, was also upregulated
sarcoidosis, are not yet clear. by lesional T cells. IL-12 from dendritic cells
Multiple lines of evidence support that granuloma seemed to reinforce this inflammatory signal. IL-6
formation in sarcoidosis is a T cell-dependent and IL-15 derived from stromal cells may also rein-
process. This includes (1) the observation that ge- force the inflammatory milieu.
netic variation at major histocompatibility complex A recent study by Krausgruber and colleagues
(MHC) class II loci is associated with sarcoid- that used scRNA-seq as well as spatial transcrip-
osis51,52; (2) the observation that BTNL2, a B7 re- tomics in CS similarly identified CD41 T cells pro-
ceptor family protein involved in T cell receptor ducing IFN-g and GM-CSF as prominent
signaling (probably acting as a costimulatory mole- molecular features in this disease.66 We have inte-
cule) also exhibits genetic variation in sarcoid- grated these molecular findings into a working
osis53,54; (3) the observed expansion of CD41 T model of CS pathogenesis (Fig. 12).
cell subclones in sarcoidosis, including in CS55;
and (4) the observation that sarcoidosis can be
Treatment
unmasked or triggered by T cell-stimulating
cancer immunotherapies.56,57 Prednisone and corticotropin gel are the only US
The infiltrate in sarcoidosis is CD41 T cell pre- Food and Drug Administration (FDA)-approved
dominant. The exact signals used by CD41 T cells therapies for (pulmonary) sarcoidosis. There are
to recruit monocytes to the skin and promote no FDA-approved therapies for CS, or sarcoidosis
macrophage activation and granuloma formation in other organs. In patients with other organ involve-
are not fully understood. Pulmonary sarcoidosis ment, collaboration among specialists is necessary
has been most intensively studied from a molecular for selecting the optimal treatment regimen. A Euro-
standpoint and is characterized by a prominent Th1 pean Respiratory Society (ERS) task force recently
polarization, with a possible Th17 precursor and/or developed updated clinical practice guidelines for
hybrid phenotype with concomitant interleukin (IL)- the treatment of sarcoidosis using GRADE (Grading
17 production (so-called Th17.1 phenotype).58 Th2 of Recommendations, Assessment, Development,
polarization has also been identified in some and Evaluations) methods.67 Prednisone remains
studies of pulmonary sarcoidosis and may be the recommended first-line therapy for extracuta-
more prominent in cases with fibrotic changes.59 neous sarcoidosis. The ERS guidelines have a con-
In 2011, Judson and coworkers evaluated gene ditional recommendation for consideration of the
expression in 15 cases of CS compared with normal use of prednisone for patients with active CS not
skin from healthy controls.60 They found that lesional controlled by local treatment (see further discussion
sarcoidosis was characterized by marked upregula- below). However, as stated in the guidelines, the
tion of interferon (IFN)-g, IL-12, and tumor necrosis recommendation remains conditional due to very
factor (TNF). These signals are typical of a Th1 polar- low quality of evidence; there are no randomized tri-
ized response and make immunologic sense given als in this area and recurrence on treatment discon-
the importance of these signals in productive granu- tinuation is common. Dermatologists may tend to
loma formation such as that which occurs in the avoid the use of systemic steroids for the treatment
setting of true mycobacterial infection. Notably, of CS due to the often-chronic nature of the disease
they did not find significant IL-17 expression.60 and the myriad possible adverse effects of steroids,
Whether this represents a true biologic difference although in some patients, it may still be an option.
from pulmonary sarcoidosis or instead reflects dif- A ladder-like approach is often described for the
ferences in methodology is not yet clear. treatment of patients with CS. However, in clinical
In 2018, our group showed constitutive activa- practice, in cases for which topical or localized
tion of the Janus kinase (JAK)-signal transducer therapy is unlikely to be sufficiently effective, sys-
and activation of transcription (STAT) pathway in temic therapy or systemic therapy in combination
a study evaluating 21 biopsy cases of CS.61 This with topical/localized therapy may be selected as
finding is highly consistent with persistent IFN-g first-line therapy (see Table 4).
signaling. This is also similar to the Judson and For localized or minimally bothersome CS,
colleagues findings in CS, as well as findings in topical therapies may be appropriate. Mid-to-ultra
other organ systems of sarcoidosis.62–65 Using potent topical steroids are commonly used in this

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84 Abdelghaffar et al

Fig. 12. An overview of the molecular pathogenesis in CS. Th1 polarized CD41 production of IFN-g is a patho-
genic hallmark of the disease. IL-12 production by classically activated dendritic cells (cDC1) reinforces T cell acti-
vation. CD41 T cells also overproduce GM-CSF, which contributes to the inflammatory activation of macrophages.
TNF is produced by both T cells and macrophages and along with IL-6 and IL-15 production from stromal cells
maintains an inflammatory milieu supporting granuloma persistence.

setting.57–60 Although steroids may be effective, There is some evidence for the use of physical
problematic local side effects include hypopigmen- approaches. However, these approaches have
tation, atrophy, and striae. Topical calcineurin inhib- not been rigorously studied, generally work much
itors, which do not have these side effects, may be better for patients with lighter skin tones, require
used; however, the evidence for this approach in frequent treatments, and may not be covered by
CS is limited to case reports,68–70 and real-world insurance or readily available for many patients.
experience suggests the results are often subopti- Nonetheless, the use of photodynamic therapy, ul-
mal. There is anecdotal evidence that topical JAK traviolet A light therapy, pulsed-dye laser (PDL),
inhibition may be helpful in some cases.28,71 and CO2 laser have been reported.74–76 PDL in
Topical medications for subcutaneous sarcoidosis particular can be effective for telangiectasias in
are not generally effective. patients with angiolupoid presentations.
Another option for patients with localized For patients with more widespread and/or re-
involvement is an intralesional injection of steroids fractory CS, those who had been treated with sys-
(typically triamcinolone suspension at a concentra- temic glucocorticoids and have continued active
tion of 5–10 mg/mL). Intralesional injections deliver CS, other immunomodulatory medications may
the steroid directly to the dermis and/or subcutis be used (and often combined with topical or local-
and may be very effective in some settings.60 How- ized approaches). Antibiotics are a commonly
ever, frequent clinic visits for injection may be used first-line therapy by dermatologists to treat
required and may limit compliance (or ability to CS. Although there is some evidence that tetracy-
comply) with therapy. Adverse effects including cline antibiotics may be useful,77,78 in our experi-
hypopigmentation and atrophy are still common ence they are often ineffective, and we generally
with this approach.61,72,73 Hypopigmentation from do not pursue this line of therapy in most patients.
steroids may be particularly bothersome in patients Antibiotics are generally not used for the manage-
with darker skin tones. ment of extracutaneous sarcoidosis.

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 Cutaneous Sarcoidosis 85

Other common systemic therapies used by der- patients with long-standing CS were treated with
matologists for the treatment of CS are antimalar- tofacitinib 5 mg daily for 6 months. All 10 patients
ials, including chloroquine (250–500 mg daily) and had improvement in their cutaneous disease with
more commonly hydroxychloroquine (200–400 mg an average reduction in cutaneous disease activity
daily). Most of the data for chloroquine is from of 82.7%, with 6 patients experiencing a complete
studies performed in the 1960s, which do include response.87 Disease control with a tofacitinib-
prospective, randomized trials. The consensus based regimen was superior to the baseline immu-
from these studies was that CS seemed to notherapeutic regimens in all 10 patients, most of
respond better to chloroquine than did pulmonary whom were also able to taper or completely dis-
sarcoidosis.72 Some of the best data for hydroxy- continue prednisone due to the improvement
chloroquine in CS largely comes from a 1990 case they had during this 6-month study. Improvement
series of 17 patients.79 in internal organ inflammation was also seen in a
Methotrexate and thalidomide/lenalidomide are majority of patients with tofacitinib therapy.87 The
used for their immunomodulatory effects in sarcoid- central mechanism of action of tofacitinib seems
osis and may be effective in some patients74,80; to be suppression of IFN-g signaling (signals via
however, a randomized placebo-controlled trial of JAK1/2-STAT1).87 Inhibition of GM-CSF, IL-6, IL-
thalidomide 100 mg daily for 3 months failed to 12, and IL-15 activity by tofacitinib was also
demonstrate efficacy.81 Neuropathy may limit the apparent and may also contribute to the response.
duration of therapy with thalidomide/lenalidomide. Similar success with JAK inhibitors has been
Methotrexate is commonly used as a steroid- described in case reports and small series.88 Addi-
sparing agent in patients with pulmonary involve- tional investigation into this approach will be un-
ment who require chronic prednisone therapy.73,80 derway soon.
TNF-a inhibitors are also commonly used to treat
CS. The ERS guidelines recommend infliximab for SUMMARY
patients with CS who have been treated with gluco-
corticoids and/or other immunosuppressive regi- Sarcoidosis is a multiorgan granulomatous dis-
mens that have ongoing activity, although this is a ease with recognizable cutaneous manifestations.
conditional recommendation supported by very Although progress has been made in our under-
low quality of evidence. In a double-blind trial by standing of CS, priorities moving forward include
Judson and colleagues, of patients treated with expanding our understanding of the QoL influ-
infliximab, there was a promising but not statisti- ences in sarcoidosis—especially in patients with
cally significant trend toward improvement in cuta- darker skin tones, further uncovering the molecu-
neous involvement with treatment.82,83 In a small lar pathogenesis of CS and how it relates to other
prospective, randomized study of patients with involved organs and developing and evaluating
CS treated with adalimumab 40 mg weekly, 4 of effective and safe therapeutics for CS using
10 treated patients had clearance or marked rigorous clinical methods.
improvement in their CS after 12 weeks of ther-
apy.84 In a retrospective study by Heidelberger CLINICS CARE POINTS
and colleagues, of 46 patients treated with various
TNF inhibitors, 28.3% had complete skin clear-
ance, whereas another 39% had a partial cuta-
neous response.85 Trials with etanercept in  Evaluation of skin for cutaneous sarcoidosis
sarcoidosis have been disappointing, and this may aide in diagnosis of patients with sus-
agent should not be used for sarcoidosis. pect systemic sarcoidosis.
It is important to consider that in some individ-  Patients with limited skin sarcoidosis (eg,
uals, sarcoidosis including CS, may develop in tattoo sarcoidosis) need screening and
the setting of TNF inhibition for another diagnosis. ongoing evaluation for systemic disease.
The exact reasons(s) for this phenomenon are not  Cutaneous sarcoidosis may have a significant
entirely clear but may involve paradoxic immune quality of life impact and treatment decision
activation by the TNF inhibitors.86 TNF inhibitors making should take this into account.
are also typically avoided in patients with a history
of heart failure, which may include patients with
advanced pulmonary and/or cardiac sarcoidosis. FUNDING SOURCES AND CONFLICT OF
One of the newest developments in CS involves INTEREST
the use of JAK inhibitors. JAK inhibitors can simul-
taneously block the activity of multiple cytokines. There are no funding sources. Dr W. Damsky is sup-
In our open-label trial published in 2022, 10 ported by NIAMS, United States (K08AI159229). M.

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86 Abdelghaffar et al

Abdelghaffar and E. Hwang have nothing to 16. Jorizzo JL, Koufman JA, Thompson JN, et al.
disclose. Dr W. Damsky has received research sup- Sarcoidosis of the upper respiratory tract in pa-
port from Pfizer, United States, Advanced Cell tients with nasal rim lesions: a pilot study. J Am
Diagnostics/Bio-techne, AbbVie, United States, Acad Dermatol 1990;22(3):439–43.
Incyte, United States, Bristol Myers Squibb, United 17. Stagaki E, Mountford WK, Lackland DT, et al. The
States; consulting fees from Eli Lilly, TWI Biotech- treatment of lupus pernio. Chest 2009;135(2):468–76.
nology, Incyte, Epiarx Diagnostics, Bristol Myers 18. Kluger N. Sarcoidosis on tattoos: a review of the
Squibb, and Boehringer Ingelheim; and receives literature from 1939 to 2011. Sarcoidosis Vasc
licensing fees from EMD/Millipore/Sigma. Diffuse Lung Dis 2013;30(2):86–102.
19. MADDEN JF. Reactions in tattoos. Arch Dermatol
1939;40(2):256.
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