Sarcoidosis of the skin D86.3

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Hadrian Tran

All authors of this article

Last updated on: 18.12.2020

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Synonym(s)

benigna lymphogranulomatosis; Benign lymphogranulomatosis; benign miliary lupoid; Besnier-Boeck-Schaumann disease; Besnier-Boeck-Schaumann M.; Boeck M.; Boeck's disease; Boeck's sarcoid; Cutaneous sarcoidosis; Cutaneous Sarcoidosis; miliary lupoid benignes; sarcoid boecksche; Sarcoidosis; Sarcoidosis cutaneous; Sarcoidosis cutaneous large-boned; Sarcoidosis cutaneous small nodules; Sarcoidosis subcutaneous nodular

History
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Jonathan Hutchinson 1875; Ernest Besnier 1889; Caesar Boeck, 1899

Definition
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Granulomatous, autoinflammatory multisystem disease of unknown etiology characterized by the occurrence of non-caseating epithelioid cell granulomas of the skin (and other organs - see sarcoidosis below). Sarcoidosis can affect almost any organ system, with the lungs being the most commonly affected with a 95% frequency of involvement. The skin is affected in 30% of sarcoidosis cases.

Sarcoidosis of the skin (9-37%) should be seen as an integral part of the "systemic disease of sarcoidosis" with characteristic clinical and histological changes. It may occur at any time during the disease, but is usually present at the onset of the disease. Sarcoidosis of the skin can present with or without systemic involvement. Approximately 60% of patients with sarcoidosis of the skin also have systemic involvement.

Because it is externally visible, cutaneous sarcoidosis is relatively easy to confirm clinically and biopsy.

The severity of integumentary involvement is determined less by functional limitations than by disturbances in the patient's external appearance.

Classification
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Skin symptoms of sarcoidosis can be subdivided:

  1. Large nodular form: (special form: lupus pernio)
  2. Small nodular disseminated form (most common form: face, extremities, trunk, mucous membranes
  3. Plaque-shaped (anular, circulatory or large-area) form (clinically also appearing psoriasiform or ichthyosiform)
  4. Subcutaneous nodular form (13% of patients): nodules under normal or slightly livid discoloured skin palpable (Darier-Roussy)
  5. ulcerative sarcoidosis: legs, no actual, clinically recognizable entity
  6. Special forms:

Occurrence/Epidemiology
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Incidence figures vary worldwide. The incidence for Caucasians (US data) is 10-14/100,000 inhabitants/year and for Americans of African descent 35-64/100,000 inhabitants/year. Sweden: 64/100.000 inhabitants/year; UK: 20/100.000 inhabitants/year; Spain and Japan: 1,4/100.000 inhabitants/year.

Etiopathogenesis
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Unsolved. Familial accumulation is known. There is an association with HLA-B8, HLA-DBQ1, HLA-DR3B1. The latter two HLA subtypes seem to be associated with a good prognosis. Polymorphisms of the angiotensin-converting-enzyme (ACE) coding gene have been detected.

Discussed are exuberant T-cell mediated immune responses to an as yet undefined agent as well as autoimmunological or infectious etiology. Environmental noxae and microbial pathogens are accused as trigger factors for granuloma formation (Giner T et al. 2017). Among the microbial pathogens, mycobacteria, propionibacteria and herpes simplex viruses are repeatedly suspected.

In sarcoidosis, an activation of CD4+ helper cells of the Th1 subtype occurs. In bronchial lavage, a shift in the lymphocyte population of the CD4/CD8 ratio in favour of CD4+ cells was demonstrated (CD4/CD8 > 3.5 is highly specific).

In the course of this inflammatory reaction, a multitude of Th1- cytokines(IL-2, interferon gamma) are produced, which on the one hand initiate the sarcoid tissue reaction and on the other hand lead to B-cell stimulation and hypergammaglobulinemia. Monocyte chemotactic factor (MCF) is produced to attract monocytes from the peripheral blood.

Manifestation
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Young women often fall ill. But all in all ♀ = ♂. First manifestation mostly between the ages of 20 and 40, less frequently in children. Biphasic course with maxima at 25-35 and 45-65 years of age.

Localization
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Predilection sites are the face (nose, forehead, cheeks), earlobes and the sides of the extremities. The bending sides of the arms are usually left free. The lesions typically occur in cool (reduced blood circulation) skin areas and in scars, mediastinal and peripheral lymph nodes, lungs, liver, spleen, eyes, parotis. Apart from the predilection sites, there is no particular distribution pattern, but the "disordered, random" occurrence of the lesions is typical of sarcoidosis of the skin.

Clinical features
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According to the clinical course of the disease, one separates:

  1. acute sarcoidosis(Löfgren's syndrome)
  2. subacute sarcoidosis
  3. chronic sarcoidosis

1. acute sarcoidosis occurs in 5% of cases It is defined by the triad: arthritis, bihilary adenopathy and erythema nodosum. The appearance of erythema nodosum often marks a benign course with a tendency to spontaneous regression within 2 years. The occurrence of erythema nodosum is always associated with considerable disturbances of the general condition.

The lung changes are divided into 3 stages according to radiological criteria:

  1. Stage I: biiliary lymph node enlargement
  2. Stage II: Parenchyma involvement
  3. Stage III: Fibrosis.

2.early onset sarcoidosis(EOS): Rare special form of acute sarcoidosis which manifests itself before the 5th LJ. It occurs in a triad combination with maculo-papular exanthema, arthritis and uveitis. In addition there is fatigue, anorexia, fever, hepatosplenomegaly. EOS usually occurs in isolation. A familial form is known as"blue syndrome".

3 Chronic sarcoidosis (95% of cases): relapsing episodes, usually lasting for years, involving the skin (15-35%), lungs (60% of patients), lymphatic system (20%), liver (20%), eyes (18%), parotid gland (5%), lacrimal gland (seeand the rare Heerfordt syndrome), bones (ostitis multiplex cystoid youth) and joints (mostly oligoarticular arthritis, preferably the ankle). The relapsing activities are usually accompanied by a distinct disturbance of the AZ, fever, fatigue and flu-like symptoms.

The following skin symptoms of the chronic form are distinguished:

  • Large-nodular form: brown- or blue-red, rough, over plum-sized knots and plate formations, especially on the nose, cheeks, earlobes, also extremities and trunk. Central regression is possible. Numerous telangiectasias. Diascopically small spotted or also large "lupoid" infiltrate, see below lupus pernio.
  • Small nodular or papular disseminated form: Densely standing, non follicularly bound, small, papular or small-nodular, possibly lichenoid, reddish-brownish or blue-reddish lesions mainly on the face, on the extensor sides of the extremities, rarely on the trunk and other mucous membranes. Anular formations are detectable. Diascopic lupoid infiltrate detectable. Later hyperpigmentation and formation of telangiectasias.
  • Anular or Circine Form: Annular or confluent, multiform, even large, brown or brown-red configurations of nodules or plaques with central atrophic regression.
  • Subcutaneous nodular form: Nodular, rough, painless lesions under normal or slightly livid discoloured skin.
  • Special forms:

Laboratory
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The laboratory data listed below refer mainly to acute sarcoidosis and sarcoidosis with system involvement. An isolated skin sarcoidosis can be completely silent regarding the laboratory parameters. The BSG may be elevated, the tuberculin test is usually negative, the IgG is elevated in 50% of cases; 1,25-OH vitamin D3 is often elevated. Acute Sarcoidosis:
  • BSG always elevated.
  • Angiotensin converting enzyme (ACE) (enzyme involved in the conversion of angiotensin I to vasoconstrictive angiotensin II) is elevated in about 60% of cases with acute sarcoidosis.
  • Neopterin may be elevated in up to 70% of cases (release by macrophages).
  • The soluble interleukin-2 receptor (sIL-2-R reflects the degree of activation of T-lymphocytes) is elevated in about 80% of cases with systemic involvement and is the relevant laboratory parameter with the highest sensitivity. In sarcoidosis diagnostics, sIL-2R is the parameter of choice in addition to ACE because of its easy determination, stability and high sensitivity (increased values also in all T-cell-mediated diseases, e.g. chronic infections; haemoblastosis).
  • Gamma globulins and IgG increased (50%)
  • Hypercalcaemia (15%)
  • Possible leuko and lymphopenia, also eosinophilia...

Histology
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Initially loose nodules of activated macrophages and epithelioid cells in the centre, surrounded by dendritic cells. Around the epitheloid cells there are CD4 positive lymphocytes, which are surrounded by CD8 positive lymphocytes. Rarely, central necrobiosis and fibrinoid swelling are present. If the granulomas persist for a longer time, the number and density of epithelioid cells increases. Multinucleated giant cells of the long-hand- and foreign body type occur increasingly. Also hyalinization and fibrosis of the connective tissue. Healing takes place with scarring.

Electron microscopy: Asteroids (star-shaped inclusions in giant cells), birefringent substances, Schaumann inclusions (concentric lamellar inclusion bodies).

Diagnosis
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The diagnosis of sarcoidosis is based on an exclusion and summation of different symptoms:

  • Clinic with diascopy (detection of the typical self-infiltrate)
  • Skin biopsy (most important diagnostic criterion)
  • Ophthalmological examination: Determination of the visual field to exclude ocular involvement.
  • Lymphopenia; the CD4/CD8 ratio is increased (sensitivity 0.70, specificity 0.83)17.
  • An- or hypergy with recall antigens.
  • ANA is pos. in 30% of patients.
  • BSG: increased.
  • Eosinophilia: present in 25% of patients.
  • ACE level determination: marker of the "granuloma load" of the organism and increased in about 60% of patients with systemic infestation; false positive results in about 10% of patients.

    Notice! ACE is suitable as a monitoring factor to determine progression.

  • Soluble IL-2 receptor level: increased (expression of activated T-lymphocytes).
  • Hypercalcemia (or hypercalciuria): detectable in 10% of patients. It is caused by the production of 1,25-dihydroxy-vitamin D in mononuclear cells of the granulomas. This leads to an increased intestinal Ca absorption. Determination of calcium in 24-hour urine required.
  • X-ray thorax: swelling of the mediastinal or interstitial lymph nodes.
  • X-ray examination of the skeleton: detection of bone cysts, especially in the finger and hand bones.
  • CT-thorax: detection of granulomas, possibly detection of pulmonary fibrosis.
  • Sonography of the liver.
Skin lesions and systemic involvement (modified after Trebing and Göring)
Clinical form Systemic participation
Lupus pernio/big-nodular form

+++

subcutaneous nodular form

+++

Scar sarcoidosis

+++

Erythema nodosum

+++

Plaque form

++

Ulcerating form

++

Nodular form

+

Smallnotized-disseminated form

+

"+" = hardly ever; "++" = rarely; "+++" = often

Differential diagnosis
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Varies depending on the type of sarcoidosis, the acute condition and localisation.

Location on the lower extremity: Necrobiosis lipoidica (Oppenheim-Urbach)

In the case of anular plaques in the facial area: actinic granuloma

In case of anular plaques on the hands: Granuloma anulare

granulomatous T-cell lymphomas of the mycosis fungoidestype

For lupus pernio: granulomatous rosacea

Also: Hodgkin's disease; sarcoid skin reactions in lymphomas; foreign body granulomas (e.g. caused by silicon, beryllium, zirconium, lipids, cactus or sea urchin spines, synthetic fibres); leprosy tuberculoides.

Therapy
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The data situation for skin sarcoidosis is only moderately good due to the small number of cases in the mostly monocentric studies. Most studies have evidence levels of IIb, III and IV. Thus, all systemic therapeutics, including glucocorticosteroids, have an off-label use status. This means that the clinical expertise of the therapist is of particularly high importance.

External therapy
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Glucocorticoids are at the forefront of the treatment. Either as injection with triamcinolone (e.g. Volon A 10 crystal suspension diluted 1:1 with LA like scandicain 1%) or as 0.05% clobetasol ointment (e.g. dermoxin) under occlusion.

Radiation therapy
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PUVA therapy can be tried; the success is limited. Note: Not a real alternative as the therapy would have to be followed consistently over a very long period of time (consequential damages have to be considered).

Internal therapy
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Due to an overall good prognosis with a high tendency for spontaneous regression (60% of all lung sarcoidoses in stage I heal spontaneously) as well as relatively poor efficacy of existing systemic therapeutics, the indication for internal therapy is only given under certain conditions.

Systemic therapy should be initiated in cases of disfiguring or skin manifestations that do not regress under external therapy as well as steroid-resistant changes in the ocular fundus. Symptomatic lung disease, progressive or parenchymatic lung disease after 2 years, persistent fever or weight loss, liver dysfunction, hepatosplenomegaly, lymphadenopathy, CNS involvement, hypercalcemia, myocardial involvement, myopathy or myositis and other serious organ involvement (e.g. kidney) are also systematically addressed.

Glucocorticoids (most effective systemic therapy): Prednisolone (e.g. Decortin H) initially 30-40 mg/day, slowly levelling out over about 6 months.

Alternative: Immunosuppressive drugs in combination with glucocorticoids, rarely alone if glucocorticoids are contraindicated.

  • Chloroquine: Casuistic success is shown under antimalarial drugs like chloroquine (e.g. Resochin). Initially 250 mg/day p.o., then reduction to maintenance therapy with 2 times/week 250 mg p.o. Alternatively: hydroxychloroquine (e.g. Quensyl) 2-3 mg/kg bw/day p.o.
  • Azathioprine (e.g. Imurek): 100 mg/day p.o.
  • Methotrexate (e.g. Lantarel): 15 mg/week p.o. or i.m., slow reduction to a maintenance dose of about 7.5 mg/week. A larger study over 2 years in 50 patients showed a steroid-saving effect of MTX.

Experimental:

Operative therapie
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Cryosurgery can be attempted in frustrated attempts with topical glucocorticoids.

Progression/forecast
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  • Overall, more than 60% of sarcoidosis cases heal spontaneously within 2-5 years. 10-30% of cases are progressive.
  • Nodular and nodular sarcoidosis lesions heal more quickly after months and years than plaques and lupus pernio (possible spontaneous healing in 50% of cases). Prognosis quoad vitam depending on lung findings (development of pulmonary fibrosis)
  • Chronic skin sarcoidosis: Quoad sanationem bad. The risk factors for a chronic course are: age > 40 years, hypercalcemia, lupus pernio, chronic uveitis, cardiac or neurological involvement, pulmonary sarcoidosis stage III, duration of symptoms > 6 months, nephrocalcinosis.

Note(s)
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Name: Boeck coined the term sarcoidosis in 1899 and defined the disease as an entity.

Literature
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  1. Alexis A et al (2005) Off-label dermatologic uses of anti-TNF-a therapies. J Cutan Med Surg 9: 296-302
  2. Baughman RP et al (2000) t steroid sparingin acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 17: 60-66
  3. Bergner R et al (2014) Immunosuppressive therapy of sarcoidosis. Act Dermatol 40:325-340
  4. Besnier E (1889) Lupus pernio de la face; synovites fongueuses (scrofulo-tuberculeuses) symmétriques des extrémités superieures Annales de dermatologie et de syphilographie (Paris) 2nd series 10: 333-336
  5. Boeck CPM (1899) Multiplies conditional hud-sarcoi. Med 4 tavler. (En hidtil ikke beskreven hudaffektion. Norsk Magazin for Lægevidenskaben, Kristiania (Oslo) 60: 1321-1334
  6. Brito-Zerón P et al (2016) Epidemiologic patterns of disease expression in sarcoidosis: age, gender and ethnicity-related differences. Clin Exp Rheumatol 34:380-388.
  7. Giner T et al (2017) Sarcoidosis: dermatological view of a rare multisystemic disease. Dermatologist 68:526-535.
  8. Haley H et al (2004) Infliximab therapy for sarcoidosis (lupus pernio). Br J Dermatol 150: 146-149
  9. Heffernan MP et al (2006) Adalimumab for treatment fo cutaneous sarcoidosis. Arch Dermatol 142: 17-23
  10. Howard A, White CR (2003) Non-infectious granulomas. In: Bologna JL et al (ed.) Dermatology, Mosby, London, New York, Toronto, pp. 1455-1469
  11. Huet P et al (2016) Cutaneous sarcoidosis: Correlation between dermatopathology and dermoscopy. Ann Dermatol Venereol 143:404-406.
  12. Hutchinson J (1877) Case of livid papillary psoriasis. In: Illustrations of Clinical surgery. Vol 1, J and A Churchill, London, p. 42
  13. Manalo IF et al (2016) More immune dysregulation: Sarcoidosis and chronic graft-versus-host disease after allogeneic stem cell transplant. JAAD Case Rep 2:138-140.
  14. Trebing D et al. (2003) Sarcoidosis of the skin. German dermatologist 6: 442-450
  15. Pfeiff B et al (1986) Cutaneous sarcoidosis. Z Hautkr 61: 1311-1317
  16. Tenneson, H Quinquaud CE (1892) Lupus pernio. Annales de Dermatology et de Syphiligraphy (Paris) 3: 142-144
  17. Shen, Yongchun et al. "Diagnostic Performance of Bronchoalveolar Lavage Fluid CD4/CD8 Ratio for Sarcoidosis: A Meta-Analysis." EBioMedicine 8 (2016): 302-308. PMC. Web. Sept. 15, 2018.

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Last updated on: 18.12.2020