Sarcoidosis of the skin D86.3

Granulomatous, autoinflammatory multisystem disease of unknown etiology characterized by the occurrence of non-caseating epithelioid cellular 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.

The acronym TAGU stands for "tattoo-associated granulomas with uveitis" and refers to a rare, bilateral intraocular inflammation and concomitant development of sarcoid skin reactions in tattoo areas (Carvajal Bedoya G et al. 2020).

Sarcoidosis of the skin (9-37%) should be considered an integral part of the "systemic disease of sarcoidosis" with characteristic clinical and histological changes. It can occur at any time during the disease, but it 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 system 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.

Skin manifestations in sarcoidosis can be divided:

1. Large nod ular form: (special form: lupus pernio).
2. Small nodular disseminated form (most common form: face, extremities, trunk, mucous membranes)
3. Plaque-like (discoid, annular, extensive or circine) form (clinically also appearing psoriasiform or ichthyosiform)
4. Subcutaneous nodular form (13% of patients): Nodules are palpable under normal or slightly livid skin (Darier-Roussy).
5. Ulcerative sarcoidosis: legs, ulcers without other clinically landmark morphology
6. Special forms:
   • Löfgren's syndrome
   • Cicatricial sarcoidosis (usually no systemic involvement expected)
   • Angiolupoid
   • Lupus pernio.

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.

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

Excessive T-cell-mediated immune responses to an as yet undefined agent as well as autoimmunological or infectious genesis are being discussed. Environmental toxins and microbial pathogens are blamed as trigger factors for granuloma formation (Giner T et al. 2017). Among the microbial pathogens, mycobacteria, propionibacteria and herpes simplex viruses are repeatedly suspected.

Sarcoidosis leads to activation of CD4+ helper cells of the Th1 subtype. In bronchial lavage, a shift in the lymphocyte population of the CD4/CD8 ratio in favor of CD4+ cells could be detected (CD4/CD8 > 3.5 is highly specific).

As part of this inflammatory reaction, a large number 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.Monocytes are attracted from the peripheral blood via the production ofmonocyte chemotactic factor(MCF).

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.

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.

Depending on the clinical course, a distinction is made between:

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, bihilar adenopathy and erythema nodosum. The occurrence of erythema nodosum is often characterized by 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: Parenchymal involvement
3. Stage III: Fibrosis.

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

3. chronic sarcoidosis (95% of cases): Relapsing course of the disease, usually lasting for years, with involvement of the skin (15-35%), lungs (60% of patients), lymphatic system (20%), liver (20%), eyes (18%), parotid gland (5%), lacrimal gland (see below the rare Heerfordt syndrome), bones (ostitis multiplex cystoides Jüngling) and joints (usually oligoarticular arthritis, preferably of the ankle joints). The relapses are generally accompanied by a marked disturbance of the AZ, fever, fatigue and flu-like symptoms.

The following skin manifestations of the chronic form are distinguished:

• Large nodular form: Brown or blue-red, coarse, plum-sized nodules and plaques, especially on the nose, cheeks, earlobes, extremities and trunk. Central regression is possible. Numerous telangiectasias. Diascopic small-spotted or also large-area "lupoid" infiltrate, see also lupus pernio.
• Small nodular or papular disseminated form: Dense, non-follicularly bound, small reddish-brownish or blue-reddish papules. Also small nodular, possibly also lichenoid lesions. Only slight desquamation. Flat plaques may form that are clearly marked against the surrounding skin and have blurred edges. A lupoid infiltrate can be detected diascopically. Later hyperpigmentation and formation of telangiectasias. The extensor sides of the extremities, the trunk and the face are affected.
• Anular or circinate form: Annular or confluent, multiform, also extensive, 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 discolored skin.
• Special forms:
  • Scar sarcoidosis
  • Angiolupoid (Brocq-Pautrier).

The laboratory data listed below relate primarily to acute sarcoidosis and sarcoidosis with systemic involvement. Isolated skin sarcoidosis can be completely silent in terms of laboratory parameters. The ESR may be elevated, the tuberculin test is usually negative, 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 into the vasoconstrictor angiotensin II) is elevated in approx. 60% of cases of acute sarcoidosis.
• Neopterin can 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. It is the relevant laboratory parameter with the highest sensitivity. In the diagnosis of sarcoidosis, sIL-2R is the parameter of choice in addition to ACE due to its ease of determination, stability and high sensitivity (elevated values also in all T-cell-mediated diseases, e.g. chronic infections; haemoblastoses)
• Elevated gamma globulins and IgG (50%)
• Hypercalcemia (15%)
• Possibly leukopenia and lymphopenia, also eosinophilia.

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).

Sarcoidosis is diagnosed by exclusion and summation of various symptoms:

• Clinic with diascopy (detection of the typical autoinfiltrate)
• Skin biopsy (most important diagnostic criterion)
• Ophthalmologic clarification: 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 hyperglycemia with recall antigens.
• ANA is positive in 30% of patients.
• ESR: elevated.
• Eosinophilia: present in 25% of patients.
• ACE level determination: marker of the "granuloma load" of the organism and elevated in about 60% of patients with systemic infestation; false positive results in about 10% of patients.
• Note! ACE is suitable as a monitoring factor to determine progression.
• Soluble IL-2 receptor level: elevated (expression of activated T lymphocytes).
• Hypercalcemia (or hypercalciuria): detectable in 10% of patients. The cause is a production of 1,25-dihydroxy-vitamin D in mononuclear cells of the granulomas. This leads to increased intestinal Ca absorption. Determination of calcium in 24-hour urine required.
• Chest X-ray: Lymph node 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 evidence of pulmonary fibrosis.
• Sonography of the liver.

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

• Tuberculosis cutis luposa
• Syphilis III
• Tuberculosis

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.

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.

Glucocorticoids are the mainstay of treatment. Either as an injection with triamcinolone (e.g. Volon A 10 crystal suspension diluted 1:1 with LA such as Scandicain 1%) or as a 0.05% clobetasol ointment (e.g. Dermoxin) under occlusion.

Remarkable are reports on the successful application of dithranol (NRF 11.51) in a Vaseline base (ascending concentration starting with 0.1% up to max. 2%) with an exposure time of 20 minutes. Regression of the sarcoid infiltrates of the skin after 2-3 weeks (Darr-Foit S et al. 2020).

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).

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

Systemic therapy should be initiated in cases of disfiguring or skin manifestations that do not regress with external therapy and steroid-resistant changes of the ocular fundus. Systemic approach is also recommended for symptomatic lung disease, progressive or parenchymal lung disease after a 2-year course, persistent fever or weight loss, liver dysfunction, hepatosplenomegaly, lymphadenopathy, CNS involvement, hypercalcemia, myocardial involvement, myopathy or myositis, and other severe organ involvement (e.g., renal).

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

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

• Chloroquine: Casuistic success is shown with antimalarials such as chloroquine (e.g., Resochin). Initial 250 mg/day p.o., then reduction to maintenance therapy with 250 mg 2 times/week p.o. Alternative: 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., slowly reducing to a maintenance dose of about 7.5 mg/week. A larger study over 2 years in 50 patients showed a steroid-sparing effect of MTX.
• Mycophenolate mofetil (CellCept®): 500 mg 2-0-2.

Experimental:

• Anecdotal reports exist of allopurinol (e.g., Zyloric) 300 mg/day, clofazimine (e.g., Lamprene) 200-400 mg/week, ciclosporin A (e.g., Sandimmun) 5 mg/kg bw/day), or fumaric acid esters (e.g.E.g., Fumaderm 3-6 tbl. Fumaderm® distributed throughout the day) or low-dose fumarate therapy [Fumaderm® initial (90 mg/day dimethyl fumarate)] in long-term therapy (Ref. 18).
• Biologics: Anecdotal reports and smaller studies with exceptionally good results exist on TNF-alpha inhibitors(etanercept, infliximab, adalimumab). A single study showed complete healing after 18 months of combination therapy (etanercept 2 times/day 25 mg, prednisolone 1 time/day 30 mg, hydroxychloroquine 2 times/day 200 mg, and methotrexate 1 time/week 15 mg).

Overall, more than 60% of sarcoidosis cases heal spontaneously within 2-5 years. 10-30% of cases are progressive.

Nodular and nodular sarcoidosis lesions are more likely to heal after months and years than plaques and lupus pernio (spontaneous healing possible in 50% of cases). Prognosis quoad vitam depending on pulmonary findings (development of pulmonary fibrosis).

Chronic cutaneous sarcoidosis: quoad sanationem poor. Risk factors for a chronic course are: age > 40 years, hypercalcemia, lupus pernio, chronic uveitis, cardiac or neurological involvement, pulmonary sarcoidosis stage III, symptom duration > 6 months, nephrocalcinosis.

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