Sarcoidosis (overview) D86.9

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

Granulomatous multisystemic disease of unclear etiology, characterized by the occurrence of non-cheating epithelioid cell granulomas. Chronic sarcoidosis can affect almost any organ system, with the lungs being most frequently affected with a 95% frequency of attack, followed by:

• skin (30%) - see below Sarcoidosis of the skin
• eyes (25%)- febrile uveoparotitis, isolated uveitis, lacrimal gland infection
• Bones (5%) - Osteolysis mostly in the small bones (youngling cysts)
• Joints - polyarthritis, especially ankle, knee, hand and finger joints (DD Kaplan syndrome = sarcoidosis + psoriasis + gout)
• Heart and skeletal muscles (5%)
• Spleen: Granulomas in the spleen
• Nervous system - neurosarcoidosis - (paresis of the basal cranial nerves, spinal cord, peripheral nerves; meningitis granulomatosa); Heerford's sydrome (Febris uveoparatoidea): parotitis with facial nerve palsy and eye symptoms.
• Kidney (renal sarcoidosis: mostly in the form of granulomatous interstitial nephritis, occasionally glomerulopathies (proteinuria, microhaematuria).
• Lymph nodes (generalized lymphadenopathy; mostly lymph nodes of the lower half of the body)
• other organs.

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

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.

Unknown to date.

Genetic predisposition: A familial cluster is known. There is an association with HLA-DBQ1, HLA-DR3B1. The latter two HLA subtypes seem to be associated with a good prognosis. Polymorphisms of the angiotensin-converting-enzyme (ACE) encoding gene have been detected.

Gene mutations in BTNL2 (chromosome 6) and ANXA11 increase the risk of developing sarcoidosis.

Mutation of the NOD2 (CARD 15) gene on chromosome 16p12-q21 predispose to familial sarcoidosis (blue syndrome) or to a spontaneous form of early sarcoidosis (early onset sarcoidosis).

Inhalation of beryllium dust produces a clinical picture indistinguishable from sarcoidosis.

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

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

In the course 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 of "monocyte chemotactic factor" (MCF).

w>m. First manifestation mostly between the age of 20 and 40, less often also in children. Biphasic course with maxima at 25-35 and 45-65 years. There are some indications of a familial occurrence (see also blue syndrome).

According to the clinical course, one separates:

• Acute sarcoidosis (Löfgren's syndrome)
• Chronic sarcoidosis
• Early onset sarcoidosis

1. acute sarcoidosis (Löfgren's syndrome): Acute sarcoidosis occurs in 5% of cases. It is defined by the triad: arthritis, bihilar adenopathy and erythema nodosum. Acute sarcoidosis may be febrile, occasionally even highly febrile in episodes with leukocytosis. The occurrence 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 significant disturbances of the general condition.

2. chronic sarcoidosis (90% of cases): Pulmonary involvement occurs in 95% of cases; initially asymptomatic (radiological incidental findings), possibly fatigue, later irritable cough, exertional dyspnea, characteristic is the discrepancy between good clinical findings and marked objective radiological findings (x-ray chest findings). The course of the disease is relapsing, usually lasting for years with further organ involvement: skin (15-35%), 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 (mostly oligo-, more rarely polyarticular arthritis, preferably of the ankle joints). The relapsing activities are generally accompanied by marked disturbance of the AZ, fever, fatigue and flu-like symptoms.

3) Early onset sarcoidosis (EOS): Rare special form of acute sarcoidosis that manifests before the 5th LJ. It occurs in a triadic 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 called "blue syndrome".

Lung changes in chronic sarcoidosis are classified according to 5 types of lung changes according to internationally established radiological criteria (classification according to Scadding 1967):

• Type O: normal findings in rare isolated extrapulmonary organ sarcoidosis or typical BAL findings without x-ray findings
• Type I: Bihiliary lymphadenopathy: Polycyclically limited enlargement of the hilus
• Type II: Bihiliary lymphadenopathy with lung infestation
• Type III: Lung infestation without lymphadenopathy
• Type IV: Pulmonary fibrosis with reduced lung function

A further classification divided into 3 stages (classification according to Wurm 1958):

• Stage I: Bihiliary lymph node enlargement
• Stage II: Parenchyma involvement
• Stage III: Fibrosis.
• 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

67Gallium scintigraphy and PET-CT are suitable for activity determination.

The laboratory data listed below refer mainly to acute sarcoidosis and sarcoidosis with system involvement.

Acute Sarcoidosis:

• BSG always increased.
• Angiotensin converting enzyme (ACE) (enzyme in the conversion of angiotensin I into the vasoconstricting 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%)
• Possibly leukopenia and lymphopenia, also eosinophilia

Histologically there is a non-cheesy granulomatous tissue reaction. First, loose nodules of activated macrophages and epithelioid cells form 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).

Detection of pulmonary and extrapulmonary manifestations (Rö; HRCT)

Histology: Biopsy (in the presence of skin lesions the skin biopsy is an important diagnostic criterion); biopsy of the bronchial mucosa, specific lung biopsy; skin lesions: Clinic with diascopy (detection of the typical infiltrate of the skin); furthermore specific biopsies of other organs with suspicious findings.

Bronchoalveolar lavage (BAL) with cytology: lymphocytic alveolitis with shift of the CD4/CD8 ratio in favour of the T-helper cells (normal CD4/CD8 =2; in active sarcoidosis >5).

Exclusion of an infectious genesis (bacteriological, mycological).

Additional diagnostics:

• 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 hyperglycaemia with recall antigens (tuberculin test negative in 2/3 of cases).
• ANA: in 30% of the patients pos.
• 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 the patients with system infestation; false positive results in about 10% of the 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.

DD varies depending on the sarcoidosis infestation pattern, acute condition and localization.

For dermatogenic infestation:

• 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 fungoides type
• For lupus pernio: granulomatous rosacea

For pulmonary infestation:

• Type I (type designation according to the International Classification of Pulmonary Sarcoidosis)
  • Hilus lymph node tuberculosis
  • Bronchial carcinoma
  • Leukoses
  • Berylliosis (rare)
  • Hodgkin's disease
  • Castleman's disease (benign mediastinal lymphoma)
• Type II/III
  • silicosis, asbestosis, berylliosis
  • Allergic alveolitis
  • Miliary tuberculosis
  • Ornithosis
  • Alveolar cell carcinoma
  • Carcinomatous lymphangitis
• type IV
  • Pulmonary fibrosis of other aetiology

Acute Sarcoidosis:

1. symptomatic

Chronic Sarcoidosis:

• Due to an overall good prognosis with a high tendency to 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.
• 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 as well as other serious organ involvement (e.g. kidney) are also systematically addressed.
• However, glucocorticoids (most effective systemic therapy) are controversial in their value; an indication for glucocorticoids exists from type II on, when lung function deteriorates; further in hypercalcemia and uria, in involvement of the eyes, liver, CNS, myocardium, kidneys and skin). Prednisolone (e.g. Decortin H) initially 30-40 mg/day, slowly levelling out over about 6 months. Reduction to 7.5-15.0 mg; attempt to discontinue after 4-6 months. In case of recurrence, repeat treatment as before. Maintenance dose for 12 months, then try again.
• Alternatively: Immunosuppressive drugs in combination with glucocorticoids, rarely alone if glucocorticoids are contraindicated.
• Chloroquine: Casuistic success is shown under antimalarial drugs such as 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): 50-200 mg/day p.o.
• Methotrexate (e.g. Lantarel): 10-25 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:

• Anecdotal reports exist about 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. Fumaderm® 3-6 tbl. spread over the day).
• Biologics: Anecdotal reports and smaller studies with exceptionally good results exist on TNF-alpha inhibitors (Etanercept, Infliximab, Adalimumab). In a single study, after 18 months of a combination therapy (Etanercept 2 times/day 25 mg, Prednisolon 1 times/day 30 mg, Hydroxychloroquine 2 times/day 200 mg and Methotrexate 1 time / week 15 mg) a complete healing was shown.

For arthritic complaints: NSAIDs

Acute sarcoidosis shows spontaneous healing in >95% of cases within 2 years.

Chronic type I sarcoidosis (lung infection) shows spontaneous healing of about 80% of the body within 1-3 years.

Chronic type II sarcoidosis (lung infestation) shows spontaneous healing of about 50% -70% in 1-3 years.

Chronic type III sarcoidosis (lung infestation) shows spontaneous healing of about 20%-30% in 1-3 years.

20% of patients with chronic sarcoidosis show a permanent reduction in lung function.

Risk factors for progression or chronicity:

• Age > 40 years, hypercalcemia, lupus pernio, chronic uveitis, neurosarcoidosis, cardiac involvement
• Symptom duration > 6 months
• Pulmonary Sarcoidosis Type III
• Fatalities of the disease: about 5%.

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

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