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14.

SARCOIDOSIS

DEFINITION

Sarcoidosis is a systemic inflammatory disorder characterized by the presence of


noncaseating granulomatous inflammation in involved organs. The lungs, eyes,
skin, joints, lymph nodes, and upper respiratory tract are usually affected.

EPIDEMIOLOGY

The incidence and prevalence of sarcoidosis is characterized by heterogeneity. It


appears to be 3 to 4 times more common in Afro Americans than Caucasians. The
female gender is more affected than the male one. The highest prevalence was
noted in northern Europe with a peak between 20 and 40 years of age.

PATHOGENESIS

The aetiology of sarcoidosis is unknown. The following factors (presumably


triggers/antigens) were noted in studies aiming the cause of sarcoidosis:
infectious agents: Mycobacterium tuberculosis, Propionibacterium acnes,
Human herpes virus. following transplantation ( eg. bone marrow, stem
cell, cardiac)
Kveim-Siltzbach reagent
genetic background: angiotensin converting enzyme genotypes, HLA-
B12,13, 27, 35; HLA-DR3,4,5
CD4+/CD8+ T cells the Th1/Th2 balance plays an important role in the
organisation of granulomas, the auto-resolution and/or progression of
the disease.
Cytokines Il-2 (proliferation or redistribution of the activated
lymphocytes population and B cell differentiation ), Il-6, Il-8 (disease
process), Il-15 (CD4+ T cell proliferation), Il-12, Il-18 (stimulate IFN-)
The characteristic of sarcoidosis is the non-caseating granuloma that can be
found in any organ. Sarcoidosis is mediated primarily by the CD4+ T cells (T
helper cells Th1). The initial lesion, at the level of the lung, is alveolitis. So
beside the CD4+ T cells, the alveolar macrophages (inflammation!!!) produce and
express pro-inflammatory cytokines such as: Il-12, Il-18, IFN-, TNF .
The granuloma is characterized by:
central epitheliod cells, activated monocytes-macrophages, and
multinucleated giant cells
periphery suppressor CD8+ T cells (Th2)
It is presumed that the extrapulmonary manifestations in sarcoidosis are due to
the migration of activated T cells through the blood and lymphatic vessels to
other tissues.

CLINICAL MANIFESTATIONS

1. Pulmonary involvement
90% of cases
50% detected incidentally on chest radiography hilar
adenopathy
cough
dyspnea
chest pain
wheezing (may be present)
self limited
spontaneous remission
2. Extrathoracic manifestations
cutaneous involvement: erythema nodosum, subcutaneous
nodules, plaques, paules, lupus pernio
ocular involvement: uveal tract, lacrimal gland and conjunctiva;
optic neuritis, pars planis (attention!!! differential diagnoses with
multiple sclerosis); uveitis is the most common ophthalmologic
manifestation
arthralgia/arthritis, tenosynovitis, myopathies
unilateral facial nerve palsy
heart involvement: pericarditis, left ventricular dysfunctions,
arrhythmias
hepatomegaly
diabetes mellitus hypothalamic-pituitary axis involved
vasculitis
3. Lofgrens syndrome is characterized by:
hilar adenopathy
acute arthritis/arthralgias
erythema nodosum
Caucasians
women
typically involves the ankles and knees
also associates: fever, myalgia and weight loss
excellent response to corticotherapy
90% remission rate
4. Heefordts syndrome:
anterior uveitis (iridocyclitis or iritis)
parotid gland enlargement
facial palsy
fever

LABORATORY FINDINGS

elevated ESR (non specific)


hypergammaglobulinemia
anemia secondary to chronicity
leukopenia, lymphopenia, eosinophilia, thrombocytopenia is rare
elevated angiotensin converting enzyme (ACE) is normal in acute
sarcoidosis
hypercalciuria, hypercalcemia consequence of enhance production of
1,25 dihydrocholecalciferol due to elevated levels of ACE
serum alkaline phosphatase might be elevated hepatic involvement

IMAGISTIC FINDINGS

Chest radiographic stages


Stage 0
normal
Stage 1
bilateral hilar adenopathy
Stage 2
bilateral hilar adenopathy with pulmonary infiltrates
Stage 3
pulmonary infiltrates with lung insufficiency

Chest High Resolution Computed Tomography (HRCT) the lesions are


localised in the mid-upper zones of the lungs:
lymphadenopathy (hilar and mediastinal)
nodules
fibrosis
ground glass phenomenon
cysts
parenchymal masses or bands
thickening of the bronchovascular bundles

Bone radiography - bone lesions usually occurs in the proximal and middle
phalanges:
cystic bone lesions (more cystic than sclerotic)
lytic bone lesions heads
sclerotic lesions
focal bone lesions
osteopenia/osteoporosis

Pulmonary function tests


restrictive pattern - diffusing capacity for carbon monoxide
sometimes obstructive pattern endobronchial sarcoidosis

Bronchoalveolar lavage (BAL)


reduce number of CD8+ T cells
elevated CD4 to CD8 ratio
lymphocytosis is not specific
neutrophils > 2% or eosinophils > 1% - usually is not sarcoidosis!!!

DIAGNOSIS

It is suggested if the following are present:


clinical and imagistic manifestations
biopsy non-caseating granuloma
exclusions of other diseases such as: tuberculosis, Crohns disease,
lymphomas, bacterial, viral, parasitic or fungal infections etc.

Prognosis is negative influenced by:


Afro American race
onset after 40 years old
lupus pernio (be attentive it may be tuberculosis: TB)
chronic uveitis
chronic hypercalcaemia
nephrocalcinosis
progressive pulmonary involvement
nasal mucosal involvement
cystic bone lesions
neurosarcoidosis
cardiac involvement
TREATMENT

The management of sarcoidoisis depends on the clinical manifestations lung or


extrapulmonary symptoms.

Pulmonary involvement treatment


Indications:
progressive radiographic changes
deterioration of lung function
worsening of pulmonary symptoms

Medications:

Corticosteroids are used for its suppressing effects on inflammatory response.


It is believed to reduce the progression of fibrosis and acts on pulmonary
sarcoidosis as well. There are not stipulated protocols concerning the dose of
corticosteroids in pulmonary sarcoidosis. The oral therapy can be started with
0.5 to 1 mg/kg ideal body weight for 4 to 6 weaks and after that tapered by 5 to
10mg every 4 to 8 weeks until the maintenance dose is reached (0.25mg/kg ideal
body weight for 6 to 12 months).

Immunosuppresive drugs
In case of a non response to corticosteroids the following drugs may be used:
Azathioprine
Cyclophosphamide
Chlorambucil
Cyclosporine

Lung transplantation end stage pulmonary fibrosis.

Extrapulmonary involvement treatment


Indications:
resistant symptomatic disease
resistant ophthalmic manifestations
progressive chronic pulmonary disease
neurosarcoidosis
cardiac involvement
hypercalcemia
bone and joint destruction

Medications:

Corticosteroids similar doses as in pulmonary involvement.

Methotrexate (MTX) is used as a substitute for corticosteroids in acute


sarcoidosis (except pulmonary manifestations). MTX is often associated with
liver fibrosis and progressive interstitial lung changes (especially in sarcoidosis).

Colchicine can be effective for acute arthritis.

Antimalars (chloroquine/hydroxichloroquine) cutaneous and/or


musculoskeletal disease (+/- low dose of methotrexate).

Immunosuppresive drugs
In case of a non response to corticosteroids the following drugs may be used:
Azathioprine cutaneous disease
Cyclophosphamide cardiac and neurosarcoidosis

TAKE HOME MESSAGES

Sarcoidosis is characterized by a non-caseating granuloma, that can affect


any organ.
The most common manifestations are pulmonary involvemet hilar
adenopathy (bilateral) and anterior uveitis.
An increase CD4 to CD8 ratio in BAL fluid strongly supports the diagnosis
of sarcoidosis.
ACE can be normal in acute sarcoidosis.
Corticosteroids are the cornerstone therapy for active sarcoidosis.

References:
1. 1. Stone JH, A Clinicians Pearls and Myths in Rheumatology, Springer
2009, 493: 23-26, ISBN: 978-1-84800-933-2
2. xxx