Page 1018 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Sarcoidosis

Edward S. Chen, David R. Moller

Sarcoidosis is a systemic inflammatory disorder characterized of Japanese patients with sarcoidosis, but in only 10–25% of
by the presence of noncaseating granulomas and lymphocyte European and North American patients. Retrospective studies
1,2
inflammation. The disease most frequently involves lungs suggest that sarcoidosis is the direct cause of death in 1–6%
and thoracic lymph nodes, although any organ system can be of cases, usually from pulmonary, cardiac, or neurological
involved (Table 73.1). The manifestations and clinical course involvement. 10
3
of sarcoidosis vary greatly. An estimated 30–60% of patients
with sarcoidosis are asymptomatic, usually with isolated bilateral GENETICS
hilar adenopathy, and clearly some of these patients remain
unidentified. Symptomatic manifestations most frequently involve There is substantial evidence for a genetic predisposition to
the respiratory system, with symptoms of cough, dyspnea, and sarcoidosis, including higher concordance among monozygotic
chest discomfort. Löfgren syndrome is a distinct presentation of twins than among dizygotic twins and familial clustering in
acute sarcoidosis, with polyarthritis, bilateral hilar adenopathy, 5–16% of patients. A US-based multicenter study compared 706
erythema nodosum, and often uveitis. This form of sarcoid- newly diagnosed cases of biopsy-proven sarcoidosis to age-, sex-,
osis usually resolves completely. Other clinical manifestations and race-matched relatives and found an approximate fivefold
depend on the range and extent of extrapulmonary involvement. increased relative risk in siblings and parents of individuals with
More than one-third of patients will experience chronic active sarcoidosis. 11
disease, which is associated with considerable risk of long-term Major histocompatibility complex (MHC) class II alleles are
morbidity resulting from progressive organ dysfunction and major contributors to disease susceptibility across different ethnic
12
complications of immunosuppressive treatment. Given the populations. Human leukocyte antigen–D related 3 (HLA-DR3)
lack of validated biomarkers of disease activity, the manage- is associated with increased sarcoidosis risk in Scandinavian and
ment of sarcoidosis involves serial assessment of symptoms, European populations, whereas HLA-DR1 and HLA-DR4 alleles
radiographic imaging, and objective measurement of organ are associated with disease protection. A significant association
function. was found with HLA-DRB1*11:01 in African Americans and
Caucasians, whereas HLA-DRB1*15:01 was a risk factor only in
EPIDEMIOLOGY Caucasians. Residues forming pocket 4 of HLA-DR and pocket
9 of HLA-DQ seem to influence sarcoidosis risk, which suggests
Sarcoidosis is found worldwide, although there are striking specific antigenic peptides are involved in causing sarcoidosis.
differences in the prevalence of the disease in different geographi- HLA class I alleles (B*07, A*03) also confer risk for sarcoidosis,
4
cal areas and racial groups. In Europe and North America, the independently from HLA class II alleles. Together, these HLA
estimated prevalence ranges from 10 to 64 cases per 100 000, associations with sarcoidosis may reflect the effects of an 8.1
with higher rates in African-American populations. Although it ancestral haplotype (A1, B8, DR3, DQ2) that is linked to several
can occur at any age, over 80% of cases are diagnosed between other immune-related diseases; larger studies will be neces-
4,5
20 and 50 years of age, with a further peak after age 50 years. sary to determine the independent risks associated with each
Globally, there is a slight female preponderance. Sarcoidosis may allele.
6
present differently in men and women, and it presents differently HLA class I and II alleles are associated with clinical
7
in older people, complicating case identification. Recent studies course. HLA DRB1*03:01 and DQB1*02:01 are associated
have supported prior observations of worse outcomes in African with favorable outcomes, whereas DR14 and DR15 are associ-
American women compared with other demographic groups in ated with severe, chronic disease in European and Japanese
the United States. 8,9 populations, as are the closely linked alleles DRB1*1501:01 and
The frequency of clinical manifestations and disease severity DQB1*06:02.
varies among different groups. Löfgren syndrome has a par- Studies of non-HLA polymorphisms have yielded few clues
ticularly high frequency in the Scandinavian countries and in to the genetic basis of sarcoidosis. A meta-analysis found poly-
Ireland but occurs in <5% of African American patients with morphism of the gene for tumor necrosis factor-α (TNF-α)
sarcoidosis. Lupus pernio, a disfiguring nodular facial condi- associated with a 1.5-fold increased risk of developing sarcoid-
13
tion associated with chronic sarcoidosis, is more frequent in osis. Associations were reported between sarcoidosis and the
patients of African descent. Cardiac involvement occurs in >50% CC chemokine receptors CCR2 and CCR5 and the receptor for
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