Impact of sarcoidosis

Several features in sarcoidosis phenotypes, Lofgren’s syndrome (LS) and non-Lofgren’s syndrome (non-LS), such as the variability in the clinical presentation and the lack of case definitions of disease – pose a challenge for epidemiological studies to deduce underlying causes of disease and etiology since these features are ascertainment bias. A further difficulty arises when a high proportion of patients with either sarcoidosis phenotype (LS or non-LS) are asymptomatic and the finding of the disease is by chance. Taken together, these difficulties result in a degree of disease misclassifications leaving the patient undiagnosed for the disease.

Epidemiological evidence indicates that sarcoidosis and its main phenotypes, LS and non-LS, have low prevalence across the world, and in some populations these are considered rare phenotypes. Pooled LS and non-LS cases together under the classification of sarcoidosis, the disease prevalence ranges from 0.2 per 100,000 in South America to 64 per 100,000 in Sweden. Sarcoidosis is roughly as common in men as in women and has the tendency to present in young adulthood (rarely in childhood). Race and ethnicity are strong factors that markedly influence disease presentation, prevalence, and incidence.
Sarcoidosis (either LS or non-LS) affects the life-style of young individuals who are referred to specialized respiratory clinics, generating significant direct and indirect healthcare cost.

In many patients, sarcoidosis, specifically the LS phenotype regresses on its own over a period of 2-5 years whilst in the majority of the patients, mainly those diagnosed with  non-LS, the disease progresses over the years, sometimes involving more than two organs e.g., lungs, heart, kidney, eyes, skin, nervous system, musculoskeletal system, reproductive system, lymph nodes, live, and spleen – which  are progressively infiltrated and compromised with extensive fibrosis.

Death from sarcoidosis, particularly in patients affected by the non-LS phenotype, is about five percent. Deaths are commonly attributed either to progressive lung scarring  such as fibrosis, complicated by bleeding from the lung vessels, i.e., respiratory failure or to development of granulomas in the lungs and/or in the heart causing abnormal heart rhythms and thereby resulting in failure of the heart’s right ventricle.

Genetic determinants in sarcoidosis

Evidence points out that phenotypes of sarcoidosis, that is, LS and non-LS, are disease entities enhanced by T-cell mediated immune responses at sites of granulomatous inflammation; however, specific determinants underlying molecular mechanisms and regulation in disease pathology have not yet been identified. In fact, sarcoidosis  phenotypes LS and non-LS are multifactorial disease entities likely to result from the interplay between multiple genes and perhaps also environmental factors – each exerting only a modest effect on the overall risk. The distinctive genetic arrangements in each phenotype poise important functions that contribute to the disease diversity observed in the clinical presentation and course of the disease.

Sarcoidosis and autoimmunity

The pathologic hallmark in sarcoidosis phenotypes, LS and non-LS, is characterized by granulomatous tissue comprised by epithelioid cells, CD4 lymphocytes, mature macrophages, multinucleated giant cells, CD8 lymphocytes, antigen-presenting cells (APCs), and cellular mechanisms orchestrated by assemblies of inflammatory machineries. Moreover, research evidence suggests that in both phenotypes an adaptive-mediated immune response mechanism drives the genetic architecture of each  phenotype.Whether this mechanism is the same in both is an active research field.