Research increasingly suggests that sarcoidosis results from an interplay of environmental and genetic factors.  Although the recently completed ACCESS (A Case-Control Etiologic Study of Sarcoidosis) study was not able to definitively identify a single cause for sarcoidosis, it did yield important findings regarding familial and environmental risks that have advanced our understanding of this disease.  Family clustering and differences in racial incidence of sarcoidosis support an inherited susceptibility to sarcoidosis. Siblings of patients with sarcoidosis have about a fivefold increased risk of developing sarcoidosis.  In addition, two recent genome scans have been reported in sarcoidosis. One in African Americans reporting linkage to chromosome 5 and the other in German families reporting linkage to chromosome 6. The author concludes that advances in genotyping and statistical analysis are helping to clarify the genetics of sarcoidosis.
 

The lungs are the most commonly affected organ in sarcoidosis.  Ninety percent or more of people with sarcoidosis have lung involvement, whether they have symptoms or not.  This Japanese study investigated early pulmonary involvement of 24 sarcoidosis patients using an imaging method called scintigraphy.  Comparing results from chest computed radiography (CR), high resolution computed tomography (HRCT) and scintigraphy with (99m)Tc-DTPA aerosol against confirmed biopsies, they conclude that pulmonary clearance scintigraphy with (99m)Tc-DTPA aerosol may be useful for assessing pulmonary involvement before radiological changes are evident.
 

Fibered confocal fluorescence microscopy (FCFM) is a new technique that produces microscopic imaging of a living tissue through a 1-mm fiberoptic probe that can be introduced into the working channel of the bronchoscope.   Researchers in France analyzed the microscopic structure of normal and diseased bronchial lining using FCFM during bronchoscopy and found that this procedure represents a minimally invasive method to study specific alterations associated with premalignant bronchial lesions within the body. They conclude the technique may also be useful to study the bronchial wall in nonmalignant chronic bronchial diseases, like sarcoidosis.
 

Using 33 non-smoking sarcoidosis patients, researchers in Spain evaluated the bronchoalveolar lavage fluid to determine whether quantities of white blood cells would provide predictive information as to the future course of their disease.  They found that increased percentages of specific white blood cells in the bronchoalveolar lavage fluid from patients with sarcoidosis were associated with a poor outcome and a higher probability to need treatment.
 

In this retrospective study, researchers in Turkey evaluated 492 consecutive patients with sarcoidosis to evaluate the seasonal pattern of symptoms by age and by both genders.  According to chest X-ray examinations, 185 patients had stage 1, while 307 patients in control group had stages 0, 2, 3 and 4.  Demographic features, presenting clinical features, course of the disease, initial diagnostic methods and both the month and the age at the initial diagnosis for each patient were analyzed.  The distribution of cumulative monthly presentations for patients with stage 1 peaked in April (108% above the average) and was lowest in October, November and December (48% below the average).  Their findings additionally suggest seasonal patterns were influenced by age and by gender.  They recommend further prospective studies to better understand disease development and possible  interactions among age, gender and the disease.
 

Lofgren's syndrome is a form of acute sarcoidosis that occurs for a short period with specific symptoms and which affects specific areas of the body.  Inflammation usually includes the skin of the legs (erythema nodosum), the joints and the lymph glands in the chest and occurs along with a fever.  In evaluating 150 patients, researchers in Sweden conclude that manifestations of Lofgren's syndrome differ between men and women, with skin inflammation found predominantly in women while a inflammation around the ankle joints or ankle arthritis without EN is seen preferentially in men.
 

1 Sept 2006

Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5. Hum Genet. 2006 Aug 4; Epub ahead of print.

Sarcoidosis, a systemic granulomatous disease, likely results from both environmental agents and genetic susceptibility. In the United States, African Americans are both more commonly and more severely affected than Caucasians. Previously, a sarcoidosis genetic linkage study consortium was established to recruit African-American affected sibling pair families to identify chromosomal regions that may harbor sarcoidosis susceptibility genes and to determine if environmental factors modify any genetic effects (SAGA Study - SArcoid Genetic Analysis).  Researchers report a follow up to the first genome scan for sarcoidosis susceptibility genes in African Americans.  Like the original, the present study included 229 African American nuclear families ascertained through two or more siblings with sarcoidosis and found the strongest signal was at marker D5S407 (P=0.005) on 5q11.2, using both full and half sibling pairs.  The results support, in an African American population, a sarcoidosis susceptibility gene on chromosome 5q11.2, and a gene protective for sarcoidosis on 5p15.2.  In addition, researchers conclude that multiple susceptibility loci for sarcoidosis exist in African Americans and that some may have interdependent effects on disease development.
 

8 Aug 2006

ACE I/D-corrected Z-scores to identify normal and elevated ACE activity in sarcoidosis. Respir Med. 2006 Aug 8; Epub ahead of print.

The value of elevated serum angiotensin-converting enzyme (ACE) activity in the diagnosis and follow-up in sarcoidosis is a matter of ongoing debate.  ACE activity is influenced by polymorphisms, or genetic variants, in the ACE gene. Tests that do not use genotype-specific reference intervals for ACE activity may lead to a less precise interpretation of ACE activity.  In order to assess whether determination of ACE activity requires the ACE I/D genotype to be taken into account, researchers in the Netherlands established ACE I/D-corrected reference intervals in 200 healthy volunteers.  ACE activities in sarcoidosis patients were then expressed as a Z-score (standard score) related to these reference intervals.  This data demonstrates a convenient and accurate way to circumvent the use of different intervals by introducing a Z-score for ACE activity and suggests the need to re-investigate the possible clinical value of serum ACE activity in sarcoidosis.
 

1 July 2006

Transforming growth factor-beta gene polymorphisms in sarcoidosis patients with and without fibrosis. Chest. 2006 Jun;129(6):1584-91.

Pulmonary fibrosis, or scarring of the lungs, develops in approximately 25% of patients with chronic sarcoidosis. Transforming growth factor-beta (TGF–β) is a chemical messenger protein identified as having a central role in fibrosis. Researchers in the Netherlands assessed patients and control subjects over a four-year follow up period to determine whether genetic variations in the three isoforms, or versions, of this protein might contribute to pulmonary fibrosis in sarcoidosis patients. This study is the first to suggest the implication of genetic variation of TGF–β3 in the development of pulmonary fibrosis in sarcoidosis patients.
 

1 June 2006

A new tool to assess sarcoidosis severity. Chest. 2006 May;129(5):1234-45.

Sarcoidosis is a granulomatous disorder that primarily affects the lung, however, other organs are frequently involved. There are no comprehensive scoring systems for sarcoidosis disease severity. Researchers reviewed clinical data on 104 patients with biopsy-confirmed sarcoidosis and independently scored disease severity using a visual analog scale.  From their analysis, they derived an objective disease severity scoring system that incorporates data on demographics, pulmonary function and organ involvement to produce a whole-body sarcoidosis assessment. They suggest this preliminary tool has potential applicability in the assessment of disease severity in sarcoidosis research.
 

1 May 2006

Relationship between Symptoms and Quality of Life in a Sarcoidosis Population. Respiration. 2006 Apr 7; Epub ahead of print.

Sarcoidosis is a multi-system disease and patients may suffer from various symptoms. However, the relationship between frequently reported symptoms and quality of life (QOL) has not yet been studied.  Researchers conducted a cross-sectional observational study on 150 sarcoidosis patients in Croatia to assess symptoms and QOL using the World Health Organization Quality of Life Assessment Instrument.  The four most frequently mentioned symptoms were fatigue, breathlessness, reduced exercise capacity and arthralgia, or joint pain.  Being female, using corticosteroids and fatigue were sited as factors which impacted physical and psychological health as well as level of independence, with fatigue the most important symptom in predicting QOL.  Researchers recommend to focus not only on objective health parameters, but also on fatigue in the management of sarcoidosis.
 

1 Apr 2006

Bayesian logistic regression using a perfect phylogeny. Biostatistics. 2006 Mar 23; Epub ahead of print.

Haplotypes are sets of genes on a single chromosome. Haplotype data capture genetic variation among individuals in a population and among populations. An understanding of this variation and the ancestry of haplotypes is important in genetic association studies of complex diseases like sarcoidosis. Using a candidate gene study of sarcoidosis, researchers introduce a new method for detecting associations between disease and haplotypes which uses a statistical approach based on probability to incorporates new information and even prior knowledge (Bayes’ theorem) and logistic regression to create an evolutionary history (phylogeny). Environmental factors, as well as their interactions with variations in the genetic code (SNPs) can be incorporated into the regression framework.
 

1 Mar 2006

The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006 Mar 10;312(5):561-74.

Angiogenesis is the process by which new blood vessels are formed from existing vessels.  In mammals, variations in different genes are thought to alter this process.  Genetic diversity in angiogenesis-regulating genes has been linked to increased susceptibility to multiple angiogenesis-dependent diseases in humans including cancer, arthritis, atherosclerosis, cardiovascular disease, endometriosis, diabetic retinopathy, psoriasis and sarcoidosis.  Recent studies have used genome sequences from other species to dissect the complexity of the genetic diversity that regulates angiogenesis.  Gene mapping in mouse models has identified the position of several genes involved in the process.   Comparing the human genome sequence with those of other organisms helps identify regions of similarity and difference, providing critical clues about the structure and function of human genes.
 

1 Feb 2006

Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst 2006 Jan 4;98(1):51-60.

Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL).  Researchers in Denmark and Sweden conducted a population-based case-control study of 3055 NHL patients and 3187 matched control subjects.  Patients were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity and treatment. Risks of NHL were increased in association with certain diseases including rheumatoid arthritis, primary Sjogren syndrome, systemic lupus erythematosus, and celiac disease.  However, sarcoidosis, psoriasis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype.
 

1 Dec 2005

Involvement of discoidin domain receptor 1 in the deterioration of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2005 Dec;33(6):565-73.

Although the lungs are affected in more than 90% of patients with sarcoidosis, the symptoms and severity of disease can vary greatly. Researchers in Japan sought to identify the mechanism which led to worse outcomes, or deterioration, in lung disease. In looking at 33 patients with sarcoidosis with pulmonary infiltrates, they found increased levels of DDR1, an enzyme involved in cell communication, and conclude that it is associated with the deterioration of lung disease.
 

1 Oct 2005

Difficulties in the differentiation of chronic inflammatory diseases of the central nervous system--value of cerebrospinal fluid analysis and immunological abnormalities in the diagnosis.  Acta Neurol Scand. 2005 Oct;112(4):207-13.

A number of systemic diseases can affect the nervous system including lupus erythematodes, Behcet's disease, Sjogren's syndrome (SS) and sarcoidosis.  These diseases can be difficult to diagnose because neurologic symptoms can be confused with those of another chronic inflammatory disease, multiple sclerosis (MS).  Because these diseases are treated differently, it is important to distinguish between them.  When reviewed individually, neither clinical signs nor specific tests such as blood tests or cerebrospinal fluid (CSF) analysis are able to differentiate between the diseases with certainty.  However when researchers compared all typical clinical and CSF findings together, differentiation of the respective diseases, and diagnosis was possible.
 

1 Sept 2005

Usefulness of quantifying serum KL-6 levels in the follow-up of uveitic patients with sarcoidosis.  Graefes Arch Clin Exp Ophthalmol. 2005 Aug 23;:1-5 [Epub ahead of print]

The appearance of sarcoidosis outside of the lung is common in certain populations, for example more patients in Japan have heart and eye complications from the disease. Comparing 36 patients with uveitis to the same number of healthy controls, researchers in Japan found that measuring blood levels of KL-6, a molecule that consists of protein and carbohydrates, was useful to diagnose sarcoidosis as well as to follow-up diagnosed cases because levels were less affected by systemic medication than other blood tests.
 

1 Aug 2005

Relationship of environmental exposures to the clinical phenotype of sarcoidosis. Chest. 2005 Jul;128(1):207-15.

Sarcoidosis is a multi-system disease that causes inflammation of the body’s tissues. Symptoms typically depend on which organ the disease affects. Using 718 patients at 10 A Case Control Etiologic Study of Sarcoidosis (ACCESS) centers, researchers reviewed the duration and intensity of patient exposures to different environmental elements and found that systemic and pulmonary-only sarcoidosis may be caused by different environmental exposures. Findings that include African-Americans' exposure to wood burning and Caucasians' exposure to agricultural organic dust are associated with different phenotypes of sarcoidosis also suggests that African-Americans and Caucasians are either affected differently by the same exposures or that they come into contact with different exposures.
 

1 July 2005

Genome-wide search for sarcoidosis susceptibility genes in African Americans.  Genes Immun. 2005 Jun 9; [Epub ahead of print].

The cause of sarcoidosis is not yet known, however, genetic predisposition does appear to be important.  In the US, sarcoidosis frequently occurs more often and more severely among African Americans than among Caucasians.  This study looked at 229 African-American families where two or more siblings had a history of sarcoidosis, to try to determine the specific physical location of a susceptibility gene on a chromosome.  Based on their findings, the researchers conclude that it is likely that more than one gene influences sarcoidosis susceptibility in African Americans.
 

6 June 2005

Fungal infections as a complication of therapy for sarcoidosis. QJM. 2005 Jun;98(6):451-6.

Sarcoidosis granulomas (masses of inflamed tissue, or lumps) result from a response of the immune system. Most medications used to treat sarcoidosis suppress the immune system. This can leave a person more likely to get sick from an infection.  In addition, fungal infections may be difficult to distinguish from sarcoidosis.   In this retrospective study, researchers in Ohio looked at the notes from 753 patients seen over an 18 month period and found that only seven patients (0.9%) developed fungal infections - suggesting that fungal infections occur rarely in treated patients with sarcoidosis.  However, deterioration of chest X-ray, especially a localized infiltrate (collection of of inflammatory cells), warrants investigation.
 

1 May 2005

Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics.  (Eur Respir J. 2005 May;25(5):783-8.)

Pulmonary hypertension is a condition in which the pressure of the blood vessels in the lungs is elevated. This causes the heart and lungs to strain to provide enough oxygen to the body. Pulmonary hypertension is common in advanced sarcoidosis and associated with poor outcomes, but little is known about which sarcoidosis patients are likely to develop it. Researchers reviewed the records of 363 patients in the United States and found that patients who needed higher levels of supplemental oxygen often had pulmonary hypertension. They suggest more aggressive screening for pulmonary hypertension be considered in patients with sarcoidosis.
 

1 Apr 2005

Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. (Lancet. 2005 Mar 16;365(9464):1062-72.)

Sarcoidosis is a multisystem disorder that predominantly involves the lungs and is characterized by T-cell response and granuloma formation, for which the explanation is unknown. A newly identified subset of T-cells with immunoregulatory functions has been shown in animal studies to protect against disorders with increased T-cell responses similar to sarcoidosis. Researchers took blood samples from 60 patients with sarcoidosis and found that these cells were absent or greatly reduced in all patients.  The deficiency was found in both acute and resolved disease and was unrelated to systemic corticosteroid therapy.  The authors conclude that the loss of immunoregulation by these cells could explain the amplified and persistent T-cell activity in sarcoidosis and may provide new insight into the development of sarcoidosis and draw attention to a potential target for new treatments.
 

1 Mar 2005

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of sarcoidosis. (Eur Respir J. 2005 Mar;25(3):405-9.)

Bronchoscopy is a test in which a flexible tube is inserted through the mouth to examine the airways of the lungs. In 30% of patients with suspected sarcoidosis, bronchoscopy with biopsy, or removal of tissue, is unsuccessful as a diagnostic tool and a more invasive mediastinoscopy is done to surgically remove tissue from the lymph nodes. In this study of 51 patients, researchers used a technique called “endoscopic ultrasound-guided fine-needle aspiration” (EUS-FNA) as a nonsurgical alternative to diagnose sarcoidosis by aspirating lymph nodes in the chest from the esophagus. Thirty-six patients (71%) had previously undergone a nondiagnostic bronchoscopy. EUS-FNA demonstrated a high yield in diagnosing sarcoidosis in 41 of 50 patients (82%) without complications.
 

1 Feb 2005

Histopathological Features of Conjunctival Sarcoid Nodules Using Noninvasive In Vivo Confocal Microscopy. (Arch Ophthalmol. 2005 Feb;123(2):274-6.)

In patients with inflammatory diseases of the eyes, biopsy of lesions may be helpful in confirming the diagnosis of sarcoidosis.  A technique called "in vivo confocal microscopy" (IVCM) allows for noninvasive  examination of the eye at the cellular level and has been used to describe diseases of the cornea.  Researchers performed noninvasive IVCM on sarcoid granulomas in the eyes of a patient with skin, biopsy-proven sarcoidosis and uveitis.  Results were compared with a  conjunctival biopsy specimen to detail the typical microscopic features seen in sarcoidosis.
 

1 Jan 2005

Long-term follow-up CT scan evaluation in patients with pulmonary sarcoidosis. (Chest. 2005 Jan;127(1):185-91.)

A computed tomographic (CT) scan is a complicated kind of x-ray that gives a better picture of the lungs than an ordinary chest x-ray.  In this retrospective study, researchers looked at the first and last high-resolution CT (HRCT) scans of 40 patients with pulmonary sarcoidosis with an average period of 7.4 years between the two scans.  HRCT scan findings were them compared to pulmonary function tests.  Researchers identified specific patterns on the initial HRCT scans that were helpful in predicting the outcomes of patients with sarcoidosis, specifically those patients likely to develop severe respiratory problems.
 

1 Nov 2004

Early detection of cardiac involvement in patients with sarcoidosis by a non-invasive method with ultrasonic tissue characterization. (Heart. 2004 Nov;90(11):1275-80.)

This Japanese study sought to identify a non-invasive test for the early detection of heart involvement in patients with sarcoidosis. Twenty-two consecutive patients with biopsy proven sarcoidosis were selected and divided into two groups: 8 patients with cardiac involvement (diagnosed by tests including thallium, gallium and PET scans) and 14 patients without cardiac involvement. All of these patients had normal findings on conventional two dimensional echocardiograms. Researchers used a test “cyclic variation of myocardial integrated backscatter” (CV-IB) which uses ultrasound to measure a specific area of muscle in the heart. This test discriminated 75% of patients with cardiac sarcoidosis from those with non-cardiac sarcoidosis, whereas two dimensional echocardiographic did not discriminate between these two groups.
 

1 Oct 2004

Prevalence of coeliac disease in patients with sarcoidosis. Eur J Gastroenterol Hepatol. 2004 Sep;16(9):911-5.

Genetic research has suggested an association between sarcoidosis and celiac disease.  Celiac disease is an inherited, autoimmune disease in which the lining of the small intestine is damaged in response to ingestion of gluten and other proteins found in wheat, barley, rye, possibly oats and their derivatives.  Blood tests and biopsy in this pilot study of 102 sarcoidosis patients (47 males, 55 females) and 105 (52 males, 53 females) healthy, ethnically matched, controls demonstrated a moderately increased prevalence of celiac disease in Irish patients with sarcoidosis.
 

3 Sept 2004

A Case Control Etiologic Study of Sarcoidosis: Environmental and Occupational Risk Factors. Am J Respir Crit Care Med. 2004 Dec 15;170(12):1324-30. Epub 2004 Sep 3.

Past research suggests that environmental factors may be associated with sarcoidosis risk.  This case control study tested the theory that environmental and occupational exposures are associated with sarcoidosis. Ten centers recruited 706 newly diagnosed patients with sarcoidosis and an equal number of control subjects of matching age, race and sex. Test subjects answered questions regarding occupational (or job-related) and nonoccupational exposures. The study did not identify a single, predominant cause of sarcoidosis but did identify several exposures associated with sarcoidosis risk, including insecticides, agricultural employment and microbial bioaerosols.
 

1 August 2004

Sarcoidosis and granuloma genes: a family-based study in African-Americans. (Eur Respir J. 2004 Aug;24(2):251-7.)

The evidence for a genetic component in the cause of sarcoidosis includes familial grouping, associations with genetic variants and tissue similarity. Unfortunately, the majority of genetic associations with sarcoidosis have not been consistently replicated.  This study at the Henry Ford Health System in Detroit, Michigan used a family-based study design and attempted to replicate previously reported associations between sarcoidosis and three attractive candidate genes studied primarily in case-control samples. From looking at 225 nuclear families, the authors conclude that in African-Americans, the angiotensin converting enzyme, vitamin D receptor and tumour necrosis factor-alpha genes are not significant risk factors for sarcoidosis susceptibility.
 

1 July 2004

Epidemiology of sarcoidosis and its genetic and environmental risk factors. Rev Med Interne. 2004 Jul;25(7):494-500. In French.

Studies of incidence and distribution show that sarcoidosis is a world-wide disease. This review of the scientific literature indicates that disease frequency is influenced by multiple predisposition factors. The most important factors identified by the author are racial, sex, age, familial grouping, genetic and/or an infective agent. The authors conclude that sarcoidosis occurs in patients when environmental factors (infective agent, climate, country) and predisposition ones (race, sex, familial grouping) happen in connection with one another.
 

1 June 2004

NHLBI Working Group: Future Directions in Sarcoidosis Research. Am J Respir Crit Care Med. 2004 Sep 1;170(5):567-71. Epub 2004 May 13.

Although the cause of sarcoidosis remains unclear, certain environmental, genetic, ethnic and familial factors probably modify expression of the disease. For example, African-Americans are more often and more severely affected than Caucasians, and more often have a family history of the disease. Because of the many uncertainties, the National Heart, Lung, and Blood Institute convened a working group to identify future research directions and opportunities for sarcoidosis. Recommendations include developing a tissue bank, using new methods to identify genetic factors, studying the development of the disease using human and animal models, exploring new approaches to diagnose and manage the disease and conducting randomized controlled trials to assess new therapies.
 

1 May 2004

Involvement of dendritic cells in sarcoidosis. Thorax. 2004 May;59(5):408-413.

Dendritic cells are immune cells with threadlike tentacles called dendrites used to catch antigens, which they present to T cells.  In sarcoidosis, overactive T-cell cause granulomas. This Japanese study  analyzed dendritic cells in 24 patients with sarcoidosis to determine whether dendritic cells regulate the T cell response in sarcoidosis.   Their findings suggest that dendritic cells may migrate into the affected tissues, contributing to the formation of the granulomas.
 

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