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Sarcoidosis

Sarcoidosis, also called sarcoid (from the Greek 'sark' and 'oid' meaning "flesh-like") or Besnier-Boeck disease, is an immune system disorder characterised by non-caseating granulomas (small inflammatory nodules) that most commonly arises in young adults. The cause of the disease is still unknown. Virtually any organ can be affected; however, granulomas most often appear in the lungs or the lymph nodes. Symptoms can occasionally appear suddenly but usually appear gradually. The clinical course varies and ranges from asymptomatic disease that resolves spontaneously to a debilitating chronic condition that may lead to death.

Current Research

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Epidemiology

Sarcoidosis most commonly affects young adults of both sexes, with a slight preponderance for women having been reported by most studies. Incidence is highest for individuals younger than 40 and peaks in the age-group from 20 to 29 years.

Sarcoidosis occurs throughout the world in all races with a prevalence ranging from 1 to 40 per 100,000. The disease is most prevalent in Northern European countries, and the highest annual incidence of 60 per 100,000 is found in Sweden and Iceland. In the United States, sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9 per 100,000, respectively. Sarcoidosis is less commonly reported in South America, Spain and India.

The differing incidence across the world may be at least partially attributable to the lack of screening programs in certain regions of the world and the overshadowing presence of other granulolomatous diseases such as tuberculosis, that may interfere with the diagnosis of sarcoidosis where they are prevalent.

There may also be racial differences in the severity of the disease. Several studies suggest that the presentation in people of African origin may be more severe than for Caucasians, who are more likely to suffer from asymptomatic disease.

Signs and Symptoms

Sarcoidosis is a Systemic Disease that can affect any organ. Common symptoms are vague, such as fatigue unchanged by sleep, lack of energy, weight loss, aches and pains, arthralgia, dry eyes, blurry vision, shortness of breath, a dry hacking cough or skin lesions. The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum or lupus pernio. It is often asymptomatic.

The combination of erythema nodosum, bilateral hilar lymphadenopathy and arthralgia is called Lofgren syndrome. This syndrome has a relatively good prognosis.

Renal, liver (including portal hypertension), heart or brain involvement may cause further symptoms and altered functioning. Manifestations in the eye include uveitis and retinal inflammation, which may result in loss of visual acuity or blindness. Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis.

The combination of anterior uveitis, parotitis and fever is called uveoparotitis, and is associated with Heerfordt-Waldenstrom syndrome.

Investigations

Hypercalcemia (high calcium levels) and its symptoms may be the result of excessive vitamin D activation.

Sarcoidosis most often manifests as a restrictive disease of the lungs, causing a decrease in lung volume and decreased compliance (the ability to stretch). The disease typically limits the amount of air drawn into the lungs, but produces higher than normal expiratory flow ratios. The vital capacity (full breath in, to full breath out) is decreased, and most of this air can be blown out in the first second. This means the FEV1/FVC ratio is increased from the normal of about 80%, to 90%. Obstructive lung changes, causing a decrease in the amount of air that can be exhaled, may occur when enlarged lymph nodes in the chest compress airways or when internal inflammation or nodules impede airflow.

Chest X-ray changes are divided into four stages:

Stage 1 bihilar lymphadenopathy
Stage 2 bihilar lymphadenopathy and reticulonodular infiltrates
Stage 3 bilateral infiltrates
Stage 4 fibrocystic sarcoidosis typically with upward hilar retraction, cystic & bullous changes

Because sarcoidosis can affect multiple organ systems, follow-up on a patient with sarcoidosis should always include an electrocardiogram, ophthalmologic exam, liver function tests, serum calcium and 24-hour urine calcium.

Causes and Pathophysiology

No direct cause of sarcoidosis has been identified, although there have been reports of cell wall deficient bacteria that may be possible pathogens. These bacteria are not identified in standard laboratory analysis. It has been thought that there may be a hereditary factor because some families have multiple members with sarcoidosis. To date, no reliable genetic markers have been identified, and an alternate hypothesis is that family members share similar exposures to environmental pathogens. There have also been reports of transmission of sarcoidosis via organ transplants.

Sarcoidosis frequently causes a dysregulation of vitamin D production with an increase in extrarenal (outside the kidney) production. Specifically, macrophages inside the granulomas convert vitamin D to its active form, resulting in elevated levels of the hormone 1,25-dihydroxyvitamin D and symptoms of hypervitaminosis D that may include fatigue, lack of strength or energy, irritability, metallic taste, temporary memory loss or cognitive problems. Physiological compensatory responses (e.g. suppression of the parathyroid hormone levels) may mean the patient does not develop frank hypercalcemia.

Sarcoidosis has been associated with celiac disease. Celiac disease is a condition in which there is a chronic reaction to certain protein chains, commonly referred to as glutens, found in some cereal grains. This reaction causes destruction of the villi in the small intestine, with resulting malabsorption of nutrients.

While disputed, some cases have been determined to be caused by inhalation of the dust from the collapse of the World Trade Center after the September 11, 2001 attacks.

Treatment

Corticosteroids, most commonly prednisone, have been the standard treatment for many years. In some patients, this treatment can slow or reverse the course of the disease, but other patients unfortunately do not respond to steroid therapy. The use of corticosteroids in mild disease is controversial because in many cases the disease remits spontaneously. Additionally, corticosteroids have many recognized dose- and duration-related side effects (which can be reduced through the use of alternate-day dosing for those on chronic prednisone therapy), and their use is generally limited to severe, progressive, or organ-threatening disease. The influence of corticosteroids or other immunosuppressants on the natural history is unclear.

Severe symptoms are generally treated with steroids, and steroid-sparing agents such as azathioprine and methotrexate are often used. Rarely, cyclophosphamide has also been used. As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some early indications of success using immunosuppressants, interleukin-2 inhibitors or anti-tumor necrosis factor-alpha treatment (such as infliximab). Unfortunately, none of these have provided reliable treatment and there can be significant side effects such as an increased risk of reactivating latent tuberculosis.

Avoidance of sunlight and Vitamin D foods may be helpful in patients who are susceptible to developing hypercalcemia.

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/sarcoidosis)

Findings From Current Research

Tuberculin Skin Test Among Pulmonary Sarcoidosis Patients with and Without Tuberculosis: Its Utility for the Screening of the Two Conditions in Tuberculosis-Endemic Regions

Authors: Smith-Rohrberg D, Sharma SK.

Yale University School of Medicine, New Haven, CT 06510, USA.

BACKGROUND: Sarcoidosis is an increasingly important condition in developing countries, including those with a high prevalence of tuberculosis. The tuberculin skin test (TST) is one test used in distinguishing these two granulomatous conditions. It has been shown that a negative TST is highly sensitive for sarcoidosis. This retrospective study set out to assess the converse: the role of a positive test in the assessing the likelihood that a patient with sarcoidosis might also have tuberculosis. METHODS: A retrospective chart review of 141 patients with biopsy-proved sarcoidosis, among whom there were 16 biopsy-proven sarcoidosis and tuberculosis patients and 125 sarcoidosis-only patients. The receiver operating curve was constructed by calculating the sensitivity and specificity of various levels of induration of the tuberculin skin test for the diagnosis of comorbid tuberculosis. RESULTS: The area under the curve of the ROC did not differ from 0.5, meaning that the TST was not useful as a graded measure. This was largely due to its poor sensitivity. However, a level of greater than or equal to 10 mm induration, though insensitive, had a specificity of 97.6% for the diagnosis of tuberculosis among this population of sarcoidosis patients. CONCLUSIONS: The tuberculin skin test in sarcoid patients has a high specificity but a poor sensitivity for tuberculosis. As such, while a negative TST in the general population is a sensitive test for sarcoidosis, a positive TST among sarcoidosis patients is a specific test for indicating tuberculosis. A positive TST in a patient suspected to suffer from sarcoidosis should therefore be an absolute indication for a thorough work-up for tuberculosis.

Journal: Sarcoidosis Vasc Diffuse Lung Dis. 2006 Jun;23(2):130-4.
Adapted from PubMed; click here to access full journal article.

Hospitalization for Patients with Sarcoidosis: 1979-2000

Authors: Foreman MG, Mannino DM, Kamugisha L, Westney GE.

Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA.

BACKGROUND AND AIM: Sarcoidosis is a multi-system granulomatous disease of unknown etiology with significant racial and gender differences in disease severity, incidence, and prevalence. Primarily treated in outpatients, limited information is available on hospital outcomes in patients with sarcoidosis. The National Hospital Discharge Survey (NHDS) was analyzed over a 22-year period to determine trends in hospitalization and the impact of concurrent comorbidities. METHODS: Secondary analysis was done of the NHDS, a national survey of inpatient medical care for short stays in nonfederal facilities. RESULTS: There were a total of 750 million hospitalizations over this 22-year period, with 593,455 (0.08%) hospitalizations with a diagnosis of sarcoidosis. The number of hospitalizations increased from 22,650 in 1979 to 39,964 in 2000, and the age-adjusted rate increased from 108 per 100,000 in 1979 to 146 per 100,000 in 2000. Mean rates of hospitalization were 2.3 times higher for females than males and nine times higher for African-Americans. The mean age of patients increased over this period, particularly for white females. Cardiopulmonary diagnoses were the most frequent concurrent comorbidities. Mortality was low with an overall mortality rate of 2.3%. CONCLUSIONS: Sarcoidosis hospitalizations have increased over this time period. Hospitalization rates are highest among women and African-Americans and are frequently associated with comorbid diseases.

Journal: Sarcoidosis Vasc Diffuse Lung Dis. 2006 Jun;23(2):124-9.
Adapted from PubMed; click here to access full journal article.

Pulmonary Hypertension in Sarcoidosis

Authors: Baughman RP, Engel PJ, Meyer CA, Barrett AB, Lower EE.

Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA. bob.baughman@uc.edu

BACKGROUND: Pulmonary hypertension has been notreported in some patients with sarcoidosis. METHODS: We retrospectively studied 53 sarcoidosis patients with persistent dyspnea despite systemic therapy for their sarcoidosis. All patients underwent cardiac catheterization to determine pulmonary artery (PA) pressure. RESULTS: Of the 53 patients, six were found to have left ventricle (LV) dysfunction, including four cases of diastolic dysfunction. Of the remaining 47 patients, 26 had a systolic PA pressure > or = 40 Torr and 25 had a mean PA pressure > or = 25 Torr. Using univariate analysis of those patients with normal LV function, echocardiography, vital capacity, and diffusion lung of carbon monoxide (D(L)co) correlated with systolic and/or mean pulmonary artery pressure. For the PA systolic, only the echocardiographic estimated PA pressure and D(L)CO % predicted remained in the multiple regression model (Coefficient of determination = 0.76, p < 0.005 for both). For the PA mean pressure, the only independent variable was the echocardiographic estimate of the PA pressure (Coefficient of determination = 0.70, p < 0.005). While echocardiography was useful in many cases, in nine cases PA pressure could not be estimated because there was no tricuspid regurgitation seen. Seven of these patients had a measured PA pressure of > or = 40 Torr. Seven patients with moderate to severe pulmonary hypertension were treated with pulmonary vasodilator therapy. Five patients experienced good clinical response. CONCLUSION: Pulmonary hypertension was commonly found in sarcoidosis patients with persistent dyspnea. For some of these patients, treatment of the pulmonary hypertension was associated with improved clinical status.

Journal: Sarcoidosis Vasc Diffuse Lung Dis. 2006 Jun;23(2):108-16.
Adapted from PubMed; click here to access full journal article.

Past Achievements and Future Directions of Sarcoidosis Research: A NHLBI Perspective

Authors: Reynolds HY, Peavy HH, Gail DB, Kiley JP.

Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA. reynoldh@nhlbi.nih.gov

This history of research on sarcoidosis is largely from the perspective of the National Heart, Lung, and Blood Institute of the National Insititutes of Health which has had an interest in this disease since the inception of the Lung Program in 1969. BACKGROUND: Cutaneous sarcoidosis was described over 130 years ago and, subsequently, many reports have documented this illness affecting many organs or body sites. But a definitive cause has remained elusive. Multiple research stimuli converged in the early 1970s to begin an era of active investigation into the immunopathogensis of this granulomatous disease that included: new insights into host cellular immunity and lymphocytes; program analysis of lung research in 1971-72; new technology, especially the fiberoptic bronchoscope; and a focus by the NIH Intramural Pulmonary Branch to conduct research on interstitial lung diseases begun in 1974. During the mid 1970-80s, research into lung cellular immunity of sarcoidosis patients developed rapidly at NIH and at many other centers across the US, England, Europe, and Asia. PRESENT AND FUTURE DIRECTIONS: NHLBI has continued active support of research in sarcoidosis, both basic and clinical, such as the A Case Control Etiologic Study of Sarcoidosis (ACCESS) program, 1995-2003, whose conclusions are continuing to be published. A workshop on "Future Directions in Sarcoidosis Research" provided new research ideas to explore basic immunity mechanisms in human sarcoidosis tissue and search for latent microbial agents in tissue. The organization of sarcoidosis patient support groups has heightened awareness of the need for research on multiple organs affected by the disease in addition to the respiratory tract. In response, a trans-NIH sarcoidosis working group has been formed to assess this need and to better coordinate NIH research efforts.

Journal: Sarcoidosis Vasc Diffuse Lung Dis. 2006 Jun;23(2):83-91.
Adapted from PubMed; click here to access full journal article.

Potential Etiologic Agents in Sarcoidosis

Authors: Moller DR.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA. dmoller@jhmi.edu

The etiology of sarcoidosis remains uncertain. The hallmark of sarcoidosis is the epithelioid granuloma, which serves as a necessary starting point for considering disease etiology. Any etiologic agent of sarcoidosis must also explain the typical clinical behaviors and characteristic immunopathologic features of the disease. One clinical observation that serves as a bridge to the etiology of sarcoidosis is the Kveim reaction. In this reaction, local epithelioid granulomas develop several weeks after the intradermal injection of homogenates of sarcoidosis tissue. Our group capitalized on the known properties of the Kveim reagent to search for candidate pathogenic tissue antigens in sarcoidosis without other a priori hypotheses regarding possible microbial or autoimmune etiologies. Using a limited proteomics approach based on the physicochemical properties of Kveim reagent, we detected a limited number of poorly soluble antigenic proteins in sarcoidosis tissues by protein immunoblotting, using sarcoidosis sera. Matrix-associated laser desorption/ionization-time of flight mass spectrometry identified one of these antigens to be the Mycobacterium tuberculosis catalase-peroxidase protein (mKatG). We found IgG responses to recombinant mKatG in more than 50% of patients with sarcoidosis but rarely in purified protein derivative (PPD)-negative control subjects. These findings support the conclusion that mKatG is a tissue antigen and target of the adaptive immune response in sarcoidosis, providing further evidence of a mycobacterial etiology in a subset of sarcoidosis. More generally, the approach used in these studies might be employed to discover and validate other candidate pathogenic antigens in sarcoidosis or other granulomatous disorders.

Journal: Proc Am Thorac Soc. 2007 Aug 15;4(5):465-8.
Adapted from PubMed; click here to access full journal article.

Advances in the Genetics of Sarcoidosis

Authors: Iannuzzi MC.

Division of Pulmonary, Critical Care, and Sleep Medicine, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1232, New York, NY 10029, USA. michael.iannuzzi@mountsinai.org

Familial aggregation and racial differences in incidence support the notion that sarcoidosis occurs in genetically susceptible hosts. Siblings of those affected with sarcoidosis have a modestly increased disease risk, with an odds ratio of about 5. HLA genes have been the most extensively studied susceptibility genes in sarcoidosis. Many other attractive candidate genes have been evaluated using the case-control study design, but few have been confirmed. Confounding by population stratification likely explains much of the failure to replicate initial findings. A genomewide scan performed in German families with follow-up fine mapping studies has yielded a highly attractive candidate gene, BTNL2 in the MHC II region on chromosome 6. BTNL2, a member of the B7 family of costimulatory molecules, likely functions to down-regulate T-cell activation. A BTNL2 single-nucleotide polymorphism associated with sarcoidosis is predicted to result in a truncated nonfunctioning protein. Association of BTNL2 with sarcoidosis has been confirmed in both white and African Americans. A genomewide scan with follow-up fine mapping studies in African American families has identified chromosome 5 as potentially harboring candidate genes. Additional linkage analysis in the African American families stratified according to genetic ancestry demonstrated that linkage signals varied according to degree of admixture. Certain chromosomal regions were also found linked to specific phenotypes. Follow-up fine mapping studies of the linked regions are underway.

Journal: Proc Am Thorac Soc. 2007 Aug 15;4(5):457-60.
Adapted from PubMed; click here to access full journal article.

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