CHEST

Recent Advances in Chest Medicine

Recent Advances in Sarcoidosis

Adam S. Morgenthau, MD, FCCP; and Michael C. Iannuzzi, MD, MBA, FCCP

Sarcoidosis, a systemic granulomatous disease of undetermined etiology, is characterized by a variable clinical presentation and course. During the past decade, advances have been made in the study of sarcoidosis. The multicenter ACCESS (A Case Control Etiologic Study of Sarcoidosis) trial recruited . 700 subjects with newly diagnosed sarcoidosis and matched control subjects. Investigators were unable to identify a single cause of sarcoidosis, but ACCESS paved the way for subsequent etiologic studies. The Mycobacterium tuberculosis catalase-peroxidase protein has been identied as a potential sarcoidosis antigen. Genetic aspects of the disease have been elucidated further. Genome-wide scans have identied candidate genes. Gene expression analyses have dened cytokine dysregulation in sarcoidosis more clearly. Although the criteria for diagnosis have not changed, sarcoidosis remains a diagnosis of exclusion best supported by a tissue biopsy specimen that demonstrates noncaseating granulomas in a patient with compatible clinical and radiologic features of the disease. Endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes has facilitated diagnosis, often eliminating the need for more invasive procedures, such as mediastinoscopy. PET scanning has proven valuable in locating occult sites of active disease. Currently, no reliable prognostic biomarkers have been identied. The tumor necrosis factor inhibitors, a relatively new class of agents, have been used in patients with refractory disease. It is unclear whether phosphodiesterase-5 inhibitors, prostaglandin analogs, or endothelin antagonists should be used for the treatment of sarcoidosis-associated pulmonary hypertension. CHEST 2011; 139(1):174182
Abbreviations: ACCESS 5 A Case Controlled Etiologic Study of Sarcoidosis; BTLN2 5 butyrophillin-like 2; EBUSTBNA 5 endobronchial ultrasound-guided transbronchial needle aspiration; ePOST 5 extrapulmonary physician organ severity tool; FDG 5 18uorodeoxyglucose; FOXP3 5 forkhead box P3; HLA 5 human leukocyte antigen; IFN 5 interferon; mKatG 5 Mycobacterium tuberculosis catalase-peroxidase; NKT 5 natural killer T cells; TCR 5 T-cell receptor; Th 5 T helper cell; TNF 5 tumor necrosis factor; Tregs 5 T regulatory cells

of Sarcoidosis, a systemic granulomatous diseasevariundetermined etiology, is characterized by a

able clinical presentation and course. Although 90% of patients demonstrate thoracic involvement, any organ may be affected.1 Decreased diffusion capacity, the most common abnormality found on pulmonary function testing,2 often is accompanied by restrictive
Manuscript received January 21, 2010; revision accepted July 15, 2010. Afliations: From the Department of Medicine, Pulmonary, Critical Care, and Sleep Medicine (Dr Morgenthau), Mount Sinai School of Medicine, New York, NY; and Department of Medicine (Dr Iannuzzi), SUNY Upstate Medical University, Syracuse, NY. Correspondence to: Adam S. Morgenthau, MD, FCCP, Mount Sinai School of Medicine, 5 E 98th St, 8th Floor, New York, NY 10029; e-mail: adam.morgenthau@mssm.edu 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-0188
174

ventilatory dysfunction. The presence of obstructive airways disease occurs in at least 30% of patients.3 Sarcoidosis is a diagnosis of exclusion best supported by the following three elements: (1) compatible clinical and radiologic ndings; (2) tissue biopsy specimen that reveals noncaseating epithelioid granulomas; and (3) the absence of known granulomagenic agents.1 Most patients require no treatment. When treatment is necessary, patients usually improve with moderate doses of corticosteroids. Large, randomized controlled studies demonstrating the superiority of alternative therapy to corticosteroids do not exist. About 30% of patients with sarcoidosis develop chronic progressive disease.1 Mortality in sarcoidosis is , 5%.1 Progressive pulmonary brosis is the most common cause of death. Neurologic and cardiac involvement may present acutely and portend a poor prognosis. During the past decade, advances have been made in the study of sarcoidosis. Investigators conducted a
Recent Advances in Chest Medicine

Downloaded From: http://journal.publications.chestnet.org/ on 07/27/2012

large, multicenter study called A Case Control Etiologic Study of Sarcoidosis (ACCESS).4 The Mycobacterium tuberculosis catalase-peroxidase (mKatG) protein, a potential antigen, has been identied,5,6 and PET scanning has proven valuable in locating occult sites for diagnostic biopsy.7 Endobronchial ultrasoundguided transbronchial needle aspiration (EBUS-TBNA) of mediastinal lymph nodes has facilitated diagnosis, often eliminating the need for more-invasive procedures, such as mediastinoscopy. Candidate gene studies and genome-wide scans have identied candidate genes. Gene expression analyses have more clearly dened cytokine dysregulation in sarcoidosis. Currently, no reliable prognostic biomarkers have been identied. The tumor necrosis factor (TNF) inhibitors, a relatively new class of steroid-sparing agents, have been used in patients with refractory disease. It is unclear whether medications used to treat pulmonary arterial hypertension are safe and effective for the treatment of sarcoidosis-associated pulmonary hypertension. Although surgical intervention for sinonasal sarcoidosis often relieves symptoms, it is almost never curative.

incidence of sarcoidosis.11 Twenty-six New York City firefighters studied demonstrated biopsy-proven granulomas. Only a minority exhibited clinical features typical of sarcoidosis, suggesting that sarcoidosis associated with World Trade Center dust exposure may be clinically and phenotypically distinct from that in the general population. To date, examination of cases associated with World Trade Center dust exposure has not helped to identify sarcoidosis antigens. Genetics Genetic and host factors are involved in the pathogenesis of sarcoidosis (Fig 1).12 Twin studies indicate that monozygotic twins are more often concordant for disease than dizygotic twins.14 In the United States, blacks are more frequently affected by sarcoidosis than other ethnic groups and generally have chronic and more severe disease.12 Familial clustering of sarcoidosis cases has been observed worldwide.15 In ACCESS, subjects were ve times more likely than control subjects to report a sibling or parent affected with sarcoidosis.12 A great deal has been learned about genetic factors that inuence susceptibility and clinical phenotype in sarcoidosis.12 Two genetic linkage studies have been conducted in families with sarcoidosis, one in black Americans and the other in German families. The German study detected its strongest signal on chromosome 6p, which led to the identication of the butyrophillin-like 2 (BTLN2) gene, a B7 family member of costimulatory molecules within the major histocompatibility complex region.

Etiology Progress has been made in elucidating the cause of sarcoidosis. The ACCESS trial collected data on 704 patients with newly diagnosed, biopsy specimenproven sarcoidosis and control subjects matched by age, sex, race, and geographic area.4 The study identied several environmental exposures modestly associated with sarcoidosis risk (OR, ~ 1.5).8 The associated exposures included agricultural employment, mold or mildew, musty odors at work, and pesticide-using industries. Tobacco use was negatively associated with sarcoidosis, afrming the results of previous studies.9,10 Reduced risk also was associated with several exposures linked to allergic responses such as to household animal dust, feathers, or down pillows. In summary, no single cause of sarcoidosis was identied, suggesting that multiple triggers likely exist. The DNA of the mKatG gene has been identied in archived sarcoidosis biopsy specimens. One group6 found that nearly 50% of patients with sarcoidosis exhibited anti-mKatG antibodies compared with control subjects. In addition, strongly polarized T helper cell (Th) 1 immune responses to mKatG were more frequently present in patients with sarcoidosis compared with control subjects. Adaptive immune responses to the mKatG protein support its role as a pathogenic antigen in sarcoidosis. In the rst year after the World Trade Center disaster, New York City reghters exposed to dust from the fallen towers exhibited a higher-than-expected
www.chestpubs.org

Figure 1. Hypothetical model of the immunopathogenesis of sarcoidosis and immunologic rationale for treatment of the disease. IFN 5 interferon; MHC 5 major histocompatibility complex; TCR 5 T-cell receptor; TGF 5 transforming growth factor; TNF 5 tumor necrosis factor; T Reg 5 T regulatory cell. Reproduced with permission from Chen and Moller.13
CHEST / 139 / 1 / JANUARY, 2011

175

DwlaeFo :tp/oraulaincete.ro0/702 o n dd rm : unpb t shsnt gn7 / 1 o h j l i o . o / 22 . c

BTNL2 Gene The BTNL2 single-nucleotide polymorphism associated with sarcoidosis (rs2076530 GA) may inuence T-lymphocyte activation and regulation. Rybicki and colleagues16 reported that BTNL2 rs2076530 GA is associated with sarcoidosis risk in white patients but not in black patients. Other single-nucleotide polymorphisms within the BTNL2 gene were associated with risk in black Americans. Multivariable logistic regression analyses showed that BTNL2 effects were independent of human leukocyte antigen class 2 genes in whites and interacted antagonistically in blacks. Nucleotide-Binding Oligomerization Domain Containing 2 Gene Mutations in the nucleotide-binding oligomerization domain 2 gene, also known as the caspase recruitment domain family member 15, have been associated with Crohns disease and Blau syndrome.17,18 Blau syndrome, a rare, autosomal-dominant disorder, is characterized by granulomatous polyarthritis, panuveitis, cranial neuropathies, and exanthema. In contrast to sarcoidosis, lung involvement and Kveim skin test reactivity are absent in Blau syndrome. Although nucleotide-binding oligomerization domain 2 is an attractive candidate gene, studies in patients with sarcoidosis have yielded conicting results.19,20 Genome-Wide Association Studies Hofmann and colleagues21 conducted a genomewide association study of 499 German patients with sarcoidosis and 490 control subjects. The strongest signal mapped to the annexin A11 gene on chromosome 10q22.3. Validation in an independent sample conrmed the association. Annexin A11 has regulatory functions in calcium signaling, cell division, vesicle trafcking, and apoptosis. Depletion or dysfunction of annexin A11 may affect the apoptosis pathway in sarcoidosis.
Human Leukocyte Antigen: Class 2 human leukocyte antigens (HLAs) are cell surface proteins that are essential for immune recognition and function. The DR subtype of class 2 antigens is associated with many inammatory conditions, including sarcoidosis. Early genetic linkage studies suggested that genes coding for class 1 and class 2 HLA molecules confer risk in sarcoidosis.22 HLA-DRB1*01 and HLA-DRB1*04 have been negatively associated with sarcoidosis risk. HLA-DRB1*03, HLA-DRB1*11, HLA-DRB1*12, HLA-DRB1*14, and HLA-DRB1*15 have been associated with an increased risk of developing the disease. HLA-DRB1*03 has been found to be associated with Lfgren syndrome, an acute form of sarcoidosis
176

with a favorable course and high rate (~ 80%) of spontaneous remission.23 The HLA-DRB1*1501/ DQB1*0602 haplotype has been found to be associated with a chronic course24 and severe pulmonary sarcoidosis.25
T-Cell Receptor: An immunologic feature of sarcoidosis is the nding that T cells at sites of inammation in sarcoidosis display a restricted repertoire of T-cell receptor (TCR) ab or gd genes. The selective expression of specic Vb, Va, or g,d 1 T-cell receptor genes in T-cell subsets from the lung, from the blood, and at sites of Kveim-Siltzbach skin reactions demonstrates that sarcoidosis is an antigen-driven disorder.26 Grunewald and Eklund27 described the expansion of AV2S3 (Va2.3) 1 T cells in BAL uid from HLA-DR*0301 Scandinavian patients with sarcoidosis. Increased proportions of AV2S31 lung T cells were found in patients with disease duration , 2 years.28 A strong association also was identied between lungrestricted AV2S31 T cells and both an acute disease onset and the CD41/CD81 cell ratio in BAL uid. Using the environmental questionnaire developed in the ACCESS study, Iannuzzi and colleagues29 attempted to identify gene-exposure interactions for previously associated DQB1 alleles. Exposures to high humidity and water damage were found to enhance the protective effect of the DRB1*0201 allele. No exposures interacted with the DQB1*0602 susceptibility allele.

Cellular and Chemical Mediators of Inammation and Immunity During the past decade, the immunopathogenesis of sarcoidosis has been elucidated more clearly. Recent studies have demonstrated that numerous cellular and chemical mediators of inammation and immunity are involved in the immunopathogenesis of sarcoidosis.
Natural Killer T Cells: The natural killer T cell (NKT) produces large quantities of both Th1 interferon-g (IFN-g) and Th2 IL-4 cytokines. Most NKT cells are CD41 and express an invariant TCR. Reduced numbers of NKT cells have been found in sarcoid blood and BAL uid.30 Blood NKT cells obtained from patients with sarcoidosis and stimulated with a potent glycolipid stimulator, a-galactosylceramide, exhibited impaired production of IFN-g.31 Additional investigation is required to further elucidate the role of NKT cells in sarcoidosis. T Regulatory Cells: T regulatory cells (Tregs) suppress proliferation and cytokine production of activated
Recent Advances in Chest Medicine

Downloaded From: http://journal.publications.chestnet.org/ on 07/27/2012

T cells through cell-to-cell contact. Several types of Tregs exist, including those that express the CD8, CD4, CD25, and transcription factor forkhead box P3 (FOXP3). In mice, Tregs inhibit autoimmune diseases.32 Mice and humans who lack FOXP3 are afflicted with severe autoimmune disorders.33 Grunewald and Eklund27 observed downregulation of the Tregs marker FOXP3 in sarcoid BAL fluid compared with healthy control subjects.
BAL T Cells With a Restricted Repertoire of TCR Genes: Investigators have identied a subpopulation

Diagnosis BAL can be used as an adjunctive measure to support the diagnosis of sarcoidosis by demonstrating a reduced number of CD8 cells and an elevated CD4/CD8 ratio. But the diagnosis of sarcoidosis is best supported by obtaining tissue specimens that show noncaseating granulomas. EBUS-TBNA allows real-time ultrasound localization and aspiration of hilar and mediastinal lymph nodes. Tremblay and colleagues55 compared the diagnostic yield of TBNA using a 19-gauge needle vs EBUS-TNBA in 50 patients with sarcoidosis and hilar or mediastinal adenopathy. The diagnostic yield was 53.8% compared with 83.3% in favor of EBUS-TBNA. In a minority of patients with sarcoidosis, a diagnostic site is not readily apparent by physical examination or radiographic imaging. 18F-uorodeoxyglucose (FDG) PET scanning has proven valuable in identifying occult sites of disease for diagnostic biopsy in many of these patients.7 Cardiac Sarcoidosis Cardiac sarcoidosis is a potentially sudden and life-threatening manifestation of sarcoidosis. Current studies likely underestimate the true prevalence of disease. Cardiac sarcoidosis is difcult to diagnose. Most patients have minimal or no symptoms, and no gold standard for diagnosis exists. Results from endomyocardial biopsy specimens, which may be difficult to obtain, are positive in , 10% of patients.56 Occasionally, echocardiogram or nuclear stress testing will reveal ndings consistent with but not pathognomonic for disease. Most cases of cardiac sarcoidosis are confirmed by using various imaging tests, such as contrast-enhanced MRI and myocardial PET scanning. Diagnosis is further complicated by the absence of an evidenced-based diagnostic approach to the disease. Whether sophisticated imaging tests such as contrast-enhanced MRI or PET scanning should be used initially is controversial. Further studies are needed to develop a diagnostic algorithm for the evaluation of cardiac sarcoidosis. PET technology shows increased FDG uptake in the myocardium of patients with sarcoidosis and allows for acquisition of perfusion images. Small studies suggest that PET scanning is 82% to 100% sensitive for the detection of cardiac sarcoidosis.57,58 The specicity of PET is less clear, but two small studies reported specicities of 91% and 82%.58,59 Recent studies suggested that PET may be more sensitive than MRI, whereas MRI may have a higher specicity.60 Unlike PET scanning, MRI does not expose patients to ionizing radiation.
CHEST / 139 / 1 / JANUARY, 2011

of T cells (AV2S31 CD41 T cells) in DRB1*0301positive patients with sarcoidosis34 but not in patients with other inammatory lung diseases. The magnitude of AV2S31 BAL T cells at the onset of disease correlated with a better prognosis, indicating that AV2S31 BAL T cells may have a protective function. These cells do not express FOXP3 and weakly express CD25 and CD27, suggesting that they have effector and not regulatory functions. It has become increasingly well recognized that polymorphisms within the genes encoding for cytokines, cytokine receptors, Toll-like receptors, and various chemical mediators of inflammation contribute to the immunopathogenesis of sarcoidosis. Table 1 presents a partial list of these mediators.

Biomarkers of Disease Activity Investigators continue to search for potential biomarkers of disease activity in sarcoidosis. Chitotriosidase, an enzyme involved in the degradation of chitin, is expressed by activated macrophages. Bargagli and colleagues53 found elevated levels of chitotriosidase in the serum of patients with sarcoidosis compared with control subjects, with . 90% exhibiting increased levels of the marker. Signicantly higher levels were observed in patients with active sarcoidosis than in those with inactive sarcoidosis. Chitotriosidase may induce the overexpression of probrotic type-2 (Th2) cytokines and forecast disease severity and prognosis in sarcoidosis. IL-2 is a Th1 cytokine that induces T-cell proliferation and activation after interaction with its receptor. Recent evidence suggests that IL-2 receptor is elevated in serum and BAL uid of patients with sarcoidosis and that it may have prognostic value in sarcoidosis,54 where patients with extrapulmonary disease, excluding Lfgren syndrome, have demonstrated higher serum soluble IL-2 receptor levels than those with isolated pulmonary sarcoidosis. To date, practical and reliable biomarkers of disease activity have not been identied.
www.chestpubs.org

177

Downloaded From: http://journal.publications.chestnet.org/ on 07/27/2012

Table 1Partial List of Chemical Mediators Involved in the Immunopathogenesis of Sarcoidosis

Mediator Function Role in Sarcoidosis TGF-B1 polymorphism associated with more chronic and severe disease.35 TGF-B3 polymorphisms associated with pulmonary brosis.35 Elevated concentration of IL-8 found in BAL uid compared with control subjects.36 SNPs in CCR2 may protect patients from developing sarcoidosis.37 TNF-a G-308A polymorphisms are associated with a favorable prognosis.38 CCR-2 polymorphism is associated with Lfgren syndrome.39 CXCR3 ligands orchestrate Th1 cytokine immunity via the recruitment of CD41/CXCR31 T cells for granuloma formation.40 VEGF gene haplotypes are associated with genetic susceptibility and course in sarcoidosis.41 SNPs in the HLA-DRB locus are associated with erythema nodosum.42 TLR-4 polymorphisms are associated with sarcoidosis.43 A specic HSP70 allele may be associated with uveitis in sarcoidosis.44

Cytokines, chemokines, chemokine receptors Protein that controls proliferation and TGF-b cellular differentiation in most cells.

IL-8 CCR2 TNF-a

Proinammatory cytokine produced by macrophages and epithelial cells. Chemokine that mediates monocyte chemotaxis. Proinammatory cytokine produced by macrophages and epithelial cells.

Angiogenic cytokines

Cytokines involved in angiogenesis; the physiologic process that involves the growth of new blood vessels.

Regulators of immunity HLA molecules TLR-4

HSPs

STAT-1

A group of genes that encode cell surface proteins essential to immune function. A cell surface protein whose recognition of bacteria and other substances triggers activation of the innate immune system. Proteins expressed by cells in response to environmental stresses like heat, cold, and hypoxia. A group of proteins that regulate cellular growth, survival, and differentitation.

TIMs

MPKs

The expression of many genes under the regulation of STAT-1 is increased in the peripheral blood of patients with sarcoidosis.45 A family of genes that encodes protein Reduced expression of mRNA and protein receptors on T cells that regulate levels of TIM-3 in BAL uid CD41 T cells in patients with sarcoidosis.46 cell-mediated immunity. Respond to extracellular stimuli (mitogents, The level of TIM-3 mRNA correlated osmotic stress, heat shock and negatively with the CD41/CD81 T-cell ratio in patients with sarcoidosis.47 proinammatory cytokines) and regulate Reduced expression of mRNA levels of TIM2 various cellular activities, such as gene in BAL CD41 T-cells from healthy control subjects expression, mitosis, differentiation, proliferation compared with patients with Lfgren syndrome.46 and cell survival and/or apoptosis. Abnormal regulation of MKP-1 contributes to heightened inammation in sarcoidosis.48 Increased RAGE expression associated with certain genotypes that also are associated with sarcoidosis.47 RAGE and its ligands are expressed in sarcoidal granulomas.49 A PTG99S2 polymorphism is associated with the development of brotic sarcoidosis.50 Reduced COX2 expression is found in bronchiolar epithelial cells and macrophages of patients with sarcoidosis.51 Increased MMP-12 and ADAMDEC1 gene and protein expression in BAL samples is associated with more severe sarcoidosis.30 Plasma levels of ascorbic acid, uric acid, and glutathione are reduced in patients with sarcoidosis compared with control subjects.52

Inammatory mediators RAGE

PTG99S2 COX-2

A transmembrane receptor of the Ig superfamily that binds pattern-recognition receptors, stimulating inammatory processes. An enzyme critical for the synthesis of the antibrotic mediator prostaglandin E2. A key enzyme in the synthesis of the prostanoids, which are involved in inammation and mitogenesis. Proteins involved in the breakdown of extracellular matrix in normal physiologic processes and disease processes. Molecules capable of slowing or preventing oxidation. Oxidation reactions can produce free radicals, which can damage cells.

Miscellaneous mediators MMP-12/ADAMDEC1

Antioxidants

ADAM 5 a disintegrin and metalloproteinase; CCR 5 chemokine receptor; COX 5 cyclooxygenase; CXCL 5 group of chemokines with N-terminal cysteines separated by an amino acid; HLA 5 human leukocyte antigen; HSP 5 heat shock protein; Ig 5 immunoglobulin; MIG 5 monokine induced by interferon-g; MMP 5 matrix metalloproteinase; MPK 5 mitogen-activated protein kinase; PTG99S2 5 prostaglandin-endoperoxidase synthase 2; RAGE 5 receptor for advanced glycation end products; SNP 5 single-nucleotide polymorphism; STAT 5 signal transducers and activators of transcription; TGF 5 transforming growth factor; Th 5 T helper cell; TIM 5 T-cell Ig-mucin; TLR 5 toll-like receptor; VEGF 5 vascular endothelial growth factor. 178 Downloaded From: http://journal.publications.chestnet.org/ on 07/27/2012
Recent Advances in Chest Medicine

Therapy Patients with chronic sarcoidosis often require prolonged treatment. Sustained treatment with even modest doses of systemic corticosteroids may result in disabling side effects. Steroid-sparing agents often are administered to minimize the long-term side effects of systemic corticosteroids. TNF inhibitors have been investigated for the treatment of sarcoidosis. Utz and colleagues61 assessed the efcacy of etanercept in a preliminary clinical trial of patients with progressive pulmonary sarcoidosis. Treatment failure occurred in nearly 65% of participants. Baughman and colleagues62 performed a randomized double-blind study of etanercept for the treatment of ocular sarcoidosis. Most treated patients did not experience signicant improvement in chronic ocular disease. Baughman and colleagues63 also conducted a randomized double-blind trial in patients with chronic pulmonary sarcoidosis. Patients who received low-dose iniximab therapy (3 mg/kg) demonstrated at 24 weeks a statistically signicant 2.8% increase in percent-predicted FVC compared with baseline. The percent-predicted FVC was unchanged in the placebo group. The proportion of patients who reported adverse drug effects was similar among the treatment groups. Judson and colleagues64 evaluated the same cohort of patients in a randomized, double-blind, placebocontrolled trial to determine whether iniximab was effective for the treatment of both extrapulmonary and chronic steroid-dependent pulmonary sarcoidosis. The investigators used a novel assessment, extrapulmonary Physician Organ Severity Tool (ePOST), to measure the severity of organ involvement. The ePOST was adjusted for number of organs involved. A modest and transient improvement in ePOST and adjusted ePOST was noted at 24 weeks in the treatment group compared with the placebo group. Rossman and colleagues65 performed a doubleblind randomized controlled trial of iniximab in the treatment of active pulmonary sarcoidosis. After 6 weeks, there was a trend toward improvement of the vital capacity in the treatment group, but many patients experienced serious adverse effects. Although iniximab may improve vital capacity in patients with active sarcoidosis, larger scale and longer term studies are needed to assess the safety and efcacy of the drug. Stagaki and colleagues66 retrospectively evaluated the treatment of lupus pernio with iniximab alone or in combination with other antiinammatory agents. Treatment regimens that included iniximab were statistically superior to all other treatment regimens evaluated. More than 75% of all treatment regimens containing iniximab resulted in resolution or near
www.chestpubs.org

resolution of lupus pernio lesions. Although iniximab appears to be efcacious for the treatment of lupus pernio, additional studies are needed to validate the method of its quantitative and qualitative assessment used in this study. Ustekinumab, a human monoclonal antibody directed against IL-12 and IL-23, has been approved for dosing in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Patients currently are being recruited for clinical trials evaluating the safety and efcacy of ustekinumab and golimumab, a TNF-a antagonist, in the treatment of chronic sarcoidosis. The anticipated completion of the study is July 2011. Pulmonary hypertension is a common and potentially life-threatening complication of sarcoidosis. The prevalence of pulmonary hypertension associated with sarcoidosis is unknown. Treatment of sarcoidosis-associated pulmonary hypertension remains uncertain. Although favorable outcomes with epoprostenol, bosentan, and sildenal have been described in small case series,67,68 prospective clinical trials do not exist. Barnett and colleagues69 conducted a retrospective study of 22 patients with sarcoidosis and pulmonary hypertension to determine whether sildenal, bosentan, epoprostenol, or combination therapy with two of these agents was effective for the treatment of pulmonary hypertension secondary to sarcoidosis. New York Heart Association functional class, exercise tolerance as assessed by the 6-min walk distance, and hemodynamic parameters improved with these treatments, but mortality among the study population was high. Clearly, prospective, controlled trials are needed to determine whether these agents are safe and effective for the treatment of sarcoidosis-associated pulmonary hypertension. The indication for surgical intervention in certain forms of sarcoidosis, particularly sinonasal disease, remains controversial. Although surgery may reduce symptoms, it may not eradicate or prevent recurrence of disease. Neville and associates70 evaluated 34 patients with sarcoidosis of the upper respiratory tract, three of whom underwent submucous resection. In two of the three patients, the resection was complicated by nasal septal perforation. Aubart and colleagues71 operated on seven patients in whom nasal and sinus involvement recurred in all and sinus symptoms worsened in one after surgery. Studies suggest, however, that endoscopic sinus surgery may play a therapeutic role in patients with nasal obstruction or chronic sinusitis caused by anatomic blockage from sinonasal sarcoidosis.72,73 Removal of the obstructing lesions may facilitate improved sinonasal hygiene by permitting endoscopic debridement, nasal irrigation, and topical administration of medicines into the sinonasal tract. Although surgery may improve ones
CHEST / 139 / 1 / JANUARY, 2011

179

Downloaded From: http://journal.publications.chestnet.org/ on 07/27/2012

quality of life by relieving severe symptoms and may even reduce the need for oral steroids, it is almost never curative.

References
1. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/ WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis. 1999;16(2):149-173. 2. Marshall R, Smellie H, Baylis JH, Hoyle C, Bates DV. Pulmonary function in sarcoidosis. Thorax. 1958;13(1):48-58. 3. Sharma OP, Johnson R. Airway obstruction in sarcoidosis. A study of 123 nonsmoking black American patients with sarcoidosis. Chest. 1988;94(2):343-346. 4. Baughman RP, Teirstein AS, Judson MA, et al; Case Control Etiologic Study of Sarcoidosis (ACCESS) research group. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(10 pt 1): 1885-1889. 5. Chen ES, Wahlstrm J, Song Z, et al. T cell responses to mycobacterial catalase-peroxidase prole a pathogenic antigen in systemic sarcoidosis. J Immunol. 2008;181(12):8784-8796. 6. Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med. 2005;201(5):755-767. 7. Teirstein AS, Machac J, Almeida O, Lu P, Padilla ML, Iannuzzi MC. Results of 188 whole-body uorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis. Chest. 2007;132(6):1949-1953. 8. Newman LS, Rose CS, Bresnitz EA, et al; ACCESS Research Group. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170(12):1324-1330. 9. Peros-Golubici T, Ljubi S. Cigarette smoking and sarcoidosis. Acta Med Croatica. 1995;49(4-5):187-193. 10. Valeyre D, Soler P, Clerici C, et al. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax. 1988;43(7):516-524. 11. Izbicki G, Chavko R, Banauch GI, et al; World Trade Center. World Trade Center sarcoid-like granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131(5):1414-1423. 12. Rybicki BA, Iannuzzi MC, Frederick MM, et al; ACCESS Research Group. Familial aggregation of sarcoidosis. A casecontrol etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001;164(11):2085-2091. 13. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29(3):365-377. 14. Grunewald J. Genetics of sarcoidosis. Curr Opin Pulm Med. 2008;14(5):434-439. 15. Rybicki BA, Kirkey KL, Major M, et al. Familial risk ratio of sarcoidosis in African-American sibs and parents. Am J Epidemiol. 2001;153(2):188-193. 16. Rybicki BA, Walewski JL, Maliarik MJ, Kian H, Iannuzzi MC; ACCESS Research Group. The BTNL2 gene and sarcoidosis susceptibility in African Americans and whites. Am J Hum Genet. 2005;77(3):491-499. 17. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohns disease. Nature. 2001;411(6837):599-603. 18. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29(1):19-20. 19. Schrmann M, Valentonyte R, Hampe J, Mller-Quernheim J, Schwinger E, Schreiber S. CARD15 gene mutations in sarcoidosis. Eur Respir J. 2003;22(5):748-754. 20. Milman N, Nielsen OH, Hviid TV, Fenger K. CARD15 single nucleotide polymorphisms 8, 12 and 13 are not increased in ethnic Danes with sarcoidosis. Respiration. 2007;74(1):76-79.
Recent Advances in Chest Medicine

Conclusion Although the etiology of sarcoidosis remains uncertain, recent studies suggest that mKatG is a pathogenic antigen in sarcoidosis. Much has been learned about the genetic aspects of the disease. HLA gene loci and polymorphisms in transforming growth factor-b and TNF-a strongly inuence individual susceptibility to sarcoidosis and clinical phenotype. Novel genes that determine the immunologic features of sarcoidosis have been identied. Reduced numbers of NKT cells may promote an exaggerated Th1 immune response in sarcoidosis. The pathogenic role of Tregs is controversial. Recently identified immunogenetic factors likely will serve as therapeutic targets in sarcoidosis. The diagnosis of sarcoidosis is best supported by a tissue biopsy specimen that demonstrates noncaseating, epithelioid granulomas in a patient with compatible clinical and radiologic features of the disease. EBUS-TBNA may be superior to standard TBNA for sampling of the mediastinal lymph nodes. In cases where a readily available diagnostic site is not detected by physical examination or conventional imaging techniques (ie, standard radiography and CT scan), FDG-PET scanning has proven extremely valuable in identifying occult sites of disease. Because cardiac tissue rarely is obtained in the diagnosis of cardiac sarcoidosis, clinicians often rely on cardiac MRI or PET scanning. A standardized diagnostic approach to cardiac sarcoidosis is needed. Corticosteroids are the most effective treatment of sarcoidosis, but longstanding treatment may result in disabling side effects. The TNF inhibitors have been investigated for the treatment of sarcoidosis. Although there is a sound pathophysiologic basis for their use in sarcoidosis, randomized clinical trials do not support their routine use. It is unclear whether medications used to treat pulmonary arterial hypertension are safe and effective for the treatment of sarcoidosisassociated pulmonary hypertension. Surgical intervention for sinonasal sarcoidosis may relieve symptoms, but it is seldom curative. Acknowledgments
Financial/nonnancial disclosures: The authors have reported to CHEST the following conict of interest: Dr Morgenthau owns stock in Johnson & Johnson. Dr Iannuzzi has reported to CHEST that no potential conicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
180

Downloaded From: http://journal.publications.chestnet.org/ on 07/27/2012

21. Hofmann S, Franke A, Fischer A, et al. Genome-wide association study identies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet. 2008;40(9):1103-1106. 22. Schrmann M, Lympany PA, Reichel P, et al. Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med. 2000;162(3 pt 1):861-864. 23. Hedfors E, Lindstrm F. HLA-B8/DR3 in sarcoidosis. Correlation to acute onset disease with arthritis. Tissue Antigens. 1983;22(3):200-203. 24. Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med. 1997; 156(5):1601-1605. 25. Voorter CE , Drent M, van den Berg-Loonen EM. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150101. Hum Immunol. 2005; 66(7):826-835. 26. Moller DR, Konishi K, Kirby M, Balbi B, Crystal RG. Bias toward use of a specic T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis. J Clin Invest. 1988;82(4):1183-1191. 27. Grunewald J, Eklund A. Role of CD41 T cells in sarcoidosis. Proc Am Thorac Soc. 2007;4(5):461-464. 28. Grunewald J, Eklund A. Lfgrens syndrome: human leukocyte antigen strongly inuences the disease course. Am J Respir Crit Care Med. 2009;179(4):307-312. 29. Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA. Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med. 2003; 167(9):1225-1231. 30. Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ. Deciency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet. 2005;365(9464):1062-1072. 31. Kobayashi S, Kaneko Y, Seino K, et al. Impaired IFN-gamma production of Valpha24 NKT cells in non-remitting sarcoidosis. Int Immunol. 2004;16(2):215-222. 32. Powrie F. T cells in inammatory bowel disease: protective and pathogenic roles. Immunity. 1995;3(2):171-174. 33. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurn, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68-73. 34. Grunewald J, Olerup O, Persson U, Ohrn MB, Wigzell H, Eklund A. T-cell receptor variable region gene usage by CD41 and CD81 T cells in bronchoalveolar lavage uid and peripheral blood of sarcoidosis patients. Proc Natl Acad Sci U S A. 1994;91(11):4965-4969. 35. Jonth AC, Silveira L, Fingerlin TE, et al; ACCESS Group. TGF-beta 1 variants in chronic beryllium disease and sarcoidosis. J Immunol. 2007;179(6):4255-4262. 36. Cui A, Anhenn O, Theegarten D; et al. Angiogenic and angiostatic chemokines in idiopathic pulmonary brosis and granulomatous lung disease. Respiration. 2009. 37. Kruit A, Grutters JC, Ruven HJ, et al. Transforming growth factor-beta gene polymorphisms in sarcoidosis patients with and without brosis. Chest. 2006;129(6):1584-1591. 38. Wijnen PA, Nelemans PJ, Verschakele JA, et al. The role of tumor necrosis factor alpha G-308A polymorphisms in the course of pulmonary sarcoidosis. Tissue Antigens. 2010; 75(3):262-268. 39. Spagnolo P, Renzoni EA, Wells AU, et al. C-C chemokine receptor 2 and sarcoidosis: association with Lofgrens syndrome. Am J Respir Crit Care Med. 2003;168(10):1162-1166. 40. Crouser ED, Culver DA, Knox KS, et al. Gene expression proling identies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2009;179(10):929-938.
www.chestpubs.org

41. Pabst S, Karpushova A, Diaz-Lacava A, et al. VEGF gene haplotypes are associated with sarcoidosis. Chest . 2010; 137(1):156-163. 42. McDougal KE, Fallin MD, Moller DR, et al; ACCESS Research Group. Variation in the lymphotoxin-alpha/tumor necrosis factor locus modies risk of erythema nodosum in sarcoidosis. J Invest Dermatol. 2009;129(8):1921-1926. 43. Pabst S, Baumgarten G, Stremmel A, et al. Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis. Clin Exp Immunol. 2006;143(3):420-426. 44. Spagnolo P, Sato H, Marshall SE, et al. Association between heat shock protein 70/Hom genetic polymorphisms and uveitis in patients with sarcoidosis. Invest Ophthalmol Vis Sci. 2007;48(7):3019-3025. 45. Rosenbaum JT, Pasadhika S, Crouser ED, et al. Hypothesis: sarcoidosis is a STAT1-mediated disease. Clin Immunol. 2009; 132(2):174-183. 46. Idali F, Wahlstrm J, Dahlberg B, et al. Altered expression of T cell immunoglobulin-mucin (TIM) molecules in bronchoalveolar lavage CD41 T cells in sarcoidosis. Respir Res. 2009; 10:42. 47. Campo I, Morbini P, Zorzetto M, et al. Expression of receptor for advanced glycation end products in sarcoid granulomas. Am J Respir Crit Care Med. 2007;175(5):498-506. 48. Rastogi R, Du W, Ju D, et al. Dysregulation of p38 and MKP-1 in response to NOD1/TLR4 stimulation in sarcoid bronchoalveolar cells. Am J Respir Crit Care Med. In press. doi:10.1164/rccm.201005-0792OC. 49. Morbini P, Villa C, Campo I, Zorzetto M, Inghilleri S, Luisetti M. The receptor for advanced glycation end products and its ligands: a new inammatory pathway in lung disease? Mod Pathol. 2006;19(11):1437-1445. 50. Hill MR, Papali A, Booth H, et al. Functional prostaglandinendoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis. Am J Respir Crit Care Med. 2006;174(8):915-922. 51. Petkova DK, Clelland CA, Ronan JE, Lewis S, Knox AJ. Reduced expression of cyclooxygenase (COX) in idiopathic pulmonary brosis and sarcoidosis. Histopathology. 2003; 43(4):381-386. 52. Boots AW, Drent M, Swennen EL, Moonen HJ, Bast A, Haenen GR. Antioxidant status associated with inammation in sarcoidosis: a potential role for antioxidants. Respir Med. 2009;103(3):364-372. 53. Bargagli E, Bianchi N, Margollicci M, et al. Chitotriosidase and soluble IL-2 receptor: comparison of two markers of sarcoidosis severity. Scand J Clin Lab Invest. 2008;68(6):479-483. 54. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM, van Velzen-Blad H. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation. Chest. 2003;124(1):186-195. 55. Tremblay A, Stather DR, Maceachern P, Khalil M, Field SK. A randomized controlled trial of standard vs endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis. Chest. 2009;136(2):340-346. 56. Ardehali H, Howard DL, Hariri A, et al. A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J. 2005;150(3):459-463. 57. Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with 18F-uoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging. 2008;35(5):933-941. 58. Kaminaga T, Takeshita T, Yamauchi T, Kawamura H, Yasuda M. The role of iodine-123-labeled 15-(p-iodophenyl)-3R, S-methylpentadecanoic acid scintigraphy in the detection of local myocardial involvement of sarcoidosis. Int J Cardiol. 2004;94(1):99-103.
CHEST / 139 / 1 / JANUARY, 2011

181

DownloadedFrom:http://journal.publications.chestnet.org/on07/27/2012

59. Ishimaru S, Tsujino I, Takei T, et al. Focal uptake on 18F-uoro2-deoxyglucose positron emission tomography images indicates cardiac involvement of sarcoidosis. Eur Heart J. 2005; 26(15):1538-1543. 60. Tadamura E, Yamamuro M, Kubo S, et al. Images in cardiovascular medicine. Multimodality imaging of cardiac sarcoidosis before and after steroid therapy. Circulation. 2006; 113(20):e771-e773. 61. Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest. 2003;124(1):177-185. 62. Baughman RP, Lower EE, Bradley DA, Raymond LA, Kaufman A. Etanercept for refractory ocular sarcoidosis: results of a doubleblind randomized trial. Chest. 2005;128(2):1062-1067. 63. Baughman RP, Drent M, Kavuru M, et al; Sarcoidosis Investigators. Iniximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med. 2006;174(7):795-802. 64. Judson MA, Baughman RP, Costabel U, et al; Centocor T48 Sarcoidosis Investigators. Efcacy of iniximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J. 2008;31(6):1189-1196. 65. Rossman MD, Newman LS, Baughman RP, et al. A doubleblinded, randomized, placebo-controlled trial of iniximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2006;23(3):201-208.

66. Stagaki E, Mountford WK, Lackland DT, Judson MA. The treatment of lupus pernio: results of 116 treatment courses in 54 patients. Chest. 2009;135(2):468-476. 67. Fisher KA, Serlin DM, Wilson KC, Walter RE, Berman JS, Farber HW. Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment. Chest. 2006; 130(5):1481-1488. 68. Milman N, Burton CM, Iversen M, Videbaek R, Jensen CV, Carlsen J. Pulmonary hypertension in end-stage pulmonary sarcoidosis: therapeutic effect of sildenal? J Heart Lung Transplant. 2008;27(3):329-334. 69. Barnett CF, Bonura EJ, Nathan SD, et al. Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience. Chest. 2009;135(6):1455-1461. 70. Neville E, Mills RG, Jash DK, Mackinnon DM, Carstairs LS, James DG. Sarcoidosis of the upper respiratory tract and its association with lupus pernio. Thorax. 1976;31(6):660-664. 71. Aubart FC, Ouayoun M, Brauner M, et al. Sinonasal involvement in sarcoidosis: a case-control study of 20 patients. Medicine (Baltimore). 2006;85(6):365-371. 72. Long CM, Smith TL, Loehrl TA, Komorowski RA, Toohill RJ. Sinonasal disease in patients with sarcoidosis. Am J Rhinol. 2001;15(3):211-215. 73. Kay DJ, Har-El G. The role of endoscopic sinus surgery in chronic sinonasal sarcoidosis. Am J Rhinol. 2001;15(4): 249-254.

182

Recent Advances in Chest Medicine

D w l a e Fo :ht :j un lp biai n.hsntogo 0 / 72 1 o no dd r m tp/o r a. u lc to sc et e. r / n 72 / 0 2