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Table of Contents

Daniel A.
Culver, DO

Department of
Pulmonary and
Critical Care
Medicine

Oluranti
Aladesanmi,
MD, MPH

Mani S.
Kavuru, MD

Department of
Pulmonary and
Critical Care
Medicine

Definition

Unresolved Issues In Sarcoidosis

Epidemiology

Genetics

Pathophysiology

Etiology

Signs and Symptoms

Diagnosis and Course

Treatment

References

Sarcoidosis is a systemic disorder characterized by the accumulation of non-necrotizing granulomas in affected organs, with varying degrees of concomitant inflammation or fibrosis. Since its first description at the end of the19^th century, it has been identified on all continents and may affect all races, ages and genders. The pattern of organ involvement and course of disease may vary widely between patients, and are often difficult to predict at presentation.

Several aspects of the disease remain poorly understood. Further research is needed in the following areas:

• What agent(s) cause sarcoidosis?


• Is sarcoidosis one polymorphic disease or is it a syndrome of stereotyped immune responses to diverse insults? If it is one disease, what accounts for the wide degree of clinical heterogeneity?


• Is there a marker (or panel of markers) that can predict disease progression or
  serve as a reliable index of disease activity?


• Does treatment alter the natural history of the disease?


• What is the optimal treatment regimen and duration for treatment of sarcoidosis?

This chapter will discuss current understanding of sarcoidosis epidemiology, genetics, clinical manifestations, diagnosis and course, treatment and pathophysiology. For a discussion of lung diseases that may present with similar manifestations, please refer to the "Idiopathic interstitial lung disease" chapter.

Epidemiologic characterization of sarcoidosis is problematic due to variability in case definitions, ascertainment bias, and lack of precise diagnostic methods. Population-based chest x-ray screening programs in Scandinavia and the U.K. have suggested that there are a sizeable number of asymptomatic patients whose disease never becomes overt. Based on these studies, prevalence rates have ranged from less than 1/100,000 population in the U.K. to 102/100,000 in Sweden.¹ A community-based autopsy study in Northeast Ohio also suggested that there might be a significant proportion of unrecognized disease.²

Demographic factors, including race, ethnicity, age, and gender markedly influence incidence. In the U.S., incidence in African-Americans is 3.8-fold higher than Caucasians, conferring an overall lifetime risk of 2.4% versus 0.85%.³ Most patients present between the ages of 20-40, although a number of studies have suggested a second peak after 50 years, especially for females.^4,5 Also, most surveys have demonstrated a slightly higher overall frequency in females. For example, the sole U.S. population-based survey (from Rochester, Minnesota) found an age-adjusted incidence of 5.9/100,000 in males and 6.3/100,000 in females.⁵ Similarly, a review of all cases in a health maintenance organization revealed an adjusted relative risk of 1.3 for females.³

Familial clustering of sarcoidosis was first recognized 80 years ago. The first large series described 121 cases in 59 families, and noted an increased incidence in monozygotic compared with dizygotic twins.⁶ In a case-control etiologic study of sarcoidosis (ACCESS), a recently completed descriptive U.S. study, the familial relative risk of sarcoidosis was estimated using 736 patients, matched for age, sex, and geographic location with 10,862 first-degree and 17,047 second-degree relatives.⁷ The relative risk for development of disease in a first or second degree relative was 4.7 after adjustment for age, sex, relative class, and shared environment. Surprisingly, there was a trend toward a higher familial relative risk in Caucasians than African-Americans (18.0 vs. 2.8, p=0.098). It should be recognized, however, that the absolute risk of coincident disease is low (less than 1%), and therefore screening of asymptomatic family members is not generally necessary.

Disease presentation and natural history are also influenced by epidemiologic factors. White patients tend to present more often without symptoms, while severe, multi-system disease occurs more frequently in blacks.^8-10 It is well-described that black race confers added mortality,¹¹ however, data from population-based settings have suggested that the differential outcome may be related more to access to medical care than to inherent differences in disease behavior.^12,13 The recently completed ACCESS study systematically characterized 736 newly diagnosed patients at 10 U.S. centers.⁹ Organ involvement was significantly influenced by demographic variables, including age, gender and race (Figure 1).

The observation that disease incidence is linked to race and clusters in families led early investigators to hypothesize that there might be a genetic predisposition to sarcoidosis. More recently, genetic studies of sarcoidosis have demonstrated that specific gene polymorphisms are involved in both susceptibility to and phenotypic determination of the disease.¹⁴ These polymorphisms include genes governing antigen presentation, such as human leukocyte antigen (HLA) genes for the major histocompatibility complex (MHC), cytokines such as tumor necrosis factor-α (TNFα), and several chemokines.¹⁵ Until recently, studies of HLA associations with sarcoidosis used mainly case-control designs, which may produce biased results because of population stratification.¹⁶ In addition, methodological issues such as low-resolution molecular identification, frustrated prior attempts to definitively link HLA molecules to sarcoidosis.

Recently, the ACCESS investigators used high-resolution typing to define HLA class II associations with sarcoidosis in a study of the first 474 ACCESS patients and case-matched controls.¹⁷ They screened for the HLA-DPB1, HLA-DQB1, HLA-DRB1, HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus. In this cohort, the HLA-DRB1*1101 allele was associated with a population attributable risk of 16% in blacks and 9% in whites. A specific amino acid residue [HLA-DRB1-F (47)] most strongly associated with sarcoidosis, especially in whites. In contrast to chronic beryllium disease, a non-E (69) allele at the HLA-DPB1 locus, HLA-DPB1*0101, conveyed most of the risk.¹⁷ HLA class II alleles may be markers for the phenotypic pattern of sarcoidosis, such as DRB1*0401 for ocular disease in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites.¹⁷

HLA-DQB1 and not HLA-DRB1 plays an important role in sarcoidosis susceptibility in African Americans. Identification of the specific HLA-DQB1 alleles that influence sarcoidosis susceptibility in African Americans and the study of their antigenic-binding properties may reveal why African Americans suffer disproportionately from this disease.¹⁸ A study of the transmission of HLA-DQB1 alleles in 225 African American families with at least one offspring with sarcoidosis found major differences in the amino acid sequences encoded by *0201 and *0602 alleles, which may explain the differential effects these alleles have on sarcoidosis susceptibility and progression in African Americans.¹⁶ The DQB1*0201 allele is also strongly protective against severe sarcoidosis in British and Dutch whites, in whom it is strongly associated with Stage I disease (by the Scadding scale; see below), whereas DQB1*0602 tended to have opposite effects. A clear association was found between the *0201 allele and Löfgren's syndrome and carriage of this allele reduced the risk of disease progression.¹⁹ HLA-B8 and -DR3 occur in association with the acute form of sarcoidosis.²⁰

The TNFB*1 allele, was recently identified in a population of Japanese sarcoidosis patients as a marker for prolonged clinical course in patients with sarcoidosis. It is the first link of cytokine gene polymorphism to the prognosis of sarcoidosis.²¹ In the future, epidemiologic and genomic information will be needed to define distinct phenotypes, based on biomarkers for both the disease and disease prognosis. Large population based studies will help, because sarcoidosis is relatively rare and certain biomarkers, such as specific T cell receptor usage, are expressed in only a subset of patients. Certain markers of immune function, namely HLA types and T-cell receptor expression, should be correlated with sarcoidosis phenotypes. A genome-wide linkage analysis screen for sarcoidosis susceptibility genes in African-Americans, recently completed by a multi-center U.S. group (Sarcoidosis Genetic Analysis Consortium-SAGA), is a first step. Two hundred twenty-nine affected sib-pairs and their relatives were recruited for the study. The results may lead to candidate genes modulating development of disease or clinical phenotype.

Sarcoid inflammation is characterized by non-necrotizing granulomas (Figures 2 and 3). The granuloma is a compact mass of cells that walls off foreign antigens, typically microbes. Epithelioid histiocytes, together with a few multinucleated giant cells comprise the core, surrounded by an outer rim of T-lymphocytes. The lymphocyte population is oligoclonal, with restricted T-cell receptor repertoires, consistent with an antigen-driven process. Inflammation in sarcoidosis is dependent on persistent stimulation by CD4+ T cells. Current thinking holds that a poorly degradable antigen is responsible for the inability of some individuals to resolve cell-mediated immune stimulation. Thus, polymorphisms of the major histocompatibility complex and the T-cell receptor that modulate affinity for the antigen may be responsible for development or course of the disease.

Most of the pathophysiologic research to present has focused on the inflammatory, or early, stages of sarcoidosis.^22,23 Characterization of sarcoidosis inflammation in humans has consistently demonstrated a Th1-predominant cytokine profile, with important roles for IFN-λ, IL-12, IL-18, and TNFα.^23-26 Interferon gamma, IL-12 and IL-18 are likely to be important in directing the development of the Th1 phenotype and may account for failure of feedback mechanisms to down-regulate immune activation. In accordance with this, IL-12 and IFN-λ knockout mice fail to develop granulomatous inflammation after challenge with granuloma-inducing agents.^27,28 Additionally, TNFα is an essential mediator, directing monocyte proliferation and differentiation of macrophages into the epithelioid cells of granulomas.²⁹ Other mediators include IL1β, and IL-6 which both amplify and maintain granuloma formation.³⁰ The inflammatory nature of the disease can be demonstrated by excess production of these mediators by alveolar cells obtained from bronchoscopic lavage.^22,26 Other mediators that are important in sarcoidosis include IL-2, IL-15, GM-CSF, and osteopontin.

For chronic sarcoidosis, there is a striking degree of heterogeneity between patients: some have persistent inflammation, while others "shift" to a fibrotic phenotype. This shift is not seen in all patients, and the onset and pace of the fibrosis are likewise highly variable. The factors that instigate the fibrotic process are unknown. Several authors have speculated that production of Th2 cytokines is important to trigger widespread pulmonary fibrosis, although there have been no efforts to date to characterize the cytokine milieu in fibrotic sarcoidosis.^29,31,32 While IFNλ has anti-fibrotic properties by down-regulating the production of collagen and TGF-ß, the Th2 cytokines IL-4 and IL-13 directly enhance fibroblast production of TGF-ß and collagen.^33,34 In accord with this, Th2 dominant murine models of granulomatous lung disease have a much greater propensity to develop fibrosis than Th1-directed granuloma models.³⁵ At present, it is also unknown whether the development of fibrosis occurs in a persistent Th1-type milieu, or requires ascendance of Th2 T-cell phenotypes.

It is generally accepted that exposure to an exogenous agent is necessary to develop disease. Evidence in support of this includes:

• Case-clustering among groups of nurses, firefighters and U.S. Navy personnel.³⁶
  
• Well-documented cases of sarcoidosis transferred from affected donors to recipients of heart, lung and bone marrow transplants.³⁷
  
• Epidemiologic investigations correlating disease incidence to space-time clustering. The most well-known example is a case-control study from the Isle of Man, which suggested that prolonged close contact was an important risk for disease.³⁸
  
• Development of intradermal, typical non-necrotizing granulomas in sarcoidosis subjects inoculated with extracts from the spleen or lymph nodes of individuals with sarcoidosis (the Kveim-Siltzbach reaction).³⁹

The search for an etiologic agent has spanned more than a century so far. It is still unknown whether a single agent triggers the disease, or if sarcoidosis represents a stereotyped immune response to diverse etiologies. A large number of infectious and non-infectious agents have been proposed (Table 1). Recent attention has focused most prominently on Mycobacteria sp. and P. acnes,^31,40 but the evidence to date has been inconclusive and sometimes contradictory.

The Kveim-Siltzbach reaction has helped support the concept that sarcoidosis is antigen-driven. Intradermal injection of a homogenate of splenic or lymphatic tissue provokes development of nodular skin lesions. Histologically, there is noncaseating granulomatous inflammation that is dependent on an oligoclonal population of CD4+ T-lymphocytes. The potential to induce granulomas is resistant to heat, acidity, denaturing detergents, nucleases, proteases, and organic solvents; powerful denaturants, however, can eliminate its activity, suggesting that the crucial component may be a small, antigenic polypeptide.

Sarcoidosis may affect any organ, although the lungs are involved in up to 95% of patients (Figure 4). Other organ systems commonly affected include the skin, eyes, and lymphoreticular system. Estimates of organ involvement are confounded by the method of discovery, referral bias, and the sensitivity of diagnostic modalities. Why different organs are differentially affected in various individuals is unclear. When sarcoidosis is suspected in extra-pulmonary organs, chest imaging or random transbronchial biopsy may be helpful to help confirm the diagnosis.⁴¹

Systemic
Constitutional symptoms such as fatigue, weight loss, low-grade fevers and anorexia may dominate the clinical picture. A high prevalence of depression has been reported in sarcoidosis, and differentiation of mood disorders from sarcoidosis symptoms is often difficult.⁴²

Lungs
Cough, exertional dyspnea, and non-specific chest pain are the most common symptoms. Features mimicking asthma, including wheezing, may be present. Airflow obstruction is the most common physiologic abnormality on pulmonary function testing, occurring in 57% of patients.⁴³ Biopsy evidence of endobronchial disease also occurs in 57% of patients (Figure 5A), while abnormal methacholine responsiveness is present in 21%.⁴⁴ Obstruction is occasionally due to endobronchial stenosis, a situation that should be suspected in the presence of localized wheezing, and that may be remedied with interventional bronchoscopic modalities (Figure 5B). Other physiologic findings may include restricted lung volumes, impaired carbon monoxide diffusing capacity, and evidence of pulmonary arterial hypertension that is disproportionate to the degree of parenchymal disease. Even in the presence of widespread infiltrates, lung auscultation is usually unremarkable. Rare manifestations of pulmonary involvement (that should lead to reconsideration of the diagnosis) include hemoptysis, clubbing, pleural effusions, and pneumothorax. With advanced disease, pulmonary fibrosis may ensue, with the physiologic sequelae of pulmonary restriction, reduced diffusing capacity, impaired exercise capacity, and occasionally hypoxemia. The prevalence of fibrotic sarcoidosis is probably underestimated, since chest radiographs are relatively insensitive. Large-scale epidemiologic surveys have suggested that between 5.4 and 10% of cases are fibrotic at presentation alone.^9,10 Mycetoma formation rarely may complicate fibrotic disease.

Skin
Dermatologic manifestations of sarcoidosis are protean. Ultimately, one-quarter of patients will develop at least one dermatologic feature.⁴⁵ Erythema nodosum (EN) is associated with acute onset of disease and confers a good prognosis. Tender erythematous raised lesions, usually on the shins, often with associated regional arthritis or periarthritis, are characteristic. Biopsy of the lesions will reveal panniculitis rather than granulomas, since EN is a nonspecific autoimmune phenomenon. Lupus pernio is a chronic plaque-like induration of the face, usually appearing with violacious discoloration of the cheeks, lips, nose and ears (Figure 6). It may erode into cartilage or bone, causing permanent disfigurement. Lupus pernio generally portends chronic, multisystem sarcoidosis, is more common in older African-American or West Indian females, and is notoriously difficult to treat. Other skin lesions include plaques, maculopapular eruptions, hypo- or hyperpigmented patches, subcutaneous nodules, and alopecia (Figure 7). Often, the lesions arise in scars or tattoos.

Eyes
Any ocular structure may be affected. In acute disease, anterior uveitis (iritis) causes photophobia, conjunctivitis, tearing, pain, and blurred vision (Figure 8). It is usually easily treated with topical therapy. Chronic inflammation is typically more insidious, and may affect the anterior or posterior structures. Retinal involvement, with characteristic "candle-wax dripping" exudates (Figure 9), multifocal choroiditis (Figure 10), macular edema and neovascularization may be asymptomatic but always requires treatment. For chronic uveitis, prolonged treatment is generally necessary to prevent loss of vision.

Nervous System
Clinically apparent neurologic disease occurs in 5-13% of patients, often in the absence of symptomatic disease in other organs.^46,47 Any neurologic structure may be involved. CNS disease has a predilection for the base of the brain (Figure 11). Cranial nerve VII palsy is the leading single manifestation in most case series; however, a recent large series noted a higher frequency of optic nerve involvement.⁴⁸ In general, cranial nerve palsies, hypothalamic or pituitary infiltration and aseptic meningitis are more commonly associated with an acute or subacute pace, a favorable course and treatment responsiveness. Chronic presentations include space-occupying masses, peripheral nerve involvement, myelopathy, seizures and chronic meningitis. Peripheral nerve involvement may manifest as mononeuritis multiplex, symmetric polyneuropathy (sensory, motor, or mixed), Guillain-Barre syndrome, paresthesias or polyradiculopathy.

MRI with gadolinium or gallium scans are useful for suggesting the diagnosis but are nonspecific. However, leptomeningeal enhancement after gadolinium has been shown to predict reversibility of sarcoid lesions.⁴⁹ Lumbar puncture should be performed in the appropriate clinical context to exclude mycobacterial or fungal infections. CSF analysis may reveal lymphocytosis, elevated protein, oligoclonal bands, and elevated angiotensin converting enzyme levels.⁴⁸ As a diagnostic aid, CXR should be obtained in patients with suspected neurologic disease, since asymptomatic intrathoracic disease is present in up to 30% of cases.⁴⁸ Corticosteroids have been used most often in neurosarcoidosis treatment, with mixed results. In general, prolonged administration of relatively intense immunosuppression is necessary if treatment is required.

Heart
Cardiac involvement in sarcoidosis is often occult, with less than one-third of affected patients diagnosed during life.⁵⁰ In necropsy studies, the prevalence of cardiac disease among U.S. sarcoid patients ranges from 20-76%, but clinical disease manifests in only 2-7%.⁵⁰ In Japan, cardiac involvement is both more frequent and more severe. Seventy-seven to 85% of sarcoid deaths in the Japanese population are attributable to cardiac involvement, versus 13-50% in the U.S. Since early aggressive treatment improves the prognosis, a high index of suspicion is warranted.

Disease manifestations may be due to active granulomatous inflammation or fibrosis; any cardiac structure may be affected. The most frequent diagnoses include electrophysiologic abnormalities (heart block, dysrhythmias, sudden death), infiltrative cardiomyopathy with systolic or diastolic dysfunction, cor pulmonale, angina-like chest pain and pericardial disease. Ventricular aneurysm, papillary muscle dysfunction, valvular infiltration, and stenoses of intramural coronary arteries occur rarely.

Thallium scintigraphy is useful to identify areas of active or inactive myocardial involvement. Abnormal thallium uptake, with a characteristic pattern of improvement after exercise or dipyridamole infusion ("reverse distribution"), may be indicative of microvascular ischemia.⁵¹ In the presence of unremarkable coronary angiograms, abnormal thallium scans in patients with known sarcoidosis are highly suggestive of myocardial involvement. However, asymptomatic patients with abnormal thallium scans are unlikely to have clinically bothersome long-term disease.⁵² Newer imaging techniques, such as FDG-PET scanning and gadolinium-enhanced MRI are promising modalities for diagnosis and monitoring treatment response. However, there are no data comparing the accuracy of these expensive tests with conventional studies, and their role in diagnosis and follow-up is unclear. ECG, Holter monitoring and event monitoring may identify patients with dysrhythmias, and baseline ECG is recommended for all newly diagnosed patients. Endomyocardial biopsy is rarely useful, due to poor sensitivity.⁵³ Therefore, a nondiagnostic biopsy should not preclude treatment when clinical suspicion is high.

Liver
Biopsies reveal granulomas in 50-80% of cases and mild elevations of transaminases or alkaline phosphatase are common, but such findings are rarely of clinical importance.⁵⁴ Differentiation from primary biliary cirrhosis can be difficult. Occasionally, liver disease can progress to portal hypertension or cirrhosis. Histopathologic findings include cholestasis, focal necroinflammatory lesions, vascular involvement and widespread fibrosis.⁵⁵ Usually, active inflammation responds to corticosteroids. Therapy is not indicated in asymptomatic patients or for mild elevations of liver enzymes. There is no evidence that pre-existing mild elevation of liver enzymes increases the risk of hepatic toxicity from methotrexate; despite concern for acute or chronic hepatic toxicity, it can normalize liver enzyme abnormalities and can be used effectively with careful monitoring.⁵⁶

Spleen and Lymph Nodes
In addition to the high frequency of intrathoracic lymphadenopathy (90%), approximately a third of patients have palpable peripheral nodes.³⁹ In the neck, posterior triangle glands are more commonly involved than anterior ones. The nodes are firm, nontender and nonulcerating. Palpable splenomegaly, usually asymptomatic, occurs in 14% of cases,⁵⁷ while histologic disease is present in around 50%.

Kidneys
Clinical involvement of the kidneys is uncommon, but biopsy may reveal granulomas in up to 20% of patients.⁵⁸ Renal lithiasis or nephocalcinosis due to hypercalciuria are the most common manifestations, but granulomatous nephritis and rarely glomerulopathy may also occur. Drug-induced granulomatous inflammation may cause similar pathologic findings.

Endocrine System and Calcium Metabolism
Autonomous uncontrolled conversion of 25-hydroxy-Vitamin D to 1,25-dihydroxy-Vitamin D by activated sarcoid macrophages accounts for the presence of hypercalcemia or hypercalciuria in up to 11% and 20% of patients, respectively.⁵⁹ Ectopic Vitamin D production usually responds easily to moderate doses of oral corticosteroids or antimalarial agents. Cytochrome P450 oxidase inhibitors, such as ketoconazole may also be effective. Patients with deranged calcium metabolism should be instructed to avoid excessive sunlight and high-calcium diets, including calcium supplements.

Upper Airway Disease
Involvement of the upper airway, including the middle and inner ear, occurs in less than 5% of patients. It can be challenging to diagnose, owing to the frequency of nasal symptoms in the general population. Besides the typical manifestations of chronic rhinitis, the nasal mucosa may be very friable with crusting or bleeding, and there may be nodularity or marked thickening. Other manifestations include otitis media, vestibular symptoms, hearing loss, exocrine gland swelling, xerostomia, chronic sinusitis, oral ulcerations and oral-nasal fistulae. First-line management of all but the most advanced cases should include nasal saline spray and saline irrigation. Topical corticosteroids may be helpful, sometimes requiring doses higher than those typically used for rhinitis. In the event of severe disease, systemic medical management may be needed.

Musculoskeletal System and Joints
Muscle involvement may cause weakness, elevated muscle enzymes, and pain; the diagnosis is supported by electromyographic abnormalities and enhancement on gadnolinium MRI or gallium scan. The proximal muscles are usually most affected, while involvement of the bulbar or respiratory muscles is very rare. Although the incidence of symptomatic sarcoid myositis is reportedly less than 5%, muscle biopsy in asymptomatic patients will reveal granulomas in 50-80% of patients.⁶⁰ Unrecognized myositis may be an important contributor to fatigue and exercise limitation.

Acute arthritis with overt synovitis tends to occur early in the course of the disease, and may be the presenting feature. It is generally symmetric, with involvement of the ankles most commonly, and often the knees, hands, wrists, and elbows as well. Chronic arthritis is uncommon (1-4%), and is almost always associated with multiorgan disease. In the chronic form, the shoulders, knees, wrists, ankles and hands are affected most frequently, and response to treatment is poor.

Osseous sarcoidosis is often clinically occult; pain and swelling may occur, but overt bony disease is uncommon overall (<5%). Any bony structure may be involved, but the middle and distal phalanges of the hands and feet are the most frequent sites.⁶¹ Significant osseous involvement is associated with multisystem disease, especially lupus pernio, and portends a poor prognosis.

Specific Syndromes
Löfgren's syndrome, characterized by bilateral hilar lymphadenopathy, fever, erythema nodosum and polyarthralgias, accounts for 20-50% of acute presentations. It is more common in Caucasians. With few exceptions, it portends an excellent prognosis.⁶² Heerfordt's syndrome, or uveo-parotid fever, is characterized by fever, facial nerve palsy, parotid gland enlargement and anterior uveitis.

Sarcoidosis is a diagnosis of exclusion. In an appropriate clinical setting, the presence of non-necrotizing granulomas, without evidence for infection, is the usual criterion to suggest the diagnosis. Sarcoidosis mimics and non-specific granulomatous reactions should be excluded by a careful examination and medical, occupational and medication history. Table 2 lists pulmonary diseases that are often confused with sarcoidosis. In practice, the disease is most often diagnosed by biopsy of the most accessible tissues, usually skin, lungs, or peripheral lymph nodes. We recommend a histologic diagnosis prior to commencing any treatment, or in the presence of any atypical clinical features.

The Scadding Scale, a descriptive schema that allows a loose characterization of the chance for disease remission, is used widely to describe chest x-ray findings (Figure 12).⁶³ Use of the scale entails several caveats: the "stages" of the Scadding scale do not represent sequential or temporal disease states; the predictive ability of the scale allows an approximation of outcome only; there are no data correlating stages of the scale with treatment response; the scale was developed over fifty years ago in only 136 British patients; the utility of the scale has not been validated in comparison with chest CT. The most common radiologic findings include bilateral hilar and mediastinal lymphadenopathy and bilateral nodular or reticulonodular infiltrates. In a sentinel study of 100 consecutive patients with bilateral hilar lymphadenopathy on plain chest-x-ray, Winterbauer et al. showed that the absence of abnormal exam findings, symptoms, or anemia strongly suggested sarcoidosis, and importantly, excluded all cases of malignancy.⁶⁴ Other features that should prompt consideration of an alternate diagnosis include pleural effusion, unilateral abnormalities, and the presence of calcification in the lymph nodes.

The clinical impact of sarcoidosis varies widely, and is dependent on the distribution and intensity of granulomatous inflammation or fibrosis in the affected organs. The initial evaluation should include an assessment accounting for the common manifestations. The natural history of disease is similarly variable. Features thought to predict poor prognosis vary among studies (Table 3): of all the putative risk factors, no study to date has comprehensively ascertained which are independently associated with disease chronicity or progression.

Staging of pulmonary disease based on the CXR (Figure 12) allows a general prediction of outcome. While chest CT may delineate the extent of pulmonary fibrosis or uncover infiltrates not seen on plain film, there are few data supporting accurate prognosis by CT exam. Other assays of disease "activity" have been the subject of intense investigation, including serum angiotensin converting enzyme level, gallium-67 scan, and bronchoalveolar lavage fluid characteristics (CD4/CD8 ratio, total lymphocyte count); unfortunately, none has consistently been predictive of disease course.^60,61 For now, CXR stage, demographic features, clinical involvement and serial pulmonary function testing remain the best indicators in assessing prognosis and therapeutic decisions. Refer to the "Pulmonary Function Testing" chapter for a detailed discussion.

Several situations warrant aggressive systemic treatment. The most-commonly accepted indications include active neurologic or cardiac involvement of any degree (except Bell's palsy), severe hypercalcemia, ocular disease refractory to topical therapy, lupus pernio, significant hepatic involvement, symptomatic splenic disease, and bulky lymphadenopathy resulting in symptomatic compression of surrounding structures. Other scenarios that require case-by-case decisions include sarcoid myositis, sinonasal, gastrointestinal, exocrine gland or skin involvement, granulomatous nephritis, and bone disease. Constitutional symptoms, such as fatigue and achiness, are clinically bothersome for a large proportion of patients; they are best approached with non-steroidal anti-inflammatory medications and careful assessment for the presence of depression, reserving the toxicities of steroids for patients with potentially-life-threatening progressing disease.

Several principles guide treatment strategy. First, corticosteroids prevent granuloma formation in most patients, and reverse immunologic derangements; second, granuloma formation proceeds at variable rates between patients, necessitating individualized treatment strategies; third, a threshold dose of medication is usually required for effectiveness; fourth, different tissues respond differently to various medications.⁶⁵ For example, antimalarial medications are effective for hypercalcemia and skin disease, but have little effect on pulmonary disease. Decisions to treat pulmonary sarcoidosis should be framed in the context of the lack of evidence that treatment significantly changes the natural history of the disease. The likelihood of spontaneous remission, degree of physiologic impairment, magnitude of symptoms and chronicity of disease must be considered. For patients with acute (less than 2 years) disease, systemic treatment is generally withheld unless there are significant symptoms, moderate to severe physiologic impairment, or rapid progression and chest imaging suggestive of the presence of reversible disease (eg, infiltrates that are not wholly fibrosis). For patients with chronic disease (>2 years), the chances of spontaneous remission are low. The general goal of therapy in this group is to define the lowest dose of medication needed to maintain stability. Significant pulmonary symptoms may also be due to pulmonary vascular involvement, a diagnosis that should be considered in patients whose symptoms are disproportionate to the degree of parenchymal involvement.

Corticosteroids are the current first-line agents for treatment, since clinical experience is greatest with them, they generally have acceptable (and reversible) side-effect profiles, and the time to onset of effect is quicker than most alternatives. For pulmonary disease, initial doses of 30-40 mg/d of prednisone are probably sufficient. Although some authors have advocated higher doses (1 mg/kg/day), the ratio between benefit and toxicity of such doses is usually unfavorable. Improvements in symptoms, chest radiographs and lung function tests are typical; failure to respond within 3-4 months suggests the presence of steroid-refractory disease. Although some authors have advocated every-other-day dosing regimens, this approach may not be sufficient to control active granuloma formation. In general, we suggest that systemic treatment of pulmonary disease should entail at least weeks to months of therapy.

Inhaled corticosteroids may be useful for symptoms of bronchospasm and cough, in conjunction with bronchodilators. Numerous trials have assessed their utility is treating parenchymal disease, with the net result suggesting that they have very modest to no benefits. However, for patients with mild disease, a trial of inhaled corticosteroids is generally well tolerated and may be helpful.

Steroid-sparing agents are used when steroids are ineffective or cause unacceptable side effects. Methotrexate, a folic acid analogue with anti-inflammatory and anti-proliferative properties, is generally used as a second-line agent, but has not been subjected to rigorous controlled studies. In small trials, it has been effective for disease control and corticosteroid dose reduction for both acute and chronic disease.^66,67 Doses of 10-20 mg/week are typically used, and treatment response may require 3-6 months of therapy. The purine analogue azathioprine is also effective as a steroid-sparing agent, but its use is limited due to its potential for substantial toxicity.⁶⁸ A recent series suggested that leflunomide may be useful in conjunction with methotrexate.⁶⁹ For severe or refractory disease, agents with greater potential for toxicity may be necessary, including cyclophosphamide and chlorambucil. Antimalarial agents are frequently efficacious for treatment of dermatologic disease, sinonasal sarcoid, osseous disease and hypercalcemia. Newer approaches include antagonists of TNF-α, including thalidomide and monoclonal antibodies such as infliximab.^70,71

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