Sarcoidosis: An Update for the Primary Care Physician

Abstract

Sarcoidosis is a systemic inflammatory disorder of unknown etiology, characterized by the formation of noncaseating granulomas, multisystem involvement, intrathoracic (pulmonary and lymph node) involvement in more than 90% of cases, and activation of T cells and macrophages at sites of granulomatous inflammation with the release of various chemokines and cytokines including tumor necrosis factor (TNF)-alpha.

Despite the fact that sarcoidosis is seen all over the world, the study of its epidemiology has been a challenge for several reasons, including the lack of consistency in case definition, variability in disease presentation, the lack of sensitive and specific diagnostic tests, underrecognition and misdiagnosis of the disease, and a dearth of systematic epidemiologic studies.[1]

The ACCESS (A Case Control Etiologic Study of Sarcoidosis) study,[2] a multicenter study done at 10 centers in the United States, is an attempt to better characterize the disease. A study of a subset of patients in the ACCESS study showed that there was a delay in making the diagnosis of sarcoidosis, even when patients presented with pulmonary symptoms.

The role of the primary care physician includes the establishment of a supportive physician-patient relationship. The morbidity and psychosocial problems associated with this condition necessitate educating patients about the disease because of the overwhelming concerns about its etiology, prognosis, and potential adverse effects of medication. This supportive role enhances patients' roles in the process of shared decision making during testing and treatment decisions.

The ACCESS study is an attempt to better characterize sarcoidosis by targeting the delay time in making its diagnosis.

Epidemiology

Sarcoidosis affects people of all races, all ages, and both males and females. It is most prevalent in African American, Afro-Caribbean, Swedish, and Danish individuals. It is rarely reported in Spain, Portugal, India, Saudi Arabia, or South America because of the absence of mass screening programs and the prevalence of more commonly recognized granulomatous diseases such as tuberculosis, fungal infections, and Hansen's disease.[1]

It is important to note whether incidence or prevalence data are derived from general population-based, hospital record-based, mass radiography-based or sarcoidosis registration-based data. Since asymptomatic cases may be detected by chest x-rays showing bilateral hilar adenopathy, the best studies are based on a sarcoidosis registration system that includes cases detected by mass radiographic screening and those detected by symptoms. In a Swedish study done from 1966 to 1980, a total of 57% of the cases were detected by mass chest radiographs. In a 1972 Japanese survey, a 50% prevalence rate of asymptomatic cases was reported.[3]

A mortality study in the United States using death certificates, conducted from 1979 to 1991, found that the annual mortality rate was highest in African American females, especially those aged 45–54 years.[4]

Sarcoidosis was listed as the cause of death in 64.2% of the 9014 death records, similar to the 60.6% of 320 deaths in a Japanese study,[5] except for the fact that 77% of Japanese deaths were due to cardiac complications of sarcoidosis. In contrast, a US-based study found that 87% of these deaths were due to pulmonary complications.[6]

Researchers at the Cuyahoga county coroner's office in Ohio reviewed 9324 autopsies done between 1990 and 1997 and found a standardized prevalence of 320 ± 72 per 100,000. Crude prevalence rates suggested young black females were most affected, and overall prevalence was 10 times greater than state-wide death certificates indicated.[7] This study suggests sarcoidosis is more prevalent than reported and is an underrecognized cause of unexpected death, especially in young African American women. Autopsy studies, however, may not be representative of patients with sarcoidosis because of the prevalence of spontaneous resolution; absence of detailed occupational, social, and past medical histories; and the less than 5% mortality rate in sarcoidosis.

In the only population-based incidence study of sarcoidosis in the United States, the age-adjusted annual incidence was 35.5 per 100,000 for black individuals and 10.9 per 100,000 for white individuals, 5.9 per 100,000 person years for men and 6.3 per 100,000 person years for women.[8] Using cumulative incidence estimates, the lifetime risk of sarcoidosis is 0.85% for white individuals and 2.4% for black individuals in the United States.[9]

The ACCESS Study

The ACCESS study,[2] a case-controlled, multicenter study, involved 10 centers in the United States between 1997 and 1999. Incident cases and matched controls were compared on the prevalence of various exposures. Cases were confirmed by tissue diagnosis, compatible clinical course, and exclusion of other possible causes of granulomas. There probably was an overrepresentation of pulmonary disease because the principal investigators were pulmonologists; and since the study involved incident cases over a 2-year period, another limitation was the absence of chronic sarcoidosis patients, who are likely to have more severe disease.

The study examined the etiology, demographics, and clinical course of sarcoidosis patients. A total of 736 patients were enrolled, 63.6% female, 36.4% male, 53.4% white, and 44.2% black. The peak age and sex affected were females aged 35–39 years. Lung involvement was seen in 95% of patients, skin involvement other than erythema nodosum in 16%, extrathoracic lymph node involvement in 15%, eye involvement in 11.8%, and liver involvement in 11.5%.

Women were more likely to have eye involvement, erythema nodosum, and neurologic involvement, while men were more likely to have hypercalcemia. African American patients were more likely to have extrathoracic lymph node involvement and skin involvement other than erythema nodosum.

Some of the characteristics of lung involvement in patients enrolled in the study include the fact that 8% of patients in the study had Stage 0, 40% Stage 1, 36% Stage 2, 10% Stage 3, and 5% Stage 4 Scadding chest x-ray findings; 85% of patients had a forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) of 70% or more; while almost 50% had Grade 0 dyspnea (ie, only with strenuous exercise). The authors found organ involvement differed by race, age, and sex, with race being the major determinant, and suggested future etiologic and therapeutic studies are mindful of this.

Racial and Ethnic Disparities

Racial differences in the clinical manifestations and course of sarcoidosis are well documented; however, there is no specific association between mortality and ethnicity.[10] Black patients are more likely to have extrapulmonary symptoms; constitutional symptoms; severe musculoskeletal symptoms; uveitis, hepatic, bone marrow, or extrathoracic lymph node involvement; lupus pernio; and cystic bone lesions. Their clinical course is more likely to be chronic and progressive, with a worse prognosis.

White patients are more likely to have asymptomatic disease, limited intrathoracic disease, and erythema nodosum, while Japanese patients have a higher prevalence of cardiac and ocular sarcoidosis. Lupus pernio is more common in Puerto Rican and black patients.

Geographic, ethnic, and genetic determinants play a role in these varied clinical manifestations. A 5-fold increase in familial relative risk was demonstrated using a multivariate mode in the ACCESS study,[11] which is consistent with previous evidence of familial clustering.

White individuals had a markedly higher familial relative risk compared with African American individuals, and differential effects of specific alleles on sarcoidosis susceptibility and progression in African American individuals have been identified.[12]

Evidence of Delayed Diagnosis

Judson and colleagues[13] studied the time from the first physician visit to the diagnosis of sarcoidosis in a subset of 189 patients enrolled in the ACCESS study. Patients had to recall the date of onset of symptoms, their first physician visit, number of physician visits, and types of physicians seen. Only 15.3% of patients had the diagnosis of sarcoidosis made after the first physician visit, almost 50% of patients required 4 or more physician visits, and 1 patient in the study required 23 physician visits before the diagnosis was made.

Patients who presented to their physicians with pulmonary symptoms or had higher Scadding chest x-ray stages were less likely to be diagnosed within 6 months. Patients diagnosed more than 6 months after the onset of symptoms or after their first physician visit had a lower FEV₁ but not FVC than those diagnosed within 6 months after symptom onset or physician visit. These findings imply that sarcoidosis was not usually in the differential diagnoses of patients with airflow obstruction or pulmonary infiltrates on their chest radiograph.

It was suggested that common diagnoses such as asthma, bronchitis, and reactive airway disease, which may be treated empirically, tend to delay the diagnosis of sarcoidosis, and the finding of nonspecific parenchymal involvement on chest x-ray would prompt suspicion for other pulmonary diseases such as pneumonia, other interstitial lung diseases, etc. The Stage 0 and 1 chest x-rays may be accompanied by extrapulmonary involvement such as skin involvement, allowing early diagnosis by biopsy, unlike stage 2, 3, and 4 chest x-rays with accompanying pulmonary symptoms, which may need further evaluation with a chest computed tomography scan and transbronchial biopsy.

It is worth noting that the patient's race, gender, and whether the first visit was to a generalist or specialist had no effect on the time between first physician visit and diagnosis in this study.

The take-home point for the primary care physician is to obtain a chest x-ray early in the diagnostic evaluation of a patient who presents with pulmonary symptoms (cough, wheezing, chest pain, and dyspnea), and/or extrapulmonary signs or symptoms compatible with sarcoidosis and to include it in the list of differential diagnoses early.

Clinical Presentation

• Asymptomatic: hilar lymphadenopathy on routine chest x-ray in 30% to 60% of patients.

• Pulmonary: 20% to 30% of patients with symptoms; bronchial hyperreactivity in 20% of patients:

  • Cough, dyspnea, wheezing, chest pain — commonest symptoms;
  • Hemoptysis in < 5% of cases (advanced disease with mycetomas, bronchiectasis, and endobronchial disease); and
  • Rarely, pleural effusions, pleural thickening and calcification, pneumothorax and lymph node calcification.

Extrapulmonary

• Constitutional: fever, fatigue, malaise, and weight loss in 30% of patients; night sweats occasionally.

African American and Asian Indian Individuals: More Often Symptomatic

• Lymphatics: palpable peripheral lymphadenopathy in 30% of patients (nontender, discrete, firm, rubbery, and nonadherent):

  • Intrathoracic lymphadenopathy in 75% to 90% of patients; and
  • Splenomegaly, mild and asymptomatic, may cause abdominal discomfort, cytopenias.
• Skin: 30% of patients:

  • Erythema nodosum, lupus pernio, subcutaneous nodules, plaques, maculopapular rashes, alopecia, abnormal skin pigmentation;
  • Erythema nodosum: common in European, Puerto Rican, and Mexican individuals. Rare in Japanese and African American individuals;
  • Lupus pernio: common in African American women, represents chronic sarcoidosis, indurated plaques, and discoloration of nose, cheeks, lips and ears; nasal mucosa often involved, associated with bone cysts and pulmonary fibrosis; and
  • Chronic sarcoidosis skin lesions: do not cause itch, pain, or ulcerate.
• Eyes: redness, photophobia, decreased visual acuity in 9% to 25% cases:

  • Anterior uveitis: the commonest eye manifestation, chronic uveitis can cause glaucoma, cataracts, and blindness; and
  • Lacrimal gland involvement can cause keratoconjunctivitis sicca.
• Cardiac: clinically diagnosed in 5% of cases, found in 20% to 30% of cases at autopsy:

  • Sudden cardiac death, ventricular tachycardia, other arrhythmias, conduction abnormalities, cardiomyopathy, right heart failure due to advanced interstitial lung disease.

• Hepatic: granulomas in 50% to 80% of cases, palpable hepatomegaly in less than 20% of cases. Mild LFT abnormalities.

• Musculoskeletal: arthralgia in 25% to 40% of patients; deforming arthritis is rare; knees, elbows, wrists, and small joints of hands and feet are most commonly involved.

• Neurologic: less than 10% cases:

  • Base of brain predilection, cranial nerve involvement, especially transient unilateral facial nerve paralysis;
  • Diabetes insipidus: hypothalamus and pituitary involvement; and
  • Space occupying lesions, peripheral neuropathy, and neuromuscular involvement occur late with chronic course.
• Endocrine/renal:

  • Excessive 1,25 dihydroxyvitamin D production by granulomatous tissue causing hypercalcemia (2% to 10% of cases) and hypercalciuria (6% to 30% cases), may lead to nephrocalcinosis, renal calculi, and renal failure.
• Reproductive:

  • Breast masses, infertility is rare, no direct adverse effect on mother or fetus, may flare up postpartum; and
  • Testicular masses, leading to unnecessary orchiectomies because of suspected malignancy.

Acute Sarcoidosis Syndromes

• Lofgren's syndrome: erythema nodosum, bilateral hilar/right paratracheal lymphadenopathy, fever, polyarthralgia.

• Heerfordt's Waldensröm syndrome: fever, uveitis, parotid enlargement, and facial nerve palsy.

Radiographic Staging

• Stage 0: Normal chest radiograph

• Stage 1: Bilateral hilar lymphadenopathy

• Stage 2: Bilateral hilar lymphadenopathy with diffuse pulmonary infiltrates

• Stage 3: Diffuse pulmonary infiltrates without lymphadenopathy

• Stage 4: Pulmonary fibrosis

These stages are prognostic, the 5-year mortality being 0% in Stage 1, 11% in Stage 2, 18% in Stage 3, and more than 50% in Stage 4.[14]

Diagnostic Criteria

• Typical clinical and radiological findings

• Histologic evidence of noncaseating epitheloid cell granulomas

• Reasonable exclusion of other granulomatous diseases

Differential Diagnoses[14]

• Infection

  • Tuberculosis
  • Atypical mycobacterial infections
  • Histoplasmosis and other fungal infections
  • Nocardiosis
  • Actinomycosis
• Reactions to foreign agents

  • Hypersensitivity pneumonitis
  • Chronic berylium disease
  • Talc lung
• Vasculitis

  • Wegener's granulomatosis
  • Allergic granulomatosis
  • Lymphomatoid granulomatosis
• Malignancy (local sarcoid reaction)

  • Lymphoma
  • Carcinoma
• Other

  • Eosinophilic granuloma

Initial Evaluation of Sarcoidosis Patients[15]

• Determine extent and severity of disease

  • Chest x-ray
  • Pulmonary function tests spirometry, DLCO
  • Liver enzymes
  • BUN and creatinine, electrolytes and calcium
  • Complete blood count
  • Urinalysis
• Exclude critical organ involvement

  • EKG
  • Complete ophthalmologic exam
  • Complete neurologic exam
• Exclude other diseases

  • Occupational and environmental exposure history
  • PPD

Treatment

Observation would be appropriate in asymptomatic patients with mild disease, provided they are monitored periodically for evidence of clinical and radiologic progression.

Corticosteroids

Corticosteroids should be initiated when clinically necessary, and collaborative care with other subspecialists, including pulmonologists, rheumatologists, ophthalmologists, cardiologists, gastroenterologists, or dermatologists, may be necessary.

A recent systematic review of evidence from randomized, controlled trials for the effect of corticosteroids in sarcoidosis provided only limited guidance to physicians.[16] Because of the lack of evidence of sustained benefit and the potential adverse effects of corticosteroids, their use should be restricted to those patients in whom careful clinical assessment with monitoring of chest radiographs and lung function confirm a clear need for treatment.

Corticosteroids are usually effective and are indicated for progressive pulmonary disease, threatening critical organ involvement such as the eye, and central nervous system and cardiac involvement. After 6 months to 2 years, they should be withdrawn with careful patient monitoring. Chest x-rays may improve in patients with Stage 2 or 3 disease. Inhaled steroids may be useful for confirmed bronchial hyperreactivity.

Noncorticosteroids

Noncorticosteroids may be effective. Antimalarials are used for skin, bone, and joint involvement; methotrexate and azathioprine are steroid-sparing or steroid-replacing agents for serious organ involvement when steroid therapy is ineffective or not tolerated. Other agents include anti-TNF-alpha inhibitors such as pentoxyfylline, thalidomide, etanercept, and remicade, which have recently shown successes.[17]

The Role of the Primary Care Physician

Sarcoidosis patients have a disease burden that is physical, emotional, and usually complicated by psychosocial problems because it affects people during the most productive years of their lives. African American individuals are disproportionately affected, and sociodemographic factors such as financial, employment, health insurance, and literacy issues affect the processes and outcomes of healthcare in these patients and must be explored in all patients.

Communication skills are vital in the recognition and management of psychosocial contributors to health and illness.[18] In particular, sarcoidosis patients may present with vague or classic clinical problems, and the prevalence of depression in these patients may be as high as 60%.[19] A supportive primary care physician relationship is important and would likely improve health outcomes and facilitate collaboration with other subspecialists involved in the care of the patient.

It has been reported that psychosocial difficulties may prompt up to 50% or more of outpatient generalist visits and cause as much or even more functional impairment than do strictly physical complaints.[20]

The delay in the diagnosis of sarcoidosis is a problem because of the potential for unnecessary healthcare costs that may be out of pocket, extra office visits, unnecessary diagnostic testing, inappropriate treatments before the diagnosis is made, and the frustration, anxiety, and depression experienced by patients when physicians do not diagnose or treat their illness in a timely way.[13]

Another important function of the primary care physician is the education of patients about the unknown etiology of the disease, its prognosis, and treatment options, including the risks and benefits. Exploring patients' explanatory model of illness, sociocultural background, and particular fears and concerns would be helpful in negotiating a therapeutic plan, especially when decisions about invasive tests like bronchoscopic biopsies or initiation of corticosteroid therapy have to be made. This model of communication, abbreviated ESFT, has been applied to the care of hypertensive patients in minority communities to facilitate communication with patients who may have limited understanding of their illness and are nonadherent to testing and treatment plans recommended by their physicians.[21]

Quality-of-Life Measurement

Recently, a new disease-specific quality-of-life instrument, the Sarcoidosis Health Questionnaire (SHQ) for the measurement of the health-related quality of life of sarcoidosis patients, was developed, tested, and validated.[22]

Even though this is still a research tool, there are trends in using such tools during routine clinical care. It is completed in 10 minutes, and it has been proposed that using the SHQ may improve communication between clinicians and patients by facilitating discussion about depression, which may not always be adequately addressed in routine clinical visits, or fatigue and musculoskeletal pain, which are not easily measured in similar encounters. It could also allow clinicians to focus more on patients' individual perceptions of their illness rather than just the clinical measures of the disease.

The instrument has 29 items in 3 domains: daily, physical, and emotional functioning. It was found to be sensitive to differences in health-related quality of life based on the number of involved organ systems.

Patient Education Resources

There are online resources available to patients who have access to a computer, including the sarcoidosis interactive tutorial at the National Library of Medicine MEDLINE Web site. At healthcare institutions where electronic medical records are used with Internet access on the same PC, physicians and other healthcare providers can educate patients who don't have access to a computer or are functionally health illiterate at this Web site. The information is presented in a graphic way and in an interactive format.

• Interactive tutorial: http://www.nlm.nih.gov/medlineplus/tutorials/sacroidosis.html

• Overview of sarcoidosis (requires Adobe Acrobat): http://www.nhlbi.nih.gov/health/public/lung/other/sarcoidosis/sarcoid.pdf

• Cleveland Clinic overview of sarcoidosis: http://www.clevelandclinic.org/health/health-info/docs/2900/2993.asp?index=10673

Other Resources for Patients

The role of online discussion groups as a source of patient advice is increasingly being recognized. These online support groups take different forms, including bulletin boards, chat rooms, instant messaging, and listservs. Patients with chronic medical conditions, including sarcoidosis, who are Internet users participate in these groups. It has been reported that about 54% of Internet users participate in online support groups.[23]

The National Sarcoidosis Resource Center was founded by a patient who reports that she “knows first-hand the frustrations and obstacles that are often encountered by persons with this disease.” The organization is international, with a registry of more than 30,000 patients, and is available online at: http://www.nsrc-global.net.