Concise Review for Primary-Care Physicians

Transcription

1 Concise Review for Primary-Care Physicians Sarcoidosis RICHARD A. DEREMEE, M.D. Sarcoidosis is a systemic granulomatous process of unknown cause. Pathologically, it is characterized by noncaseous granuloma, and in more than 90 % of patients, the lung or intrathoracic lymph nodes are affected. A roentgenographic staging system (stages I, II, and III), based on the appearance of the plain chest roentgenogram, conveys important information about prognosis, degree of symptoms, and pulmonary function abnormalities. The diagnosis should be confirmed by histopathologic examination and exclu- Sarcoidosis is a relatively common problem in a pulmonary disease practice. At the Mayo Clinic, approximately 100 new cases are evaluated each year. Among the diffuse interstitial pulmonary diseases, the two major entities are sarcoidosis and idiopathic pulmonary fibrosis. I Worldwide, the incidence of sarcoidosis ranges from 11 to 640 cases per 100,000 population.' The mean age of affected patients is approximately 40 years, although the age range is broad and includes some patients in their 70s. Although many published series report a larger proportion of women than of men, data from the Mayo Clinic (unpublished) suggest that this seeming preponderance may be inaccurate because of a higher incidence of symptoms in women that probably leads to more frequent medical attention. Furthermore, sarcoidosis is often more symptomatic and aggressive in Afro-Americans than in Caucasians. Thus, drawing firm conclusions from studies that combine data from AfroAmerican and Caucasian cohorts is unwise. DEFINITION Because the cause of sarcoidosis is unknown, a somewhat lengthy and descriptive definition is necessary. In a sense, sarcoidosis is a syndrome-a collection of signs, symptoms, and laboratory, roentgenographic, and pathologic data that presumably identify a group of patients for whom the prognosis and management are predictable. Authorities may From the Division of Pulmonary and Critical Care Medicine and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. R. A. DeRemee, Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN Mayo cu«proc 1995; 70: sion of known causes for the noncaseous granulomatous reaction. When indicated, treatment with alternate-day regimens of prednisone is highly effective. Serial chest roentgenography, pulmonary function studies, and the serum angiotensin-converting enzyme level are useful for monitoring the course of the disease. (Mayo Clin Proc 1995; 70: ) SACE = serum angiotensin-converting enzyme offer various definitions, all of which should include four major points. First, a noncaseous or nonnecrotizing granuloma (the more modern parlance) is the characteristic pathologic finding. Obviously, this finding is not specific for sarcoidosis but can be caused by specific agents or conditions, such as mycobacteria, fungi, beryllium, or syphilis. It may also be associated with Crohn's disease (regional enteritis). Thus, the finding of noncaseous granuloma alone is nondiagnostic but must be assessed in the context of the total clinical framework, and reasonable efforts should be exerted to exclude these alternative causes. The second point is that, thus far, the cause of sarcoidosis is unknown. Continued investigations may ultimately elucidate specific etiologic mechanisms. Third, sarcoidosis should be considered a systemic disease. For example, noncaseous granuloma isolated to skin in a foreign body reaction or in regional lymph nodes that drain areas of a malignant lesion represents a local "sarcoid reaction" and is not sarcoidosis. Fourth, sarcoidosis should have clinical consistency. This concept is the most difficult to convey but should be clarified by the subsequent discussion. INITIAL CLINICAL MANIFESTATIONS In general, the initial manifestations or clinical picture will be a function of the predominant organ involvement (Table 1). In more than 90% of patients, the lung or intrathoracic lymph nodes will be affected. Paradoxically, few (if any) symptoms are attributable to lung involvement, at least in the early phase of the disease. In Caucasian cohorts, pulmonary symptoms such as dyspnea and cough may be absent, even with extensive lung disease manifested on a chest roentgenogram. Symptoms, particularly dyspnea, usually occur when Mayo Foundation for Medical Education and Research

2 178 SARCOIDOSIS Table I.-Sites of Manifestation of Sarcoidosis Lymph nodes (especially intrathoracic) Lungs Liver Spleen Eyes Bones (especially small bones of hands and feet) Salivary and lacrimal glands Central nervous system Skin Heart (infrequently) the disease is in a late fibrotic phase associated with obstruction of the airways. This characteristic contrasts with idiopathic pulmonary fibrosis, wherein dyspnea is a cardinal, early symptom. Sarcoidosis may be diagnosed because of involvement of the eyes with uveitis, iritis, conjunctivitis, or perhaps dry eyes due to involvement of the lacrimal glands. Twenty-five percent of Mayo patients have such involvement. In approximately 20% of patients, characteristic skin involvement, such as erythema nodosum, lupus pernio, or salmoncolored to brown plaques, may be the first manifestation that leads to further investigations for sarcoidosis. In patients with a seventh cranial nerve palsy (Bell's palsy), an obscure peripheral neuropathy, or perhaps even a mass lesion in the central nervous system that proves to be noncaseous granuloma, sarcoidosis should be included in the differential diagnosis. Approximately 10% of patients with sarcoidosis will have neurologic involvement. A physician may suspect sarcoidosis in patients with pituitary gland dysfunction or an increased serum calcium concentration. Other sundry manifestations include hepatosplenomegaly, cystic or erosive lesions of bones (particularly in the hands), or a symmetric ascending polyarthritis. Clinically significant heart involvement is infrequent, but sarcoidosis is a possible cause of conduction disturbances, arrhythmias, and cardiomyopathies. Fever may be present in up to 10% of affected patients, particularly those with extensive involvement of retroperitoneal lymph nodes (as may be assessed by a computed tomographic scan of the abdomen). In summary, intrathoracic involvement is often asymptomatic but may be attended by cough or dyspnea, particularly in late phases of the disease. Other symptoms will be dictated by specific organ involvement, such as the eyes, skin, nervous system, bones, or joints, and by the presence of hypercalcemia. ROENTGENOGRAPHIC STAGING SYSTEM For more than 30 years, a roentgenographic staging system, as proposed by Wurm and colleagues,' has been used in the classification of sarcoidosis. This system is based solely on Mayo Clin Proc, February 1995, Vo170 the appearance of the plain chest roentgenogram and has no foundation in data from computed tomography, gallium scanning, or other findings. Stage I consists of bilateral hilar adenopathy, often in conjunction with a right paratracheal node (Fig. 1). In stage II sarcoidosis, patients have bilateral hilar adenopathy and diffuse parenchymal infiltration, which usually is interstitial but occasionally is finely nodular or miliary (Fig. 2). Parenchymal infiltration without hilar adenopathy constitutes stage III (Fig. 3). Some authoritie s use a stage IV classification to indicate irreversible fibrosis, but this category must be based on information other than that available from the plain chest roentgenogram and, in my opinion, is not helpful. More than simply transmitting roentgenographic visual information, the staging system also imparts information on prognosis, frequency of symptoms, and degree of derangement of pulmonary function.' Relative to prognosis, the probability of spontaneous remission is approximately 80% in patients with stage I sarcoidosis, 50% in those with stage II, and 30% in those with stage III. In a study of 256 Mayo patients (unpublished), only 1 of 125 with stage I sarcoidosis, 6 of 48 with stage II, and 30 of 83 with stage III complained of dyspnea. The complaint of dyspnea was correlated with the finding of airways obstruction. In another study of pulmonary function (unpublished ), only 1 of 32 patients with stage I sarcoidosis had an abnormal finding-a mild obstructive change. Of21 patients with stage II disease, 7 had abnormalities (l obstructive and 6 restrictive patterns). Of21 patients with stage III disease, 15 had abnormalities of pulmonary function, including 12 restrictive and 3 obstructive patterns (3 had a combination of obstruction and impairment of diffusing capacity). Thus, the roentgenographic staging system effectively reflects not only the prognosis but also the frequency of symptoms and pulmonary function abnormalities. Of importance, many patients with stage II or III sarcoidosis may have no symptoms and may have pulmonary function variables within normal limits at the time of initial assessment. MAKING THE DIAGNOSIS Because more than 90% of patients have intrathoracic disease often as the sole manifestation of sarcoidosis, many will likely be asymptomatic and brought to medical attention only because of abnormal findings on a chest roentgenogram. Roentgenography of the chest may have been performed during a mass screening program (infrequent today), in the course of a routine physical examination, or during investigation of other problem s or seemingly unrelated symptoms. As previously mentioned, other organ system involvement may have prompted attention. Once the diagnosis of sarcoidosis is considered, tissue confirmation should be sought. In patients with stage I sarcoidosis, I recommend mediastinoscopy. Some clinicians might argue

3 Mayo Clin Proc, February 1995, Vol 70 SARCOIDOSIS 179 Fig. 1. Chestroentgenographic appearance of stagei sarcoidosisbilateral hilaradenopathy without parenchymal infiltration. Fig. 2..Chest roentgenographic appearance of stage II sarcoidosis-bilateral hilar adenopathy in conjunction with parenchymal infiltration. that an asymptomatic patient without physical findings but with stage I roentgenographic abnormalities needs no tissue confirmation. This may be a reasonable approach, but because the diagnosis necessitates tissue confirmation, the patient cannot be given a finn diagnosis and hence prognosis. If the patient is comfortable with this degree of uncertainty, tissue confirmation may be postponed, but careful follow-up is imperative-that is, chest roentgenography every 3 to 6 months, until the course is clarified. For patients with stage II or III sarcoidosis, bronchoscopy in conjunction with bronchial and transbronchial lung biopsy is recommended. With experienced investigators, tissue confirmation should be achieved in more than 80% of cases. Should these measures fail, open-lung biopsy can be considered; however, before such a biopsy is done, a diligent search should be made for possible sarcoidal lesions in the skin or conjunctiva. A conjunctival biopsy is unlikely to reveal sarcoidosis if no gross abnormalities of the conjunctiva are evident on visual inspection. Open-lung biopsy should be resorted to infrequently. In a series of99 consecutive Mayo patients (unpublished), only 5 required open-lung biopsy for final diagnosis. All biopsy material should be cultured for mycobacteria and fungi, and the diagnosis of sarcoidosis cannot be confirmed until a specific cause for the noncaseous granulomahas been excluded. The Kveim test is primarily of historical interest. Although it may still be used, the antigen is not commercially available, and few centers are still actively engaged in its production and validation. TREATMENT After sarcoidosis has been diagnosed, the next challenge is management and treatment. The treatment of lung manifestations remains controversial more than 40 years after the Fig. 3. Chest roentgenographic appearance of stage III sarcoidosis-parenchymal infiltration without hilar adenopathy. Notepreponderant upperzoneinvolvement.

4 180 SARCOIDOSIS Mayo Clin Proc, February 1995, Vol 70 Stage I Observation Remission No improvement Continue prednisone therapy at 40 mg on alternate days or increase dose to 60 mg. + Stages Il and III Observation for 6-12 mo,/ -, No improvement or Improvement deterioration Continue observation + Prednisone, 40 mg on alternate days for 3 mo,/ ~ + Improvement Decrease prednisone dose 10 mg at each 3-mo observation,/ ~ Reactivation Inactive Increase prednisone + to last effective dose Fig. 4. A method of treatment of pulmonary sarcoidosis. introduction of glucocorticoids. On the basis of a large experience, I advocate use of glucocorticoids in all patients with stage II or III sarcoidosis if, after a period of observation of 6 to 12 months, the disease either shows no evidence of spontaneous clearing or has worsened, as determined by serial roentgenography and pulmonary function studies.' Alternate-day regimens of prednisone, usually beginning at 40 mg, are uniformally effective. The recommended management approach is outlined in the algorithm depicted in Figure 4. Rarely is stage I disease an indication for treatment unless symptoms of erythema nodosum and arthritis must be alleviated. If nonsteroidal agents such as indomethacin, 25 mg three times a day, are ineffective, a short course of alternate-day prednisone therapy beginning at 20 mg can be used. Although some authorities would invoke pulmonary symptoms as an indication for treatment, my colleagues and I have found that the presence of dyspnea is a strong indicator of irreversible disease. Therefore, glucocorticoid treatment is best administered in the presymptomatic phase of sarcoidosis to stave off irreversible changes. Most authorities agree on the following indications for glucocorticoid treatment: (l) uveitis (local treatment may be attempted first), (2) hypercalcemia, (3) myocardial involvement (particularly cardiomyopathy), and (4) neurologic disease. If glucocorticoids cannot be used, other agents are available, but they are decidedly second-line drugs, seldom as effective as glucocorticoids, or fraught with equally consequential side effects. These second-line agents include methotrexate, chloroquine, azathioprine, and oxyphenbutazone. MONITORING THE COURSE AND EFFECT OF TREATMENT Serial chest roentgenography and pulmonary function studies are of singular importance in the management of sarcoidosis. Their intervals will be dictated by either the individual patient's course or the personal preferences of the managing physician. In addition, serum angiotensin-converting enzyme (SACE) determinations are of considerable value in monitoring the course." The level of SACE is thought to reflect the mass or "load" of granuloma in the individual patient. Mayo studies have shown that the level of SACE is increased more than two standard deviations from the mean in 67% of patient s with stage I sarcoidosis, in 87% with stage II, and in 95% with stage III. A substantial number of patients deemed to have active sarcoidosis had SACE levels in the "normal" range.' Therefore, one should not use an individual SACE determination in assessing a patient's clinical activity; the serial profile is indicative of activity. Patients with SACE levels in the normal range will manifest appreciable decreases either in the course of spontaneous remission or under the influence of glucocorticoid treatment. Thus, SACE levels can be used to detect the degree of granulomatous activity and, consequently, the ad-

5 Mayo Clin Proc, February 1995, Vol 70 SARCOIDOSIS 181 equacy of the glucocorticoid suppression. Increasing levels should raise concern about an impending relapse or an inadequate glucocorticoid dose. The levels of SACE should never be used as the sole indication for treatment. Involvement of additional sites obviously necessitates assessment of changes pertinent to the organs affected. Relapse is common after effective treatment, occurring in as many as 25% of patients with stage II or III sarcoidosis. Thus, physicians must be vigilant in maintaining periodic surveillance for years after treatment. If stability of the condition and signs of inactivity have been maintained for longer than 1 year after cessation of treatment, the possibility of relapse is considerably diminished. Only a few laboratory studies other than those previously mentioned are helpful in the diagnosis and management of sarcoidosis. Some basic studies are reasonable, such as a complete blood cell count, serum creatinine and calcium concentrations, and urinalysis. A few patients with hypersplenism may have leukopenia and even mild anemia. Every patient should be tested for hypercalcemia, a prime indication for treatment. A urinalysis and serum creatinine determination can reveal the presence of hypercalcemic nephropathy and renal stones. In the early 1980s, bronchoalveolar lavage and gallium citrate lung scanning were touted as important in determining the clinical course and need for treatment. Although bronchoalveolar lavage has led to important discoveries about the humeral and cellular mechanisms involved in the pathogenesis of sarcoidosis, neither of these procedures yields practical information for the day-to-day management of sarcoidosis. REFERENCES 1. DeRemee RA. Clinical Profiles of Diffuse Interstitial Pulmonary Disease. Mount Kisco (NY): Futura, DeRemee RA. Sarcoidosis: current perspectives on diagnosis and treatment. Postgrad Med 1984 Sep 1; 76: Wurm K, Reindell H, Hei1meyerL. Der Lungenboeck im Rontgenbild. Stuttgart (Germany): Thieme, DeRemee RA. The roentgenographic staging of sarcoidosis: historic and contemporary perspectives. Chest 1983; 83: DeRemee RA, Offord KP. The treatment of pulmonary sarcoidosis: the house revisited. Sarcoidosis 1992; 9(Suppll): DeRemee RA. The treatment of sarcoidosis. In: Lieberman J, editor. Sarcoidosis. Orlando (FL): Grune & Stratton, 1985: DeRemee RA, Rohrbach MS. Normal serum angiotensin converting enzyme activity in patients with newly diagnosed sarcoidosis. Chest 1984; 85:45-48 Questions About Sarcoidosis (See article, pages 177 to 181) 1. Which two of the following are true about the diagnosis of sarcoidosis? a. Noncaseous granuloma is specific and diagnostic b. Sarcoidosis can be caused by a variety of fungi and mycobacteria c. Beryllium may cause a noncaseous granuloma that simulates sarcoidosis d. The diagnosis may be made by biopsy of skin in a patient with consistent chest roentgenographic findings e. An increased SACE level is diagnostic 2. Which two of the following are true about the staging of sarcoidosis? a. Is based solely on plain chest roentgenography b. Has a bearing on prognosis c. Is unrelated to degree of pulmonary function abnormality d. Stage III implies the best prognosis for spontaneous remission e. Has no relevance to treatment decisions 3. Which of the following organs or tissues can be involved in sarcoidosis? (more than two answers may be correct) a. Heart b. Bones of hands and feet c. Eyes d. Skin e. Cranial nerves Correct answers: 4. Which three of the following tests are helpful in monitoring the course of sarcoidosis? a. Pulmonary function b. Chest roentgenography c. SACE d. Serum potassium e. K veim test 5. Which one of the following is true about the SACE level? :J'5; ':J pun 'q '0'17 'a a. Is always increased in active sarcoidosis b. Should be used as a prime indicator for treatment of sarcoidosis c. Serial profiles are more important than single values in determining the course of sarcoidosis d. Levels are unaffected by glucocorticoid therapy e. Is not increased in diseases other than sarcoidosis q ~ n Oo'f l q'ql pun o z: 'p puc o '1