THE LONGITUDINAL STUDY OF CHRONIC ... - Europe PMC

THE LONGITUDINAL STUDY OF CHRONIC SARCOIDOSIS* t CAROL J. JOHNS and (BY INVITATION) JIMMY B. ZACHARY, M. ISABELLE MACGREGOR, JEFFREY L. CURTIS, PENELOPE P. SCOTT and PETER B. TERRY BALTIMORE

Many studies of sarcoidosis have reviewed the varied manifestations of the disease and some have summarized the occurrence of spontaneous remissions or radiographic clearing with or without treatment (1-4). The Hopkins group has previously reported the extended study of changes in pulmonary sarcoidosis during and after long-term corticosteroid treatment (5, 6). Although disease of two years' duration is often described as "chronic" sarcoidosis, the present study selectively directs attention to patients whose clinical evidence of sarcoidosis extends over five years or more. No conclusions can be drawn about the relative frequency of occurrence of this type of chronic disease as the patients represent a highly selected group drawn to The Johns Hopkins Hospital from a wide area. The Sarcoid Clinic and Consultation Service have provided the opportunity to follow such patients over a period of many years. It has been observed that significant numbers of patients have severe and often progressive disease requiring prolonged treatment. This study addresses the following major questions. What are the patterns of disease in chronic sarcoidosis and are there differences between white and black patients? What are the effects and complications of corticosteroid treatment and how long is treatment required? MATERIAL AND METHODS It had been intended to review approximately 100 patients with equal numbers of white and black patients followed at Johns Hopkins with chronic sarcoidosis of five years' duration. However, in spite of more than 20 years of referral experience, only 31 white patients meeting the criteria were known to the senior author. Seventy-two black patients, were included according to recent visits and prolonged disease. The group included 36 males (18 white and 18 black) and 67 females (13 white and 54 black) making a total of 103 patients. The medical records and pulmonary function tests were reviewed, usually by the physician who * From the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. t Supported in part by The Hospital for Consumptives of Maryland (Eudowood Fund) and by the Out-Patient Department Clinical Research Grant 5 M01 RR 00722-10, United States Public Health Service.

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had primarily been responsible for the care of the patient. The initial manifestations of the disease and biopsy support for the diagnosis were identified. All patients had a compatible clinical picture and histologic support for the diagnosis from tissue biopsy or Kveim test, although two patients were later found to have scleroderma or systemic sclerosis. Patients were categorized as to the major manifestation initially requiring treatment or evaluation. Other associated manifestations were identified. Treatment responses and relapses were reviewed. Progression, regression and new clinical features of the disease were noted. The individual case reviews were then summarized and analyzed by the senior author and Director of the Sarcoid Clinic (CJJ) who had had the privilege of seeing almost all of these patients at some time in the course of their disease. RESULTS The age at diagnosis and at the time of the last information is presented in Table 1. The numbers of patients represent approximate percentages since the total is 103 patients. Sarcoidosis was diagnosed during the third decade in 57 patients with 19 in the fourth and 15 in the fifth decade. Ten black patients were diagnosed under age 20 and no white patients were in this category. Table 2 identifies the major early manifestation for each patient and also shows the number of patients fitting each category as an associated or subsequent feature. Pulmonary symptoms of cough and shortness of breath were the most frequent, initially occurring in 19 white patients and 43 black patients for a total of 62. In total, 88 patients had pulmonary symptoms as an associated or subsequent feature. There were six white patients without symptoms who had persistent pulmonary parenchymal changes on chest x-ray. Involvement of the nervous system, skin, eyes, mucosa, liver, spleen and joints was more common in black patients. Hypercalcemia was observed more frequently in white patients. This has been noted in another previously analyzed series (7). Two black TABLE 1 Age at Diagnosis (Last Information*) Age

20 Total

VWhite No. of Pts.

Black No. of Pts

12 12 5 2 31

16 24 20 12 72

administered in six month courses in order to avoid ocular toxicity. The latter was not observed. Skin lesions usually regressed during treatment but gradually recurred when chloroquine was withdrawn and improved again when chloroquine was reinstituted. The duration of prednisone treatment and the numbers of patients requiring continued treatment are presented in Table 4. The treatment period was generally longer in black patients than in white patients. Seventy-one patients required treatment for more than five years (14 white, 57 black). Table 5 summarizes the current treatment status. Fiftyseven patients (15 white, 42 black) continue to require systemic prednisone in daily doses of 5-15 mg for control of their disease. Thirty-seven patients (10 white, 27 black) no longer require treatment. Alternate day dosage has been used infrequently because of the increased difficulties of compliance. Complications of treatment have been infrequent. Seven black patients had excessive weight gain during treatment. Four black patients developed diabetes. One 39 year old black male required bilateral hip replacements for aseptic necrosis after 12 years of treatment at usual dosages for recurrent pulmonary disease. One white female, with previous psychotic episodes, and recurring skin lesions and pulmonary infiltrates, developed a manic-depressive psychosis requiring withdrawal of corticosteroids. In one white male patient, tuberculosis of the knee joint occurred during prednisone treatment and recovered completely with isoniazid and ethambutol. Three other patients had proven adequately treated tuberculosis before the diagnosis of sarcoidosis. Isoniazid was continued with the prednisone for several years. Table 6 summarizes the most recent vital capacity expressed as percent of the predicted normal. Thirty-eight patients had a vital capacity of less than 65% of the predicted normal (5 white and 33 black). The less favorable pulmonary outcome is more frequently observed in the black patients. Intracavitary pulmonary fungus balls were identified in 11 patients (1 white and 10 black). All of these patients eventually presented with

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THE LONGITUDINAL STUDY OF CHRONIC SARCOIDOSIS

TABLE 4 Treatment Period Completed Years

15

Total

Continued

White

Black

White

Black

1 3 3 2 1 10

3 2 3 12 7 27

2 1 1 7 4

1 5 19

15

44

Total

6 7 12 40 22 9 96

10 9

TABLE 5 Current Treatment Status White

Black

Total

2 4 10

1 0 27

3 4 37

15 0 31

42 2 72

57 2 103

Dead Never treated Treatment ended Treatment continued Prednisone Chloroquine Total

TABLE 6 Most Recent Vital Capacity % Predicted

85

Total

White

Black

Total

1 1 3 3 7 16 31

8 8 17 18 11 10 72

9 9 20 21 18 26 103

varying hemoptysis ranging from 100 to 1500 ml and all were managed conservatively without surgical intervention. Two recent patients had therapeutic embolization by interventional radiologic techniques. This experience has been previously reported (8, 9). Four black patients had endobronchial disease and two presented with reversible right middle lobe atelectasis. Three black patients had a pneumothorax which was recurrent in two patients. Two other black patients with extensive fibrosis were observed to have severe hypoxia. Renal stones were observed in four white patients. Five black patients had severe nasal obstruction and

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sinusitis and four black patients had severe loss of vision. Other features noted in black patients included three with severe laryngeal disease, with one requiring tracheostomy. One patient had an isolated episode of regional enteritis documented at laparotomy. One patient demonstrated galactorrhea and amenorrhea suggesting pituitary involvement. Neurologic manifestations were demonstrated in four patients with Bell's palsy (1 white, 3 black). Two other patients demonstrated involvement of the first, fifth and sixth cranial nerves. Two patients showed persistent bilateral nerve deafness and in one it was characterized by an abrupt onset and permanent complete loss of hearing. Three patients showed signs of meningeal disease attributed to sarcoidosis. Two were associated with cranial nerve palsies. In one white male patient, meningitis developed as steroids were being tapered. All improved with prednisone treatment. A 30 year old black male initially presented with internal hydrocephalus and submental and hilar adenopathy. In two patients, herpes zoster occurred, attacking the ophthalmic branch of the trigeminal nerve in one case, and the eighth nerve with impairment of hearing and vestibular function in the other. The major feature of the disease outcome is categorized for each patient in Table 7. Three white patients required neither local nor systemic treatment, with only the single manifestation of asymptomatic persistent hilar adenopathy. Twenty patients (7 white, 13 black) remain asymptomatic off treatment. Six white patients with pulmonary disease are presently asymptomatic but continue on treatment. Pulmonary disease with pulmonary fibrosis is the most prominent feature in 44 patients, with 35 (7 white, 28 black) requiring continued treatment. Two patients have cor pulmonale and 2 have required pacemakers because of heartblock. Three deaths have occurred but only one seemed related to sarcoidosis. This 56 year old white male died suddenly at home with recurrent cardiac ventricular arrhythmias after 13 years of known sarcoidosis. Unrelated deaths were occasioned by cancer of the colon in a 38 year old black male and mesenteric thrombosis occurring in the 64 year old white male with scleroderma. Sarcoid involving the skin was most prominent in 6 patients (1 white, 5 black). Other features of black patients included severe loss of vision in three, recurrent liver disease in two, severe joint pains with bone and skin involvement in two, and recurrent hypercalcemia in one patient. One patient with biopsy proven pulmonary sarcoidosis responded well to an initial course of prednisone treatment but because of glomerulonephritis and developing renal insufficiency subsequently required a renal transplant. For this reason, he continues on prednisone treatment as part of his immunosuppressive regimen. His pulmonary sarcoidosis has never recurred and it is unclear whether his renal disease was directly related. Table 8 summarizes the most frequent clinical patterns of chronic

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TABLE 7

Disease Outcome-Major Feature White

Never treated-asymptomatic Asymptomatic Off treatment On treatment Pulmonary symptoms Off treatment On treatment Cor pulmonale Heart block (Pacer) Cardiac arrhythmia (death) Skin Mucosa (nose, larynx) Severe vision loss Orbital mass (lacrimal) Liver disease-recurrent Joint pain (bone & skin) Hypercalcemia-recurrent Hip aseptic necrosis Bilateral deafness Scleroderma (1 death) Psychosis (skin, lungs) Renal transplant (glomerulonephritis) Cancer colon (death) Total

Black

3 7

3

13

20 6

9 28 1 1

9 35 2 2 1 6 3 3 1 2 2 1 1 1 2 1 1

6 7 1 1 1 1

5 3 3 1 2 2 1 1 1

2 1 1

31

Total

1 72

TABLE 8 Clinical Patterns of Chronic Sarcoidosis (Overlapping) Symptomatic parenchymal lung disease (untreated -. irreversible fibrosis) Progressive asymptomatic lung disease (Caucasians) Persistent and progressive skin lesions Hepatosplenomegaly Persistent ocular disease Mucosal disease with nasal obstruction, sinusitis, laryngeal and endobronchial disease Joint disease Heart disease (arrhythmias and conduction defects) Nervous system disease-cranial nerves, meningitis, internal hydrocephalus Hypercalcemnia (esp. Caucasians)

1 103

85% 9% 34% 23% 21% 15% 11% 11% 8% 6%

sarcoidosis. A single patient frequently presents with two or more of these patterns. Eighty-five percent had symptomatic parenchymal lung disease with residual pulmonary fibrosis. Persistent and progressive skin lesions were identified in 34%. Hepatosplenomegaly was a feature in 23% and persistent ocular disease in 21%. Mucosal disease-with nasal ob-

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struction, sinusitis and laryngeal and endobronchial disease-was observed in 15% and all were black. Eleven percent had significant joint disease. Cardiac arrhythmias and conduction defects were observed in 11% of the patients but myocardial sarcoidosis was only a presumptive diagnosis. Eight percent had nervous system disease and 6% had hypercalcemia.

SUMMARY Although spontaneous remissions are frequent in sarcoidosis, chronic persistent disabling disease is also observed. This feature seems more frequent and more severe in black patients, as has been previously reported (10). The more extensive and severe the initial disease manifestations, the more likely it is that the disease will continue. Corticosteroids are usually beneficial and complications are infrequent. Delayed or interrupted treatment seems to allow progression or irreversible disease or both. Patient compliance is an obvious important factor. Relapses are frequent as treatment is withdrawn but are usually at least partially reversible. Some deterioration is observed with repeated relapses. Low dose daily prednisone (5-15 mg) seems to prevent relapses. Patient compliance is facilitated with daily treatment rather than alternate day therapy. Prolonged treatment for 10 to 15 or more years is often required. Chloroquine is particularly helpful in skin and mucosal disease. The necessity for long-term thoughtful management is obvious. REFERENCES 1. Longcope WT, Freiman DG: A study of sarcoidosis. Medicine 1952; 31: 1-132. 2. Mayock RL, Bertrand P, Morrison CE, et al: Manifestations of sarcoidosis: analysis of 145 patients with a review of nine series selected from the literature. Am J Med 1963; 35: 67-89. 3. Smellie H, Hoyle C: The natural history of sarcoidosis. Quart JMed 1960; 29: 539-59. 4. Wurm K, Rosner R: Prognosis of chronic sarcoidosis. Seventh International Conf on

Sarcoidosis and other Granulomatous Disorders. Ann N YAcad Sci 1976; 278: 732-35. 5. Johns CJ, Zachary JB, Ball WC Jr: A ten year study of corticosteroid treatment in

pulmonary sarcoidosis. Johns Hopkins Med J 1974; 134: 251-70. 6. Johns CJ, MacGregor MI, Zachary JB, et al: Extended experience in the long-term corticosteroid treatment of pulmonary sarcoidosis. Seventh International Conf on Sarcoidosis and other Granulomatous Disorders. Ann N YAcad Sci 1976; 278: 722-31. 7. Johns CJ, MacGregor MI, Zachary JB, et al: Chronic sarcoidosis: outcome, unusual features and complications. In: Williams WJ, Davies BH, eds. Eighth International Conference on Sarcoidosis and other Granulomatous Diseases. Cardiff: Alpha Omega

Publishing Ltd.; 1980: 558-566. 8. Kaplan J, Johns CJ: Mycetomas in pulmonary sarcoidosis: non-surgical management.

Johns Hopkins Med J 1979; 145: 157-61.

9. Johns CJ: Editorial: Management of hemoptysis with pulmonary fungus balls in

sarcoidosis. Chest 1982; 82: 400-01. 10. Sartwell PE. Racial differences in sarcoidosis. Ann N YAcad Sci 1976; 278: 368-70.


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DISCUSSION Horwitz (Philadelphia): This is an historic moment. Since I was given an extra minute by the brevity of your talk, I can now speak for a minute about the recent talk myself. I simply want to say that this is the first paper ever given by a lady member and it reminds me of something that happened recently. One lady, talking to another said, "I want to be just as good as men" and the other lady said, "You have no ambition". I understand what that means now. This is a beautiful paper, and thank you very much. Petty (Denver): I enjoyed your paper very much and agree with your conclusions on therapy. However, you must be aware of some attempts in controlled clinical trials that suggest that corticosteroid benefit is more cosmetic than real. How do you respond to those recent reports of lack of benefit from steroids in some attempts at controlled clinical trials? Johns: The question about controlled clinical trials is an enormously difficult one and a group of us from the International Sarcoidosis Committee have been meeting and once again trying to establish the basis upon which we might do such a study. There has never been an adequate study. The instances that have been cited purport to show no advantage. If you look closely at the initial pulmonary function data, most of those patients seem not to have been sick enough to require treatment in the first place. It is then very difficult to demonstrate that they have been benefitted. I acknowledge that I am very much persuaded of the benefits of treatment by many patients like the one I demonstrated, where their disease regresses, at least temporarily. If you keep them on a low dose of prednisone, improvement is maintained, but even after 11 years a relapse can occur when prednisone is reduced. We have a patient population that includes many more black patients than white patients. I had to hunt to find the 31 white patients who had persistent chronic sarcoidosis. I am quite persuaded that there are racial differences. There has never been an adequate trial, and I am not sure whether there will ever be one. We now know a little too much to make a random study very easy. We are planning to try an alternate day schedule of prednisone 50 mg one day and none the next and controls at 10 mg one day and none the next. This latter seems likely to be almost a placebo dose but perhaps easier to justify to a patient in obtaining informed consent, indicating that we are not sure of the optimal dose. We must exclude the people who are seriously incapacitated by their disease as we cannot justify the risk of little or no treatment. In my opinion, they are the people who are the most benefitted. Hammersten (Boise): I want to thank you for presenting this remarkable series of patients, followed so long by one person. I had two questions. One is, in deciding to begin prednisone, do you use the results of bronchoalveolar lavage? The second one is, how do you decide when the prednisone may be safely stopped after that many years? Johns: Our decision about starting treatment is based on clinical grounds, with a review of symptoms, of simple pulmonary tests such as vital capacity and diffusing capacity, and serial chest x-rays and observation over a period of time. We don't start treatment the first minute we see patients unless they are desperately ill. We have not used the findings from bronchoalveolar lavage to determine the initiation or cessation of treatment. I am not persuaded that there is any single laboratory test that replaces a review of the clinical course of the disease. I am delighted to have people doing those special kinds of studies. I think they are still research tools and I don't think that they should be the single determinant for treatment decisions. Periodically, we try to taper and stop treatment. It is our practice to give people at least eight months treatment, and then we try to taper them down slowly. As you have seen, we often don't succeed, particularly not in the black patients who frequently relapse. The determination of how long treatment is needed depends on the patient, using objective changes. As the dose is reduced, we follow x-ray changes, pulmonary function changes and symptoms, all of which tend to go very much in parallel. I do not find it a terribly difficult decision about reinstituting treatment. It is usually quite obvious when a relapse has occurred, and this is often significantly reversible.