Goal of the Treatment for Sarcoidosis
Minimize Harm for the Patient

	ARTICLE

TOP Article REFERENCES

Active sarcoidosis is a systemic disorder characterized by mononuclear cell infiltrates and granuloma formation (1). The most common sites of clinical disease are in the lung and lymph nodes, but almost any organ can be involved. Early in the course of the disease, the process resembles a classic Th1-type cellular immune response with well-formed granulomas and large numbers of CD-4+ T-cells that secrete interleukin-2 and interferon gamma (1). It is not clear if the more chronic, fibrotic form of the disease is driven by the same type of immune process.

The studies that delineated the immune mechanisms associated with early, active sarcoidosis were very important for our understanding of the pathogenesis of this disease (1). They also stimulated an interest in treating this disease with drugs that specifically target these immune processes. In this regard, cyclosporine was a natural choice because of its capacity to suppress the release of interleukin-2 (IL-2; 4, 5). An earlier study by Martinet and coworkers (6) showed that cyclosporine suppressed in vitro release of IL-2 from T-cells in patients with sarcoidosis; however, it had no effect on the clinical expression of the disease. This study was too small, however, to assess the effects of this agent in sarcoidosis. The current study by Wyser and colleagues (7) is much larger, yet it came to a similar conclusion, i.e., that cyclosporine plus prednisone offers no additional benefit to that of prednisone alone. Further, the complications and relapse rate were higher in the cyclosporine plus prednisone-treated group of patients. These studies strongly suggest that cyclosporine should not be used for most patients to treat this disease. As noted by the authors, the study did not exclude the possibility that there might be a subset of patients where the drug may have a positive effect and the risks of the drug might be acceptable.

Some might criticize the design of the study by Wyser and coworkers (7) and the fact that there were not enough patients to evaluate the effect of the drug in different subsets of patients. The study, however, has many strong points and its overall results cannot be dismissed. One very strong aspect of this study is that only patients who met specific criteria for treatment were included in the study, i.e., recent deterioration in lung function (the importance of this will also be discussed below). The criteria used were very similar to that of a prior study that also assessed need for therapy in sarcoidosis (8). A criticism of many other studies is that patients might have been included who did not need therapy and/or would not respond to therapy. Inclusion of these latter patients in a study "dilutes" out any potential to see an effect of the drug on a "responsive" subset of patients. A second comment that can be made is that it is clear that inclusion of more patients would not have led to a result that would have shown a positive effect of cyclosporine. These observations, combined with the toxicities of the drug, strongly support the conclusion of the authors that this drug should not be used routinely for the therapy of sarcoidosis.

Another interesting observation of this study (7) is that the clinical outcome for these patients was fairly good. This was true despite the fact that the majority of the patients had relatively advanced disease and that the major effect of the therapy in both groups could be accounted for by prednisone alone. Even patients who relapsed after therapy was discontinued responded to a second course of treatment. These observations are very similar to another study that also evaluated treatment in a similar group of patients (8).

How should we approach the treatment of sarcoidosis? To answer this, we may want to consider the natural history of the disease. For most patients with sarcoidosis of recent onset, it is important to consider that the disease may be active for only a limited period of time. The X-ray stage (and the presence of certain types of organ involvement) helps determine the probability that the disease will become inactive; but for an individual patient, only time and close observation will give a specific answer. During this initial period of time, some patients may have severe systemic symptoms that can be helped with a short course of low doses of corticosteroids. Most patients with objective evidence of recent (within the last 3 months) deterioration in lung function or other critical organ involvement should be treated (8). Most of the other patients can be observed closely and/or treated with nonsteroidal agents. If these latter patients develop criteria for treatment during this period of observation, they can be treated at that time. Patients who are treated with corticosteroids should be treated with the lowest possible dose of the drug that maintains the desired clinical effect. If the therapy is for systemic symptoms alone, it may be possible to discontinue the drug after a short period of time. If therapy is for loss of lung function or critical organ involvement, consideration should be given to stopping the drug if the patient has been stable on a low dose (i.e., 20 mg every other day or 10 mg/day) of the drug for 6 months. The goal should be to minimize exposure to corticosteroids. If patients relapse, they usually respond to a new course of treatment (7, 8). This approach will not work, however, if patients are not followed closely for a prolonged period of time.

For patients with sarcoidosis of longer duration, i.e., chronic sarcoidosis, a similar approach to therapy can be used. There is no evidence, to date, that severity of chest X-ray changes or pulmonary functions, by themselves, justify treatment with corticosteroids. This, probably, is true because many patients with chronic pulmonary sarcoidosis have "burnt-out" disease and do not improve with therapy and/or the toxicity of treatment is greater than the small clinical benefit that occurs with therapy. Many of these patients can be followed, closely, off therapy. If there is evidence of a recent loss of lung function or critical organ involvement when the patient is first seen or during a follow-up period, they should be treated and they will, usually, respond to therapy. Most of these patients should also be tapered off of their corticosteroids, if they have been stable for a period of time, as outlined above.

Some patients with sarcoidosis have severe disease and cannot be tapered off of prednisone. The reasons for this are not always the same. One group of patients may require a large amount of corticosteroids to maintain a desired clinical effect. For these patients, addition of a steroid sparing agent, like methotrexate (9), may be necessary to reduce the dosage of corticosteroids. Rarely, a patient may be resistant to high doses of corticosteroids. The first question that should be asked, in this setting, is whether the patient has active disease or "burnt-out" disease with residual functional abnormalities. A second question should be whether the changes are, primarily, due to sarcoidosis or a complication of the disease. An example would be changes on chest X-rays or pulmonary functions that are due to bronchiectasis (a substantial proportion of patients with chronic pulmonary sarcoidosis have bronchiectasis) and recurrent infection. The symptoms of these latter patients may mimic those of patients with active sarcoidosis and they improve, somewhat, with corticosteroids. The most appropriate therapy for these patients, however, is antibiotics. If the patient has active sarcoidosis that is truly resistant to corticosteroids, an agent like cyclophosphamide or methotrexate might be used. A final group of patients are those who require low doses of corticosteroids to keep the illness in remission. Some of these patients may have less side effects on low doses of corticosteroids while others may do better with addition of a steroid sparing agent.

Why doesn't cyclosporine work as therapy for sarcoidosis? The answer to this question is not clear. One possibility, as noted by Wyser and coworkers (7), is that cyclosporine levels in the lung are relatively low. Although this might be part of the answer, it is unlikely that this is the only reason. A second possibility, as also noted by the authors, is that the doses of prednisone used in the study were sufficient to achieve a maximal effect. If this is the answer, it is a compelling argument not to use cyclosporine. It is hard to justify the use of a toxic drug like cyclosporine when the desired effect can be achieved with prednisone at an initial dosage of 20 mg/day. Another reason might be that the initial Th1-like response seen early in sarcoidosis is not the driving force that determines the presence of chronic active disease. Less is known about the pathogenesis of chronic, fibrotic sarcoidosis than about newly diagnosed sarcoidosis. Finally, the cause of sarcoidosis is still unknown. Could sarcoidosis be an infectious disease that goes away in most individuals (with or without physiologic sequelae), while in others it persists in an indolent form? Whatever the reason, the question we should always ask regarding the treatment of patients with sarcoidosis should beIs the severity of the second disease that I am giving the patient as a result of treatment justified?

Division of Pulmonary/Critical Care/
Occupational Medicine
University of Iowa College of Medicine
and the Veteran's Affairs Medical Center
Iowa City, Iowa

.

	References

TOP Article REFERENCES

1. Thomas, P. D., and G. W. Hunninghake. 1987. State of art: current concepts of the pathogenesis of sarcoidosis. Am. Rev. Respir. Dis 135: 747-760 [Medline].

2. Hunninghake, G. W., and R. G. Crystal. 1981. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N. Engl. J. Med 305: 429-434 [Abstract].

3. Moseley, P. L., C. Hemken, M. Monick, K. Nugent, and G. W. Hunninghake. 1986. Interferon and growth factor activity for human lung fibroblasts: release from bronchoalveolar cells from patients with active sarcoidosis. Chest 89: 657-662 [Abstract/Free Full Text].

4. Pinkston, P., P. B. Bitterman, and R. G. Crystal. 1983. Spontaneous release of interleukin-2 by lung T-lymphocytes in active pulmonary sarcoidosis. N. Engl. J. Med. 308: 793-800 [Abstract].

5. Hunninghake, G. W., G. N. Bedell, D. C. Zavala, M. Monick, and M. Brady. 1983. Role of interleukin-2 release by lung T-cells in active pulmonary sarcoidosis. Am. Rev. Respir. Dis 128: 634-638 [Medline].

6. Martinet, Y., C. Pinkston, J. Saltini, J. Spurzem, J. Muller-Quernheim, and R. G. Crystal. 1988. Evaluation of the in vitro and in vivo effects of cyclosporine on the lung T-lymphocyte alveolitis of active pulmonary sarcoidosis. Am. Rev. Respir. Dis 138: 1242-1248 [Medline].

7. Wyser, C. P., E. M. van Schalkwyk, B. Alheit, P. G. Bardin, and J. R. Joubert. 1997. Treatment of progressive pulmonary sarcoidosis with cyclosporin A: a randomized controlled trial. Am. Rev. Respir. Crit. Care Med 156: 1371-1376 . [Abstract/Free Full Text]

8. Hunninghake, G. W., S. Gilbert, R. Pueringer, C. Dayton, C. Floerchinger, R. Helmers, R. Merchant, J. Wilson, J. Galvin, and D. Schwartz. 1994. Outcome of the treatment for sarcoidosis. Am. J. Respir. Crit. Care Med 149: 893-898 [Abstract].

9. Lower, E. E., and R. P. Baughman. 1990. The use of low dose methotrexate in refractory sarcoidosis. Am. J. Med. Sci 299: 153-157 [Medline].