Corticosteroids are the drug of choice for the treatment of sarcoidosis. Because the natural course of sarcoidosis may be self-limiting and/or cause no long-term harm, treatment is not mandatory. Corticosteroids are usually effective for all forms of sarcoidosis, and they work quickly. However, because of the potential toxicities of corticosteroids, alternative medications often need to be considered. Efforts should be made to minimize the corticosteroid dose while keeping the risk of toxicity as low as possible. This article outlines the indications for corticosteroid therapy for sarcoidosis, discusses various dosing regimens, and suggests when alternative corticosteroid agents should be considered.
Key points
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Corticosteroids are almost universally effective for the treatment of sarcoidosis. The treatment of sarcoidosis is indicated if the disease causes a dangerous health situation or significantly impairs the patient’s quality of life.
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Treatment should not be based on biomarkers of active granulomatous inflammation.
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Pulmonary sarcoidosis can usually be adequately treated with modest doses of corticosteroids.
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It is unusual for patients to be refractory to corticosteroid therapy. Alternative medications are almost exclusively used because of the frequent development of corticosteroid toxicity.
Introduction
Corticosteroids are considered the drug of choice for the treatment of almost all forms of sarcoidosis. Nonetheless, there is considerable controversy and confusion concerning the use of corticosteroids in the management of sarcoidosis for several reasons. First, sarcoidosis may be a self-limiting disease that may spontaneously remit and/or never cause significant clinical problems. In such patients, toxicity from corticosteroid treatment may cause more harm than that caused by the natural course of the disease. Second, the optimal dose of corticosteroids has not been established for sarcoidosis. Third, the duration of therapy depends on the natural course of the disease, which is highly variable and often unpredictable. Fourth, the indications for adding a corticosteroid-sparing agent have not been standardized. This article discusses an approach to corticosteroid therapy in sarcoidosis based on the available clinical data plus our understanding of the disease.
Introduction
Corticosteroids are considered the drug of choice for the treatment of almost all forms of sarcoidosis. Nonetheless, there is considerable controversy and confusion concerning the use of corticosteroids in the management of sarcoidosis for several reasons. First, sarcoidosis may be a self-limiting disease that may spontaneously remit and/or never cause significant clinical problems. In such patients, toxicity from corticosteroid treatment may cause more harm than that caused by the natural course of the disease. Second, the optimal dose of corticosteroids has not been established for sarcoidosis. Third, the duration of therapy depends on the natural course of the disease, which is highly variable and often unpredictable. Fourth, the indications for adding a corticosteroid-sparing agent have not been standardized. This article discusses an approach to corticosteroid therapy in sarcoidosis based on the available clinical data plus our understanding of the disease.
Indications to treat sarcoidosis
There are 2 indications for the treatment of sarcoidosis: (1) the development of a dangerous health situation; and (2) significant worsening of quality of life. Table 1 lists several situations of danger resulting from sarcoidosis. Note that many of these relate to the development of fibrosis, which, unlike active granulomatous inflammation, is not corticosteroid responsive. Furthermore, most of the entities listed in Table 1 are rare manifestations of sarcoidosis. Therefore, the overwhelmingly most common reason to treat sarcoidosis is for significant worsening of quality of life. Fig. 1 shows the processes leading to significant quality-of-life impairment in sarcoidosis. First, granulomatous inflammation occurs. This inflammation may not lead to any physiologic disturbance or the development of significant symptoms. For example, patients with pulmonary sarcoidosis who have bilateral hilar adenopathy and a normal lung parenchyma (stage I radiograph) often have no pulmonary symptoms, normal pulmonary function, and a benign clinical course. Even if sarcoidosis causes a physiologic disturbance, it may have no significant clinical consequences and cause minimal to no symptoms. Therefore, markers of active granulomatous inflammation, such as increased angiotensin-converting enzyme levels, pulmonary opacities on lung imaging, and positive PET scans, are not indications for treatment. Neither are the asymptomatic minor pulmonary function abnormalities that are very typically observed. Note that the presence of quality-of-life impairment is a necessary but insufficient requirement for the treatment of sarcoidosis because (1) pulmonary symptoms may be caused by an alternative process, or (2) the quality-of-life impairment may be the result of previous granulomatous inflammation resulting in fibrosis that does not respond to antigranulomatous therapy. Identifying biomarkers of granulomatous inflammation and physiologic abnormalities may provide useful evidence to support or refute that sarcoidosis is the cause of the quality-of-life impairment. Fig. 2 outlines a general algorithm for the decision to treat sarcoidosis.
| Conditions | Estimated Frequency (%) | Corticosteroid Responsive |
|---|---|---|
| Sudden death, severe arrhythmia, severe left ventricular dysfunction from cardiac sarcoidosis | 1 | Yes |
| End-stage fibrocystic sarcoidosis (FVC<50% of predicted) | <5 | No or minimally |
| Sarcoidosis-associated pulmonary hypertension | 5 | No |
| Optic neuritis | <5 | Yes |
| Severe neurosarcoidosis | 1 | Yes |
| Hemoptysis from pulmonary mycetoma | <1 | No |
| Vitamin D dysregulation causing renal failure, severe nephrolithiasis | <1 | Yes |
| Upper airway obstruction | <1 | Usually surgical resection is required if airway obstruction is critical |
| Endobronchial airway obstruction | <1 | Usually not (significant fibrosis present) |
Not only may corticosteroid treatment of asymptomatic or minimally symptomatic sarcoidosis create a risk of corticosteroid toxicity with minimal potential for clinical benefit, it may increase the likelihood of relapse. It is thought that granulomatous inflammation is an attempt by the host to clear a nondegradable antigen. Therefore, the granulomatous inflammation of sarcoidosis may be a beneficial process. Antigranulomatous therapy may prevent a putative sarcoidosis antigen from being cleared, resulting in relapse when the antigranulomatous therapy is withdrawn. As evidence that this theoretic schema may be clinically relevant, studies have shown that patients with sarcoidosis receiving corticosteroid therapy have a higher rate of relapse than those who are observed without antisarcoidosis therapy. In addition, in a study of patients with sarcoidosis who were all treated with corticosteroids, those who relapsed received a higher mean dose (17.0 vs 10.6 mg of prednisolone; P <.05; N = 82). These data add further support to withholding therapy in patients with active sarcoidosis who are not experiencing a potentially dangerous clinical condition, significant symptoms, or a significant quality-of-life impairment. Such patients should be closely monitored to ensure that these situations do not develop.
General approach to the treatment of sarcoidosis with corticosteroids
Corticosteroids are the initial drug of choice for the treatment of most forms of sarcoidosis because they are almost universally effective and a significant response is quickly observed, usually in a matter of a few weeks or less. Alternative antisarcoidosis therapies, including methotrexate antimalarials, and others, usually require several months to achieve a meaningful response. In addition, most alternative antisarcoidosis medications when used as monotherapy are effective as sole agents less than half of the time, and, therefore, are most commonly used as corticosteroid-sparing agents.
Issues of Dose
Many of the toxicities of corticosteroids are cumulative, including weight gain and cataract formation. Other side effects may develop rapidly but continue to progress over time, such as bone loss and fluid retention. Therefore, although the corticosteroid dose-response curve for the treatment of sarcoidosis may be maximized at a dose near to or more than 20 mg of prednisone equivalent per day, a lower dose may be optimal to balance the benefits of corticosteroids versus their risks ( Fig. 3 ). The optimal dose of corticosteroids depends in part on the form of sarcoidosis that is being treated, and this is discussed in detail later.
Issues of Duration
In addition to the corticosteroid dose, the duration of corticosteroid therapy is an important issue in terms of the treatment of sarcoidosis. It is important to recognize that the treatment of sarcoidosis with corticosteroids or other therapies may not affect the natural course of the disease. As previously mentioned, sarcoidosis granulomas probably develop as a response to clear a foreign antigen, as is true for most other granulomatous diseases. Antigranulomatous therapy may impair that clearance process and thus could potentially prolong the disease. To that end, adequate therapy for sarcoidosis may be more a matter of the duration of therapy than the use of specific medications or specific doses. As long as the duration of an antisarcoidosis regimen exceeds the length of time necessary to clear the antigen, the therapy will be effective. In contrast, if the regimen is discontinued while the antigen is still present, the patient will relapse ( Fig. 4 ). Because the duration of sarcoidosis is highly variable and unpredictable, it is problematic to determine how long corticosteroid therapy should be continued. All biomarkers of granulomatous activity (eg, angiotensin-converting enzyme levels, lung nodules on chest imaging) are suppressed by resolution of granulomatous inflammation. However, these biomarkers do not reliably predict relapse when therapy is withdrawn. Therefore, presently, the most reliable method to determine whether the duration of therapy for sarcoidosis is adequate is to taper and discontinue therapy and monitor the patient to determine whether the patient relapses ( Fig. 5 ). There is some indirect evidence that serum interleukin-2 receptor and PET scanning may be biomarkers of sarcoidosis activity that are impervious to effective therapy, but this conjecture remains unproved.
Issues of When to Add Additional Agents to Corticosteroids
A corollary of the above discussion concerning the duration of antisarcoidosis therapy is that, because corticosteroid toxicity is cumulative, a longer duration of corticosteroid therapy is associated with increasing risks to the patient. Therefore, the indications for corticosteroid-sparing medications for sarcoidosis are most dependent on the required duration of corticosteroid therapy (see Fig. 5 ). It is much less common for alternative agents to be needed for sarcoidosis because the disease is truly refractory to corticosteroids.
Corticosteroid therapy for specific forms of sarcoidosis
Pulmonary Sarcoidosis
A Delphi study of sarcoidosis experts reached a consensus that corticosteroids are the drug of choice for the treatment of pulmonary sarcoidosis. The American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Diseases consensus statement recommends a daily prednisone equivalent of 20 to 40 mg for the initial treatment of pulmonary sarcoidosis. It is recommended that this dose be continued for at least 1 to 3 months and then tapered to a dose of 5 to 10 mg/d for a total of 1 year before discontinuing. The rationale for a total of 1 year of therapy is based on the unproven assumption that relapses are common with regimens with shorter courses. The rationale for reducing the maintenance prednisone dose to a low level relates to the observation that, after the initial burst of corticosteroid therapy, most patients with pulmonary sarcoidosis can be maintained on a small dose. Other similar dosing regimens for pulmonary sarcoidosis have also been proposed ( Fig. 6 ). Because there is a significant risk of relapse and the natural course of the disease is unpredictable, any algorithm to taper corticosteroids for pulmonary sarcoidosis must be individualized based on the specific response of the patient.
It is our opinion that the lower range of the recommended prednisone dose is very effective for the initial treatment of pulmonary sarcoidosis, and may avoid or lessen corticosteroid toxicity. A retrospective analysis of treatment of 36 patients with acute pulmonary exacerbations of sarcoidosis who received 20 mg of prednisone per day was universally successful in returning pulmonary symptoms and spirometry to baseline levels. A double-blind randomized placebo-controlled trial performed more than 4 decades ago showed a significant improvement in pulmonary sarcoidosis after 3 months of 15 mg of prednisone daily. These data suggest that an initial dose of corticosteroids for the treatment of pulmonary sarcoidosis may be 20 mg of prednisone per day or even less. This dose seems quite effective and lessens the likelihood and severity of corticosteroid side effects. Although alternate-day corticosteroid therapy has been advocated as minimizing corticosteroid side effects, this has never formally been studied in sarcoidosis.
The use of inhaled corticosteroids for the treatment of pulmonary sarcoidosis is controversial. A meta-analysis concerning the use of inhaled corticosteroids for pulmonary sarcoidosis did not clearly show a benefit. A Delphi study of sarcoidosis experts reached a consensus that inhaled corticosteroids should not be used routinely to treat acute pulmonary sarcoidosis. Inhaled corticosteroids have been advocated for sarcoidosis-associated cough, although conclusive evidence for improvement of this symptom has not been shown. One well-designed study suggesting that inhaled corticosteroids may have some long-term benefit for the treatment of sarcoidosis was a double-blind randomized placebo-controlled trial of 189 recently diagnosed patients with pulmonary sarcoidosis who received either 3 months of systemic corticosteroids alone (prednisolone 20 mg/d tapered to 10 mg/d) followed by 15 months of high-dose budesonide (800 μg twice daily) or 3 months of oral placebo followed by 15 months of inhaled placebos. The active treatment group had modest improvements in spirometry and diffusing capacity at 18 months in only the patients with stage II chest radiographs (hilar adenopathy plus parenchymal lung opacities). Although the clinical significance of these physiologic improvements could be argued, follow-up at 5 years showed that the stage II patients who received active therapy had significantly fewer exacerbations requiring corticosteroid treatment. In assessing the available evidence, we do not recommend the routine use of inhaled corticosteroids for the treatment of pulmonary sarcoidosis. We believe that inhaled corticosteroids may have a role in selected situations, such as in patients with significant cough without significant pulmonary dysfunction, or possibly as a corticosteroid-sparing agent.
Cardiac Sarcoidosis
The criteria for the treatment of cardiac sarcoidosis remain unresolved. Symptomatic patients, those with significant arrhythmias and heart blocks, should be treated. It remains to be determined whether patients with asymptomatic cardiac sarcoidosis, such as those detected serendipitously on imaging studies, require treatment. As previously mentioned, it is a general principle that patients with sarcoidosis should not be treated for asymptomatic granulomatous inflammation. However, because cardiac sarcoidosis is a potentially life-threatening condition, some clinicians advocate an aggressive treatment approach for such patients. A recent study of asymptomatic cardiac sarcoidosis detected on nuclear magnetic imaging found that such patients had a very low risk of significant cardiac events. Some electrophysiology experts have suggested performing programmed electrical stimulation studies in patients with sarcoidosis, even if asymptomatic, for risk stratification for serious cardiac events. However, this approach has not yet been validated. A Delphi study of cardiac sarcoidosis experts did not reach a consensus concerning the treatment of asymptomatic cardiac sarcoidosis or using programmed electrical stimulation studies in such patients.
Corticosteroids are the first-line agents for the treatment of cardiac sarcoidosis because they have high efficacy, and there is usually a short delay in obtaining a significant response. Corticosteroids have been shown to improve all manifestations of cardiac sarcoidosis, including left ventricular dysfunction, ventricular tachycardia, and atrioventricular block. Corticosteroids probably improve survival from cardiac sarcoidosis.
Although the evidence supporting corticosteroids as the cornerstone of treatment of cardiac sarcoidosis is irrefutable, the optimal dosing regimen remains undetermined. Although many clinicians advocate higher doses, such as 1 mg/kg/d, of prednisone as initial therapy, others recommend 30 mg/d of prednisone based on a longitudinal study showing no difference in the prognosis of cardiac sarcoidosis between those treated with at least 40 mg/d of prednisone and those receiving 30 mg/d or less. Although there is no supporting evidence, it is rational to consider higher doses of corticosteroids in high-risk situations, such as symptomatic ventricular tachycardia and a severe acute decline in left ventricular function, to ensure that the dose is maximized. A Delphi study of cardiac sarcoidosis experts reached a consensus that 30 to 40 mg of daily prednisone should be the initial treatment dose for cardiac sarcoidosis.
Skin Sarcoidosis
Skin sarcoidosis causes no significant morbidity or mortality. It rarely causes pain or pruritus. Therefore, the main indication for the treatment of skin sarcoidosis is cosmetic importance of the lesions to the patient. Skin sarcoidosis lesions are classified as specific when the histologic examination shows typical granulomatous inflammation of sarcoidosis. Nonspecific sarcoidosis skin lesions show a nondiagnostic (nongranulomatous) inflammatory reaction pattern on histologic evaluation. Nonspecific skin lesions are often associated with acute presentations of sarcoidosis and, in general, portend a good prognosis. The prototypical nonspecific sarcoidosis skin lesion is erythema nodosum, which is often associated with Lofgren syndrome. The treatment of specific sarcoidosis skin lesions is discussed later.
Topical corticosteroids may be considered for a single or a few sarcoidosis skin lesions of concern. Although potent topical corticosteroids such as clobetasol propionate cream and halobetasol propionate ointment have shown benefit for skin sarcoidosis, they are often not completely effective, probably because the corticosteroid cannot penetrate deep into the dermis, which may contain the bulk of the skin lesion. Intralesional injections of corticosteroids such as triamcinolone may be more effective than topical preparations. Even ultrasound delivery (phonophoresis) of corticosteroid has been reported to be effective. However, all these topical therapies are impractical for widespread disease, and there is a concern for the development of skin atrophy with chronic use.
Systemic corticosteroids are the treatment of choice for generalized or highly disfiguring skin sarcoidosis. An initial dose of 20 to 60 mg/d of daily prednisone equivalent has been recommended, although we recommend initiating therapy at the lower end of that dose range because this is not a life-threatening form of the disease and the dose can always be increased if the response is inadequate. Antimalarials such as chloroquine and hydroxychloroquine, methotrexate, and the tetracyclines have been shown to be beneficial for skin sarcoidosis in case series. However, these drugs often work slowly over a range of several months to more than 1 year. Therefore, in severe cases in which there is a high likelihood of requiring chronic therapy, concomitant initial therapy with corticosteroids plus 1 or more of these alternative agents may be considered so that the alternative agent may reach a therapeutic level in the skin as quickly as possible, minimizing the time until corticosteroids can be tapered.
Lupus pernio ( Fig. 7 ), or disfiguring facial sarcoidosis, is especially problematic to treat. It may be relatively refractory to corticosteroid therapy. In a large retrospective review of treatment regimens for lupus pernio, corticosteroid regimens often resulted in improvement, but infrequently resulted in resolution or near resolution of the lesions. Regimens that included infliximab, a monoclonal antibody against tumor necrosis factor alpha, resulted in resolution of lupus pernio lesions in more than three-quarters of the cases. Noncorticosteroid, non–infliximab-containing regimens were rarely effective for this particular form of skin sarcoidosis. Because of these findings, we recommend early consideration of infliximab for patients with lupus pernio sarcoidosis skin lesions that fail to adequately respond to corticosteroids.
