INTRODUCTION — Sarcoidosis is a multisystem disease of unknown etiology characterized by tissue infiltration with noncaseating granulomas. The granulomas may occur in any organ, but the most frequently affected sites are the lungs, lymph nodes, skin, eyes, and liver. Patients with pulmonary sarcoidosis are most often asymptomatic at presentation. When symptomatic, patients usually report dyspnea, cough, or nonspecific chest discomfort. Spontaneous resolution of the disease is common, but progressive lung disease occurs in approximately 25 percent and disabling organ failure in up to 10 percent [1-3].
This extreme heterogeneity of disease activity and long-term outcomes leads to several challenges in disease management, which are only further enhanced by common adverse side effects of immunomodulatory therapy. The key questions regarding the initial treatment of sarcoidosis are the following:
●What are the indications for treatment?
●What is the initial treatment approach?
●What is the optimal duration of therapy?
●How should the disease course and the response to therapy be monitored?
●Does treatment alter the course of pulmonary sarcoidosis?
An overview of the initial treatment of sarcoidosis will be presented here. The clinical manifestations and diagnostic evaluation of sarcoidosis and treatment of refractory pulmonary sarcoidosis are discussed separately.
Severe extrapulmonary involvement, particularly of the heart, eyes, kidney, or neurologic system, can also necessitate initiation of systemic therapy. First-line treatment of cutaneous disease usually involves topical and intralesional therapy rather than systemic agents, which are reserved for extensive, rapidly progressive, or disfiguring disease. The treatment of extrapulmonary sarcoidosis is discussed elsewhere.
●(See "Clinical manifestations and diagnosis of pulmonary sarcoidosis".)
●(See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
●(See "Extrapulmonary manifestations of sarcoidosis".)
●(See "Management and prognosis of cardiac sarcoidosis".)
●(See "Neurologic sarcoidosis".)
●(See "Kidney disease in sarcoidosis".)
●(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)
●(See "Cutaneous sarcoidosis: Management".)
ASSESSING DISEASE SEVERITY AND PROGRESSION — Most patients with pulmonary sarcoidosis do not require treatment, as a high proportion have asymptomatic, nonprogressive disease and/or experience spontaneous remission. Oral glucocorticoids are associated with development of type 2 diabetes, weight gain, osteoporosis, and infections and do not lead to long-term benefit in these patients [4,5]. However, for patients with more severe or progressing lung disease, treatment with immunomodulatory therapy improves symptoms, decreases radiographic disease burden, and can prevent disease progression [6-8]. Oral immunosuppression is therefore most appropriate for patients with pulmonary sarcoidosis at moderate to high risk of disease progression and/or significantly impaired quality of life due to pulmonary symptoms [6].
Objective high-risk features, for which treatment is administered, include [9,10]:
●Stage IV radiographic disease (table 1), particularly moderate to severe pulmonary fibrosis
●Substantially reduced forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO)
●Precapillary pulmonary hypertension
Older age, Black race, lower socioeconomic status, multisystem involvement (ie, three or more organs involved), and extrapulmonary disease involving skin, bone, or joints (other than erythema nodosum) have also correlated with higher risk in some cohorts and may predispose toward treatment in borderline cases [9,11-15].
Any of the following features on follow-up indicate pulmonary disease progression requiring treatment:
●Progressive pulmonary symptoms leading to a large impairment in quality of life
●A decline in forced expiratory volume in one second (FEV1) or FVC of ≥15 percent
●A fall in total lung capacity (TLC) of ≥10 percent
●A decrease in DLCO of ≥20 percent
●A decrease in oxygen saturation on pulse oximetry of ≥4 percent at rest or with exercise (indicating worsening gas exchange)
●Progressive radiographic changes, including worsening of interstitial opacities, development of cavities, progression of fibrosis with honeycombing, or signs of pulmonary hypertension
APPROACH TO ASYMPTOMATIC PATIENTS — Most patients with asymptomatic pulmonary sarcoidosis have low risk of disease progression and do not require treatment. In the absence of symptoms, disease activity is assessed by pulmonary function testing and radiographic staging (table 1).
●Approach to most asymptomatic patients – We do not treat asymptomatic patients with Stage I-III disease or nodular sarcoidosis unless there are significant abnormalities in pulmonary function. A large majority of asymptomatic patients with stage I disease and nodular sarcoidosis will have spontaneous remission, while patients with stage II and III disease have a more variable disease course [16-18]. (See 'Long-term outcome' below.)
We follow untreated asymptomatic patients at three- to four-month intervals for the first year and every 6 to 12 months thereafter. At these follow-up visits, we assess for development of symptoms, obtain spirometry, and prefer to also obtain diffusing capacity. Every 12 months (or after development of symptoms), we obtain complete pulmonary function testing including spirometry, lung volumes, diffusing capacity, and ambulatory oximetry. We obtain chest x-ray imaging after the first six months and then yearly. We obtain cross-sectional imaging (noncontrast high-resolution computed tomography) after a change in chest x-ray, new cough or dyspnea, or declining pulmonary function. Evidence of progressive disease should prompt initiation of immunomodulatory therapy. (See 'Assessing disease severity and progression' above and 'Patients with more severe or progressive disease' below.)
●Asymptomatic patients with severe disease – A small number of asymptomatic patients at high risk for pulmonary disability with disease progression likely benefit from early treatment [6,16]. We initiate treatment in rare asymptomatic patients with stage IV radiographic disease (table 1) and in patients with moderate to severe impairment in pulmonary function, including:
•Forced vital capacity (FVC) z-score <-1.65 or ≤70 percent of predicted
•Forced expiratory volume in one second (FEV1) z-score <-2.5 or ≤50 percent of predicted
•A diffusing capacity (DLCO) z-score <-2.5 or ≤60 percent of predicted
•An oxygen saturation of 90 percent or less at rest or with exertion
The details of treatment for these patients with severe disease are discussed below. (See 'Patients with more severe or progressive disease' below.)
There are no trials that have focused on asymptomatic patients with a greater burden of pulmonary disease (moderate or severe impairments on pulmonary function testing), but data from one study suggest a potential benefit. In this multicenter trial, asymptomatic patients with stage II or III sarcoidosis who had been stable for six months were randomly assigned to receive either 18 months of glucocorticoid therapy (titrated to radiographic improvement) or selective treatment only for clinical (nonradiographic) worsening [19]. At five years, the average vital capacity was higher by 9 percent of the predicted value in the long-term glucocorticoid group. However, two-thirds of those who received glucocorticoid therapy experienced adverse effects, including weight gain, cushingoid features, and gastrointestinal disturbances. This trade-off is probably not reasonable for asymptomatic patients with normal lung function. However, for patients with initial significant impairments in pulmonary function, the benefits of early treatment are likely to be clinically meaningful.
SYMPTOMATIC PATIENTS WITH MILD LUNG INVOLVEMENT
Differential diagnosis and work-up — Most patients with stage I-II radiographic changes (table 1) and minimal or mild pulmonary function abnormalities (algorithm 1) are asymptomatic. For those with symptoms, careful evaluation for alternative causes is appropriate.
For patients with cough, we first strongly encourage cessation of smoking and vaping. We then assess for common potential causes of chronic cough, including asthma, postinfectious cough, upper airway cough syndrome, angiotensin-converting enzyme (ACE) inhibitor therapy, and reflux disorders. (See "Causes and epidemiology of subacute and chronic cough in adults".)
For patients with exertional chest discomfort or dyspnea, we typically obtain an electrocardiogram and echocardiogram to evaluate for evidence of heart failure or pulmonary hypertension, which can occur secondary to sarcoidosis or independently. If this testing is normal, some patients benefit from stress testing if their symptoms are consistent with myocardial ischemia. (See "Outpatient evaluation of the adult with chest pain", section on 'Evaluation for stable myocardial ischemia' and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
Distinguishing sarcoidosis with airway involvement from asthma can be difficult, as both can result in ventilatory obstruction with bronchodilator responsiveness. A history of childhood asthma, peripheral eosinophilia, or elevated fraction of exhaled nitric oxide (FeNO) increases the likelihood of asthma compared with granulomatous airway inflammation. Asthma will reliably respond to inhaled glucocorticoid therapy, so patients with suspicious features are appropriate for a trial of inhaled therapies.
Low-dose oral glucocorticoid therapy (preferred) — For patients with minimal or mild radiographic and pulmonary function changes, but impaired quality of life due to pulmonary symptoms, we suggest a therapeutic trial of low-dose prednisone (5 to 10 mg/day) rather than observation alone. Since these patients have a 50 to 80 percent chance of spontaneous remission [18,20] despite their bothersome symptoms, it is appropriate to engage in shared decision-making around the potential benefits and risks of low-dose glucocorticoid therapy. We closely monitor patients at increased risk for adverse effects from glucocorticoid therapy (eg, patients with type 2 diabetes, osteoporosis, or history of psychosis).
This therapeutic approach is consistent with recommendations by the European respiratory taskforce on sarcoidosis [6] and is based on indirect and older evidence from randomized trials that treatment with even low doses of oral glucocorticoids increases the rate of early radiographic improvement [7,21].
We generally allow three months for treatment response at these doses, with reevaluation of disease activity by symptoms, pulmonary function testing, and imaging thereafter. Duration of therapy should be based on degree of response balanced against any adverse effects of glucocorticoid therapy. In our experience, most patients with good response can undergo slow tapering to the minimal effective dose after six months to one year of treatment. Patients should undergo a trial of tapering off therapy in the setting of radiographic remission.
Inhaled glucocorticoid therapy (alternative) — Inhaled glucocorticoids have been evaluated for the treatment of mild or asymptomatic pulmonary sarcoidosis, but results are conflicting [7,22-32]. We use them as an alternative therapy in symptomatic patients with mild lung involvement who decline or are at high risk for complications from low-dose oral glucocorticoid treatment. In our experience, inhaled glucocorticoids are most helpful in patients with cough and mild obstruction who are likely to have airway-predominant disease.
Budesonide (800 to 1600 mcg twice daily) and fluticasone (500 to 1000 mcg twice daily) have been the most frequently studied [7,24,29-32]. These high doses (table 2) result in significant systemic absorption (similar to low-dose oral administration) and higher risks of side effects. Coadministration of medications that inhibit cytochrome p450 3A4 (CYP450 3A4) impairs metabolism of budesonide and fluticasone and may cause additional systemic build-up (table 3). (See "Major side effects of inhaled glucocorticoids".)
Patients who do not respond after four to six weeks should discontinue therapy and engage in shared decision-making regarding observation versus initiation of low dose oral glucocorticoids. (See 'Low-dose oral glucocorticoid therapy (preferred)' above.)
In trial and retrospective studies, inhaled glucocorticoids appear to modulate the alveolitis of sarcoidosis [28,29] and provide clinical benefit in some subjects, but they do not lead to consistent improvements in lung function [7,25,26,30,32]. As an example, one randomized trial of 2000 mcg/day of fluticasone in 44 patients found no significant differences in lung function but borderline improvements in cough, breathlessness, wheeze, and general health perception [30].
Recurrence of symptoms during tapering — If there are recurrent symptoms without other changes during tapering of oral or inhaled glucocorticoids, therapy may be resumed at the last effective dose for three months. If this dose is ineffective or if there is recurrence of symptoms alone after stopping therapy, resumption of the initial dosing for symptom management is appropriate.
For patients who have an exacerbation or a relapse that includes radiographic progression or worsening of pulmonary function, we initiate treatment for progressive disease. (See 'Patients with more severe or progressive disease' below and 'Relapses and exacerbations' below.)
PATIENTS WITH MORE SEVERE OR PROGRESSIVE DISEASE — The mainstay of treatment for patients with severe or progressive pulmonary sarcoidosis is glucocorticoid therapy, which is generally effective at attenuating the granulomatous inflammatory process. Optimal management of glucocorticoids improves disease while minimizing adverse medication effects.
Goals of oral glucocorticoid treatment — The goals of titrated glucocorticoid therapy are to reduce disease burden and prevent the development of irreversible end-organ damage (eg, honeycombing and fibrotic lung disease) while also minimizing adverse side effects and comorbidities. We achieve these goals by using higher upfront doses for stabilization and/or regression of active disease followed by identification of a lower longer-term dose that maintains clinical stability. We typically attempt to taper off glucocorticoids after one year or several months of disease quiescence on maintenance therapy (whichever comes later).
Oral glucocorticoids have been used for decades as the primary agents for the relief of symptoms and control of potentially disabling respiratory impairment from pulmonary sarcoidosis, even if they do not cure the disease [1,33-35]. The optimal use of glucocorticoid therapy is not known, so choosing a dose requires balancing the likelihood of response against the risk of adverse effects [2,3,23,36]. The few trials in this area involve mixed populations of patients, most of whom are not at highest risk, so extrapolation of best practice from the available data is difficult. The approach outlined below is therefore based primarily on expert opinion. (See 'Initial and maintenance dosing' below and 'Stopping glucocorticoid therapy' below.)
Initial and maintenance dosing — For all patients who demonstrate progressive pulmonary disease, we suggest initial therapy with oral glucocorticoids rather than observation alone or alternative therapies. We also suggest early initiation of therapy for patients with severe symptoms, widespread radiographic abnormalities, and moderate to severe impairment in pulmonary function at baseline. Prior to initiating therapy, we assess patients for comorbid noninflammatory conditions that might contribute to pulmonary symptoms (eg, heart failure, pulmonary hypertension) [34] as well as for infectious diseases that could worsen with immunomodulatory agents (eg, tuberculosis, strongyloidiasis).
●Initial dose – We usually begin therapy with oral prednisone at a daily dose of 0.3 to 0.6 mg/kg ideal body weight (approximately 20 to 40 mg/day), depending on the severity of disease activity [2,35,37]. For patients with shortness of breath on exertion and slowly worsening radiographic opacities, the lower dose is usually adequate. We also prefer dosing at the lower end of the range in patients with a high risk of adverse effects from glucocorticoids (eg, patients with diabetes, osteoporosis, severe obesity, or history of psychosis). For patients with rapidly progressive disease and severe impairment (eg, oxygen dependence), as well as a low risk for glucocorticoid toxicity, we favor using the higher end of the dose range.
We reassess patients four to six weeks after starting therapy. If symptoms, radiographic abnormalities, and pulmonary function testing (eg, spirometry, diffusing capacity, ambulatory oximetry) are improved, the initial dose is tapered. (See 'Assessing response to therapy' below.)
If the clinical and physiologic parameters are unimproved (but not worsened) after four to six weeks at the initial dose, we continue that dose an additional four to six weeks. However, most improvement with glucocorticoids is typically apparent in three to four weeks' time [3,38]. Delayed improvement or stabilization of previously progressing disease still merits attempted tapering, but lack of response or worsening disease should prompt reevaluation of the diagnosis followed by treatment with alternative immunosuppressants for refractory disease. (See 'Approach in patients with suboptimal response' below and "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
●Maintenance phase – Tapering schedules vary and can be more aggressive in the setting of adverse glucocorticoid side effects. A common schedule is to decrease by 5 to 10 mg decrements every 4 to 12 weeks down to 0.2 to 0.4 mg/kg (approximately 10 to 15 mg/day). Although no formal data are available to guide maintenance dosing, clinical experience and extrapolations from clinical trials suggest that maintenance dosing in this range prevents worsening of disease in most patients [2,7,8,21,39,40]. Alternate day therapy with prednisone has also been used for maintenance after initial daily therapy as an attempt to reduce the risk of adverse effects from the glucocorticoids, but few data are available to support its efficacy. Likely, the benefits and adverse effects are comparable to similar total dosing on a daily schedule [41]. During the maintenance phase, we reassess the patient at 4- to 12-week intervals for evidence of disease worsening (exacerbations) or development of glucocorticoid-related adverse effects. (See 'Assessing response to therapy' below and 'Relapses and exacerbations' below and 'Adverse effects' below.)
Recurrence of symptoms, such as cough, dyspnea, and chest pain, upon early treatment withdrawal is common (occurring in approximately 60 percent of patients), so we continue the maintenance dose for at least three to six months, giving a total treatment period of approximately one year. Frequently, a brief course of higher doses (increases of 10 to 20 mg above the maintenance dose given for two to four weeks) is required to relieve an episode of recurrent symptoms. (See 'Relapses and exacerbations' below.)
Approach in patients with suboptimal response — While most patients respond well to oral glucocorticoid therapy, there are several common scenarios where continued management with glucocorticoids is suboptimal:
●Patients who do not respond or clinically worsen despite an adequate trial of initial therapy (eg, the equivalent of prednisone ≥15 mg/day for at least three months)
●Patients who require ongoing long-term maintenance (more than two years) with the equivalent of >10 mg/day of prednisone
●Patients who become intolerant of maintenance glucocorticoids over time due to hyperglycemia, excessive weight gain, myopathy, or severe osteoporosis
These patients typically require alternative immunosuppressive agents (eg, methotrexate, azathioprine, leflunomide, or tumor necrosis factor-alpha inhibitors), sometimes in addition to lower-dose glucocorticoids. Referral to a sarcoidosis center may be prudent in this setting. The management of pulmonary sarcoidosis refractory to initial management is described separately. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
Stopping glucocorticoid therapy — Although the proper length of therapy in patients who respond to treatment is not certain, we usually aim for one year of therapy for this group [12,13,33]. The majority of these patients are able to discontinue systemic glucocorticoids after one year of treatment [42]. Regardless of a robust response, therapy should be given for at least three to six months to be effective and to reduce the likelihood of relapse. Relapses requiring another course of therapy are frequent following reduction or withdrawal of glucocorticoids, ranging from 14 to 74 percent among those with disease of recent onset (≤5 years) [3]. A small number of patients require more long-term or indefinite maintenance therapy to control their symptoms [43].
Tapering is appropriate in patients with initial improvement and clinical stability (or continued improvement) throughout the maintenance phase of treatment. We typically use the following prednisone tapering regimens:
●2.5 mg/day every two to three weeks at prednisone doses between 20 and 10 mg/day.
●1 mg/day every two to four weeks at prednisone doses between 10 and 5 mg/day.
●0.5 mg/day every two to four weeks at prednisone doses from 5 mg/day down.
Slower tapers may be appropriate in patients who have previously relapsed or suffered an exacerbation during a taper. (See "Glucocorticoid withdrawal", section on 'Recommended tapering regimen'.)
Occasional patients suffer recurrent relapses during tapering but are clinically stable on prednisone doses of ≤10 mg/day. In this setting, continued therapy at this dosing is reasonable for many years. Patients who require higher doses of prednisone for clinical stability have refractory disease that may benefit from the addition or substitution of a glucocorticoid-sparing immunosuppressant. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
Efficacy of glucocorticoids — The balance of evidence suggests that oral glucocorticoids improve respiratory symptoms and radiographic abnormalities, although not necessarily pulmonary function tests [22,33,39,44,45]. The results of individual trials have been variable, probably due to variations in patient populations, prednisone dose, and duration of therapy [33,46,47].
The best evidence in favor of glucocorticoid therapy for pulmonary sarcoidosis comes from systematic reviews that found improvement in radiographic findings after 3 to 24 months of treatment with a range of prednisone doses (4 to 40 mg) [6,22,48]. One analysis of five randomized trials assessing chest radiography found that oral glucocorticoid therapy decreased chest radiograph opacities compared with observation or placebo (risk ratio [RR] 1.46, 95% CI, 1.01-2.09) [22]. A separate systematic review of 340 patients from three placebo-controlled trials demonstrated radiographic improvement in the treatment group (RR 1.35, 95% CI 1.11-1.64) and lower prevalence of radiographic deterioration (RR 0.39, 95% CI 0.18-0.87) [6].
Although one older trial suggested short-term improvements in symptoms after glucocorticoid treatment [39], most studies have not assessed patient-centered outcomes.
In contrast, lung function tests have been assessed in several trials, but the timing, studies, and results have been variable and not easily grouped for meta-analysis [22]. At least two of the trials examined found no improvement in lung function [22,23]. Diffusing capacity was assessed in only two trials; one trial found no benefit and the other demonstrated a modest improvement among patients with stage II disease (table 1) treated for 18 months, but not at earlier interval assessments [7,8,23].
Assessing the benefit of glucocorticoid therapy for pulmonary sarcoidosis is limited not only by the paucity of clinical trial data but also by several additional challenges at the individual patient level [22,48,49]:
●Many patients with sarcoidosis undergo spontaneous remission or have a benign clinical course (see 'Long-term outcome' below). The marked variability in presentation and clinical course makes it difficult to evaluate whether an apparent response to therapy reflects a treatment effect or the natural course of that patient's disease.
●There is no easy way to globally assess disease activity or severity as symptoms may be discordant with results of pulmonary function testing and chest imaging. This makes it difficult to interpret the results of clinical studies or the response to therapy in an individual patient.
●There is a concern that early administration of systemic glucocorticoid therapy may increase the likelihood that the patient will develop relapsing disease rather than a sustained remission [50-52].
For example, in a prospective series of 215 patients with recent-onset sarcoidosis, only 8 percent of initially untreated patients required therapy after two years, whereas 47 percent of initially treated patients remained on therapy [53]. One explanation for this observation is that treatment limited the body's innate ability to clear the disease. However, a reasonable alternate explanation is that the patients, who were not randomly assigned to treatment groups, were selected for therapy based on subtle indications that they had more severe disease [54].
Data are very limited regarding the effect of oral glucocorticoids on long-term disease outcomes [55].
Adverse effects — Numerous adverse effects are associated with chronic systemic glucocorticoid therapy (table 4). For example, registry data suggest that patients with sarcoidosis treated with corticosteroids have a greater than twofold increase in the development of diabetes mellitus compared with matched patients without sarcoidosis (12.7 per 1000 person-years versus 5.5 per 1000 person-years) [5]. Patients on more than 20 mg of prednisone or the equivalent should receive prophylaxis for the prevention of Pneumocystis jirovecii pneumonia. Additional information regarding the identification and prevention of glucocorticoid adverse effects can be found elsewhere. (See "Major side effects of systemic glucocorticoids", section on 'Organ-based toxicity of systemic glucocorticoids' and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)
Prevention of glucocorticoid-induced bone loss is a complicated issue in patients with sarcoidosis compared with other glucocorticoid-requiring diseases due to production of vitamin D by sarcoid granulomas and the risk of hypercalcemia and hypercalciuria with calcium supplementation. Monitoring of serum calcium, urine calcium, Serum 25-hydroxyvitamin D (calcidiol) and serum 1,25-dihydroxyvitamin D (calcitriol) should be performed routinely in patients with sarcoidosis (table 5). In patients without baseline hypercalcemia or hypercalciuria on oral glucocorticoids, we advise calcium (1000 to 1200 mg/day) and vitamin D (600 to 800 mg/day) intake through dietary sources. If this cannot be achieved, oral supplementation should be followed by reassessment of calcium and/or vitamin D (calcidiol and calcitriol) within three months after initiation. (See "Hypercalcemia in granulomatous diseases", section on 'Sarcoidosis' and "Extrapulmonary manifestations of sarcoidosis", section on 'Renal and electrolyte' and "Calcium and vitamin D supplementation in osteoporosis", section on 'Dietary sources' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)
All patients with pulmonary sarcoidosis receiving oral glucocorticoids should have their fracture risk formally assessed, and most patients will qualify for bone mineral density (BMD) assessment as well. In general, bisphosphonates are recommended for prevention of bone loss and fractures in postmenopausal females and males ≥50 years old who require systemic glucocorticoids ≥7.5 mg/day for longer than three months, have osteoporosis by BMD assessment, or are considered at high risk for bone fragility. Additional discussion regarding evaluation of and pharmacologic therapy for patients receiving glucocorticoids is presented elsewhere. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Evaluation' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Candidates for pharmacologic therapy'.)
PATIENTS WITH LIMITED TOLERANCE OF ORAL GLUCOCORTICOIDS — A minority of patients with severe or progressive pulmonary sarcoidosis are unable to tolerate glucocorticoids. For these patients, a nonbiologic immunosuppressant, typically methotrexate, is preferred to achieve disease control.
Patients with rapid progression or an active exacerbation — For patients with rapid progression of disease or an active exacerbation when we initiate therapy, we prefer to use 10 to 20 mg of prednisone (based on patient acceptance and/or tolerance of short-term side effects) for four to six weeks while beginning an alternative agent because the alternative agents usually take some time to dose-adjust or achieve maximal effectiveness (or both). With a good response to combined therapy, prednisone can be tapered quickly (5 mg/day every two to four weeks) to 5 mg/day and then down by 1 mg/day every two to four weeks thereafter.
Other patients — Other patients can be initiated on an alternative regimen without glucocorticoid therapy. Nonbiologic agents in general require several weeks to months to achieve initial efficacy, so they should be continued for at least six months after initiation. If effective, therapy should preferably be maintained for one year to decrease the odds of relapse upon discontinuation. Most oral nonbiologic agents (methotrexate, azathioprine, mycophenolate) are appropriate to taper slowly over three to six months while monitoring for signs of relapse.
Methotrexate therapy (preferred) — For patients with severe or progressive pulmonary sarcoidosis who decline oral glucocorticoids or experience severe glucocorticoid side effects upon initiation of therapy, we suggest initial treatment with methotrexate rather than observation alone or initiation of other alternative therapies. Methotrexate is the most used nonglucocorticoid agent for the treatment of patients with sarcoidosis [37]. It is an effective steroid-sparing agent [56-59] and in one trial prevented progression and relapses better than oral glucocorticoids when used as initial therapy [60]. It is contraindicated in pregnancy and in patients with hepatic disease, and alcohol use should be minimized. Patient-reported side effects are less common than with oral glucocorticoids [61]. Pretreatment preparation, dosing, adverse effects, and efficacy of methotrexate in patients with sarcoidosis are discussed separately. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
Alternative initial therapies — There is no clear consensus on alternative nonbiologic options in those with contraindications or toxicity to methotrexate [6,35]. Azathioprine performed similarly to methotrexate in a small trial [59]; leflunomide and mycophenolate mofetil have also shown effectiveness in small cohorts [62-64]. Additional discussion of the use of these agents in the treatment of sarcoidosis, including dosing, adverse effects, and efficacy, may be found elsewhere. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Patients who progress on or cannot use methotrexate'.)
ASSESSING RESPONSE TO THERAPY — The optimal tools and timing for assessing the response to therapy in pulmonary sarcoidosis have not been well studied [1]. In the absence of a well-defined assessment tool, we use a combination of symptoms, physical examination, radiographic abnormalities, and pulmonary function tests to assess pulmonary disease activity. It is also important to concomitantly monitor patients with sarcoidosis for development of extrapulmonary disease. A general guideline and list of tests are provided in the table (table 5). An approach to monitoring sarcoidosis is presented separately. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Monitoring'.)
Many experts believe that symptoms are the most important parameter to follow, although this approach depends on the reliability of the individual patient in perceiving and reporting symptoms. A difficult situation can arise when a patient experiences subjective improvement with therapy without objective change. Due to the toxicity of therapy, we try to avoid having symptoms be the lone factor in determining whether to continue treatment.
The pulmonary function tests that we follow at three- to four-month intervals are spirometry, diffusing capacity (DLCO), and ambulatory oximetry. We obtain lung volume measurements every 12 to 24 months.
A favorable response to therapy is defined by:
●A decrease in symptoms, especially dyspnea, cough, hemoptysis, chest pain, or fatigue.
●A reduction in or clearing of radiographic abnormalities.
●Physiologic improvement, such as:
•A 10 percent or greater increase in forced vital capacity (FVC) or total lung capacity (TLC)
•A 20 percent or greater increase in DLCO
•An improvement of 4 percent or greater in oxygen saturation at rest or during exercise
Stabilization of radiographic abnormalities and lung function for prolonged periods of time (three to six months) should also be considered a positive response to treatment in patients with severe or progressive disease.
Patients who improve and remain stable for more than one year following cessation of therapy have a low rate of relapse [41].
Sarcoidal granulomas produce angiotensin-converting enzyme (ACE), and serum ACE levels are elevated in 60 percent of patients with sarcoidosis [1]. However, following serum ACE levels has not been demonstrated to be useful in the management of sarcoidosis [65,66]. Additionally, ACE inhibitor therapy suppresses ACE levels [67].
RELAPSES AND EXACERBATIONS — Relapses may occur during tapering of immunosuppression or after discontinuation of therapy. An exacerbation describes an acute worsening that occurs while on maintenance therapy. Clinically, relapses and exacerbations are characterized by two or more of the following:
●Worsening dyspnea, cough, or chest discomfort
●A fall of 10 percent or more in forced vital capacity (FVC), total lung capacity (TLC), or diffusing capacity (DLCO)
●Worsening of radiographic opacities
●Decreased gas exchange at rest or with exercise
We use the following therapeutic approach for these flares of disease activity:
●For patients who relapse during a taper or after discontinuation of therapy – For these patients, therapy can be reinitiated at the most recent effective dose. Subsequent tapering of the same agent should be more gradual than the taper that resulted in a relapse. (See 'Stopping glucocorticoid therapy' above.)
Failure to achieve disease control at this dose after three months should prompt titration of the dose to the level needed for efficacy at the time of initial therapy. If there is no improvement after a trial at that initial dose (three months for glucocorticoids, six months for alternative therapies), further treatment is needed for refractory disease. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
●For patients with acute exacerbations while on prednisone maintenance therapy – In these patients, we suggest a treatment course of prednisone 20 mg/day for three weeks. A retrospective study of 36 patients with acute exacerbations of pulmonary sarcoidosis showed that treatment with the equivalent of prednisone 20 mg/day for approximately 21 days resulted in improvement of symptoms and return of lung function to baseline [38]. Following treatment, maintenance therapy can be continued at the prior stable dose.
●For patients with exacerbations while receiving maintenance therapy with alternative nonbiologic agents – For these patients, we suggest a two-week trial of prednisone 20 mg followed by a rapid (one- to two-week) taper in those who can tolerate short-term and/or moderate-dose glucocorticoids. Otherwise, monitoring with close follow-up is reasonable for milder exacerbations, and a dose increase in immunosuppression can be attempted in more severe cases. Frequent exacerbations should prompt consideration of alternative therapy. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Patients with disease refractory to the above agents'.)
●Repeated relapses and exacerbations – Patients with pulmonary sarcoidosis who have frequent relapses and exacerbations despite this treatment approach may benefit from the addition or substitution of alternative immunosuppressive agents [31]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
LONG-TERM OUTCOME — It has been estimated that spontaneous remission occurs in approximately 60 to 80 percent of patients with radiographic stage I disease, 50 to 60 percent with stage II disease, and less than 30 percent in stage III disease (table 1) [18]. The overall death rate from sarcoidosis is less than 5 percent [1].
Causes of death in sarcoidosis include:
●Progressive pulmonary fibrosis and cor pulmonale. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)
●Pulmonary hemorrhage from aspergillomas developing in damaged lung tissue. (See "Treatment of chronic pulmonary aspergillosis".)
●Myocardial involvement and sudden cardiac death, although the proportion varies dramatically among studies (eg, 2 to 50 percent). (See "Clinical manifestations and diagnosis of cardiac sarcoidosis" and "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Prevalence'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Sarcoidosis (The Basics)")
●Beyond the Basics topics (see "Patient education: Sarcoidosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Assessing risk for progressive disease – Most pulmonary sarcoidosis does not require treatment, but progressive lung disease occurs in approximately 25 percent of patients. We assess disease severity by patient symptoms, radiographic involvement (table 1), and pulmonary function testing. (See 'Introduction' above and 'Assessing disease severity and progression' above.)
●Asymptomatic patients – For most asymptomatic patients, we suggest observation rather than initiating therapy with oral glucocorticoids (Grade 2C). We monitor symptoms, chest radiograph, and pulmonary function at three- to six-month intervals. However, for the subset of asymptomatic patients who present with severe disease, we suggest oral glucocorticoids (Grade 2C). Criteria for severe disease are discussed above. (See 'Approach to asymptomatic patients' above.)
●Symptomatic patients
•Those with mild lung involvement – For symptomatic patients with minimal or mild radiographic and pulmonary function changes, we suggest low-dose prednisone (5 to 10 mg/day) rather than observation alone (Grade 2C). Administration of moderate- to high-dose inhaled glucocorticoids is a reasonable alternative approach.
•Those with more severe and progressive disease – For symptomatic patients with pulmonary sarcoidosis who have severe lung involvement, worsening radiographic opacities, or increasing pulmonary function impairment, we suggest oral glucocorticoids rather than alternative therapies (Grade 2C). We typically start prednisone at 0.3 to 0.6 mg/kg ideal body weight (usually 20 to 40 mg/day) for at least four weeks and up to three months to allow for disease response. (See 'Patients with more severe or progressive disease' above.)
●Patients who cannot tolerate oral glucocorticoids – For patients who cannot tolerate oral glucocorticoids, we suggest initial therapy with a nonbiologic immunosuppressant for disease control, typically methotrexate (Grade 2C). (See 'Patients with limited tolerance of oral glucocorticoids' above and "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Patients who progress on or do not tolerate glucocorticoids'.)
●Assessing response to therapy – We monitor symptoms, physical examination, radiographic abnormalities, and pulmonary function tests at four- to six-week intervals during initial therapy and at three- to four-month intervals while on maintenance therapy. (See 'Assessing response to therapy' above.)
●Relapses and exacerbations – Relapses and exacerbations both describe acute worsening of pulmonary disease. Relapses occur during tapering of immunosuppression or after discontinuation of therapy. They are typically managed by increasing immunosuppressant therapy to the last effective dose. Exacerbations occur while on maintenance therapy and are usually treated with moderate-dose oral glucocorticoids (eg, 20 mg/day of prednisone) for three weeks. (See 'Relapses and exacerbations' above.)
●Refractory disease – For patients who are unable to tolerate the adverse effects of glucocorticoids, whose disease cannot be controlled on the equivalent of prednisone 10 mg or less, or who have evidence of disease progression despite a moderate dose of prednisone, an alternative immunosuppressive agent may be of benefit. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
