Treatment of pulmonary sarcoidosis: Initial approach

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 often asymptomatic at presentation. When symptomatic, patients usually report dyspnea, cough, or nonspecific chest discomfort. Most patients with pulmonary sarcoidosis do not require treatment because they either have asymptomatic, nonprogressive disease or experience spontaneous remission. Progressive lung disease occurs in approximately 25 percent and disabling organ failure in up to 10 percent of cases [1-4]. Sarcoidosis patients referred to tertiary centers are more likely to have risk factors associated with the need for systemic treatment [5].

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?

There are few randomized, placebo-controlled clinical trials specifically for sarcoidosis. Consequently, much of the ensuing discussion is based on our practical experience treating patients with this condition.

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.

●(See "Clinical manifestations and diagnosis of sarcoidosis".)

●(See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

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 frequently 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 "Overview of 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 — For patients with more severe or progressing lung disease, treatment with immunomodulatory therapy may improve symptoms, decrease 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 commonly administered, include [9,10]:

●Stage IV radiographic disease (table 1), particularly progressive moderate to severe pulmonary fibrosis

●Substantially reduced forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), and diffusing capacity of the lung for carbon monoxide (DLCO)

●Significantly reduced exercise tolerance in individuals with parenchymal lung involvement

When three or more organs are involved in the disease (multisystem involvement), or when extrapulmonary manifestations affect the skin, bones, or joints (excluding erythema nodosum), the risk of a more severe or prolonged disease course increases [9,11-15]. In some cases, the extent of disease across multiple organ systems may indicate potential benefits from treatment, even if individual systems do not meet the threshold for initiating therapy.

There are no well-defined criteria for determining changes in pulmonary function that indicate disease progression [16]. In practice, progression is identified by changes in testing that are unlikely to be due to random variation, particularly when accompanied by worsening symptoms. The decision to initiate or escalate therapy should be made cautiously, considering higher thresholds in such cases. Some markers that may prompt clinicians to consider starting or intensifying therapy include:

●Pulmonary symptoms leading to a clinically relevant impairment in quality of life (ie, when the burden of the symptoms outweighs the risks of therapy in a patient-centered decision-making process)

●A decline in pulmonary function testing that is not likely to represent testing variability

●A decrease in oxygen saturation on pulse oximetry of ≥4 percent at rest or with exercise (indicating worsening gas exchange)

●Progressive worsening of interstitial opacities

Nonimaging markers of disease progression typically lead to the use of cross-sectional imaging to evaluate changes in the extent of lung tissue and lymph node involvement over time. This helps to rule out other potential causes and establish a new baseline before starting treatment. However, if radiographic changes or spirometry are disproportionately preserved despite low DLCO or oxygen saturation, further investigation for pulmonary hypertension is necessary. Diagnosing and treating pulmonary hypertension requires a more comprehensive diagnostic and treatment strategy. (See "Sarcoidosis-associated pulmonary hypertension: Diagnostic evaluation in adults" and "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

APPROACH TO ASYMPTOMATIC PATIENTS — Most patients with asymptomatic pulmonary sarcoidosis have low risk of disease progression and do not require treatment (algorithm 1). In the absence of symptoms, sarcoidosis burden 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 to III disease or nodular sarcoidosis unless there are significant abnormalities in pulmonary function and evidence of progression. 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 [17-19]. (See 'Long-term outcome' below.)

The appropriate course of action for untreated asymptomatic patients is unknown. To monitor their condition, we recommend follow-up visits at intervals of three to six months during the first year and every six to twelve months thereafter. During these visits, we evaluate the presence of symptoms and perform spirometry as well as diffusing capacity of the lung for carbon monoxide (DLCO). We obtain a repeat chest radiograph after the initial six months followed by annual radiographs for at least two to three years to assess stability. If the chest radiographs and other tests do not provide sufficient information for confident decision-making, we may conduct cross-sectional imaging using noncontrast high-resolution computed tomography (chest CT).

There are limited data supporting the use of chest CT scans as the primary factor for making prognosis or treatment decisions, unless there is a deterioration in symptoms or changes in pulmonary function testing (PFTs). If there is evidence of progressive disease, it is advisable to consider immunomodulatory therapy. (See 'Assessing disease severity and progression' above and 'Patients with more severe or progressive disease' below.)

●Asymptomatic patients with advanced radiographic disease – A small subset of asymptomatic patients who are at high risk of developing pulmonary disability due to disease progression may potentially benefit from early treatment [6,17]. In certain cases, we provide a short trial of treatment for asymptomatic or minimally symptomatic patients with stage IV radiographic disease (table 1). Additionally, patients with significant abnormalities in PFTs may also be considered for a trial of treatment to evaluate the potential for reversibility.

The details of treatment for these patients with severe disease are discussed below. (See 'Patients with more severe or progressive disease' below.)

SYMPTOMATIC PATIENTS WITH MILD LUNG INVOLVEMENT

Common symptoms and their evaluation — Most patients with stage I to II radiographic changes (table 1) and minimal or mild pulmonary function abnormalities (algorithm 2) are asymptomatic. For those with symptoms, careful evaluation for alternative explanations is appropriate.

●Cough – 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".)

●Chest pain – Nonexertional chest pain (chest pain that arises spontaneously, at rest, or during activities that do not involve strenuous exercise) is common in sarcoidosis and can be a significant cause of impaired quality of life. Its relationship to discrete entities, such as pulmonary hypertension, cardiac sarcoidosis, or lymphadenopathy, is uncertain. For patients with exertional chest discomfort, we typically evaluate patients for causes of the pain unrelated to sarcoidosis, such as coronary artery disease, along with assessing for cardiac involvement. In cases where the chest pain is related to cardiac sarcoidosis, specific treatments may be necessary. If the chest pain is due to inflammation or granulomas in the chest wall, anti-inflammatory medications or, occasionally, corticosteroids may be prescribed. Pain management strategies including analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) are often helpful to alleviate the discomfort. (See "Outpatient evaluation of the adult with chest pain", section on 'Evaluation for stable myocardial ischemia' and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

●Asthma – Distinguishing sarcoidosis with airway involvement from asthma can be difficult, as both can result in ventilatory obstruction with bronchodilator responsiveness. Both may also exhibit positive bronchoprovocation testing. 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. Often, the distinction is clinically meaningless, as both asthma and airway-centered sarcoidosis may respond well to inhaled therapies. In rare instances, endobronchial biopsy may be helpful to distinguish the two.

●Fatigue – Fatigue is common (reported in 50 to 90 percent of patients) and may be a disabling symptom in sarcoidosis with a significant impact on quality of life [20-23]. Treating and controlling sarcoidosis itself is often important in addressing fatigue. Managing symptoms such as pain, sleep disturbances, or depression can help alleviate fatigue. Adopting healthy lifestyle and learning to manage energy levels and prioritize tasks can help in coping with fatigue. Seeking psychologic support through counseling, support groups, or therapy can also provide tools and strategies to manage fatigue-related distress.

Low-dose oral glucocorticoid therapy — For patients with minimal or mild radiographic and pulmonary function changes, but impaired quality of life due to pulmonary symptoms, a therapeutic trial of low-dose prednisone may be appropriate (algorithm 1). Since these patients have a 50 to 80 percent chance of spontaneous remission [19,24] 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, obesity, or history of psychosis).

This therapeutic approach is consistent with recommendations by the European Respiratory Society Guideline on the treatment of 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 [7,25]. We typically initiate therapy at moderate doses (eg, 20 mg of prednisone) to assess responsiveness, followed by a more rapid taper towards low-dose therapy (5 to 10 mg daily) over a few weeks after initial improvement.

Most responses to therapy can be observed within four weeks, even with lower doses of prednisone. 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 starting after four weeks of treatment. The timing and aggressiveness of trials of tapering should include several factors, in discussion with the patient [26]:

●Severity of pulmonary disease (radiographic features, pulmonary function tests [PFTs])

●Chronicity

●Results of prior tapering attempts

●Initial difficulty obtaining control of disease

●Tolerability of the immunosuppressive regimen

●Evidence of active granulomatous inflammation (eg, positron emission tomography, when available)

Inhaled glucocorticoid therapy (alternative) — Inhaled glucocorticoids have been evaluated for the treatment of mild or asymptomatic pulmonary sarcoidosis, but results are conflicting [7,27-37]. In our experience, they are most likely to be effective for symptomatic treatment of cough or airways hyperreactivity (algorithm 1).

Budesonide (800 to 1600 mcg twice daily) and fluticasone (500 to 1000 mcg twice daily) have been the most frequently studied [7,29,34-37]. 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 buildup (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' above.)

In trials and retrospective studies, inhaled glucocorticoids appear to modulate the alveolitis of sarcoidosis [33,34] and provide clinical benefit in some subjects, but they do not lead to consistent improvements in lung function [7,30,31,35,37]. 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 [35].

Recurrence of symptoms during tapering — If there are recurrent symptoms without other radiographic or physiologic changes during tapering of oral or inhaled glucocorticoids, therapy may be resumed at the last effective dose. 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 acute bronchitic symptoms' below.)

PATIENTS WITH MORE SEVERE OR PROGRESSIVE DISEASE — The mainstay of initial 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. Most patients with these pulmonary manifestations are likely to require longer term therapy, so glucocorticoid-sparing adjuncts (eg, methotrexate) should be considered as part of the therapeutic plan and discussed early in the treatment course.

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, 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 [1,38-40]. 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 [2,3,28,41]. 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 or bothersome pulmonary disease, we suggest initial therapy with oral glucocorticoids rather than observation alone (algorithm 1). For some patients at higher risk for steroid toxicities, initial therapy with steroid-sparing agents may be appropriate. Prior to initiating therapy, we assess patients for comorbid noninflammatory conditions that might contribute to pulmonary symptoms (eg, heart failure, pulmonary hypertension, obesity) [39] as well as for infectious diseases that could worsen with immunomodulatory agents (eg, tuberculosis, strongyloidiasis).

●Initial dose – We begin therapy with oral prednisone at a daily dose of 20 to 30 mg/day; 20 mg is sufficient for most patients [2,40,42,43]. This dosing is generally effective and may have lower risks of adverse side effects than higher initial ranges.

The best data to support this approach are from an open-label trial of 86 patients comparing initiation of sarcoidosis treatment with 20 versus 40 mg of prednisolone daily (followed by a protocolized six-month taper) [43]. The majority (81 percent) of the patients were initiated on therapy for pulmonary indications. All participants demonstrated improvement in or stabilization of symptoms by eight weeks after treatment initiation, with similar outcomes in both groups. Following six months of treatment, the incidence of treatment failure was likewise similar (14 percent in the 40 mg daily group and 9 percent in the 20 mg daily group), as were rates of subsequent relapse (34 and 35 percent in the higher- and lower-dose groups, respectively). Adverse effects of systemic glucocorticoids were very common and not statistically different (100 percent in the 40 mg group and 88 percent in the 20 mg group over six months of therapy).

●Monitoring initial response – We reassess patients four to six weeks after starting therapy. If symptoms, radiographic abnormalities, and pulmonary function testing (eg, spirometry, diffusing capacity of the lung for carbon monoxide [DLCO], 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 [3,44]. 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 for glucocorticoid therapy can vary, especially when considering the presence of adverse side effects from the medication. A common approach involves initially decreasing the dose more rapidly (eg, with 5 to 10 mg decrements of oral prednisone), but then reducing the magnitude of the dose reduction (<5 mg decrements) to achieve a slower taper before complete discontinuation. Our experience suggests that individuals who have been on glucocorticoids for a relatively longer duration tend to have better outcomes with slower tapering schedules, particularly when the dose is reduced to 10 mg or less of prednisone.

It is important to distinguish glucocorticoid withdrawal symptoms from adrenal insufficiency. Withdrawal symptoms, such as fatigue and arthralgias, may occur whenever the dose is tapered too quickly regardless of the starting dose. In general, steroid withdrawal symptoms can be treated with a slower taper and reassurance. Adrenal insufficiency occurs only at doses less than 7.5 mg/day; distinguishing it from steroid withdrawal symptoms may require biochemical testing. (See "Diagnosis of adrenal insufficiency in adults".)

The ideal maintenance range for control of pulmonary sarcoidosis is individualized, and it must be identified practically. Historically, 10 to 15 mg/day of oral prednisone was deemed acceptable [2,7,8,25,45,46], but in our experience, a large proportion of patients can be adequately maintained on lower doses, sometimes even less than 5 mg/day. In chronic treatment, it is not clear that any dose of prednisone is a "safe" dose with no risk for long term steroid toxicities [47]. 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 [48]. During the maintenance phase, we reassess the patient at three- to six-month intervals for evidence of disease worsening (relapses) or development of glucocorticoid-related adverse effects. (See 'Assessing response to therapy' below and 'Relapses and acute bronchitic symptoms' below and 'Adverse effects' below.)

Recurrence of symptoms, such as cough, dyspnea, and wheezing, 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 at least a year. A brief course of higher doses (eg, 20 mg/day given for two weeks) is sometimes required to relieve an episode of bronchitic symptoms. (See 'Relapses and acute bronchitic symptoms' 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 20 mg/day for at least one to two months)

●Patients who require ongoing long-term maintenance (more than six months) with prednisone, especially those in whom higher maintenance doses are needed.

●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 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 unknown, we usually aim for approximately one year of therapy for this group [12,13,38]. Many patients can discontinue systemic glucocorticoids after approximately a year of treatment [49]. 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 [50].

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 to 5 mg/day every three to four weeks at prednisone doses between 20 and 10 mg/day.

●2.5 mg/day every three to four weeks at prednisone doses between 10 and 5 mg/day.

●1 mg/day every three to four weeks at prednisone doses from 5 mg/day down.

Slower tapers may be appropriate in patients who have previously relapsed during a taper. (See "Glucocorticoid withdrawal", section on 'Recommended tapering regimen'.)

Some patients suffer recurrent relapses (cough, dyspnea, or chest pain) during tapering but are clinically stable on prednisone. Since toxicities from systemic glucocorticoids are cumulative and there is no clear-cut safe dose, patients requiring long-term treatment with steroids are candidates for glucocorticoid-sparing therapies [47]. (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 PFTs [27,38,45,51,52]. The results of individual trials have been variable, probably due to variations in patient populations, prednisone dose, and duration of therapy [38,53,54].

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) [6,27,55]. 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) [27]. 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 many studies have not assessed patient-centered outcomes, oral glucocorticoids likely improve dyspnea and fatigue within several weeks of initiation [41,45].

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 [27]. At least two of the trials examined found no improvement in lung function [27,28]. DLCO 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 [7,8,28].

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 [27,55,56]:

●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 PFTs 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 [57-59].

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 [60]. 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 [61].

Data are very limited regarding the effect of oral glucocorticoids on long-term disease outcomes [62].

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 versus 5.5 per 1000 person-years) [63]. 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 adverse 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 sarcoidosis 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 (figure 1). 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 "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' and "Overview of extrapulmonary manifestations of sarcoidosis".)

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 — For patients with rapid progression of disease when we initiate therapy, we prefer to use 20 mg of prednisone orally (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). Subsequent maintenance and tapering of prednisone are individualized based on patient response to therapy and side effects from systemic glucocorticoids.

Other patients — Other patients can be initiated on an alternative regimen without glucocorticoid therapy. Nonbiologic agents in general require several months to achieve initial efficacy. If effective, therapy should preferably be maintained for one year to decrease the odds of relapse upon discontinuation. Most oral nonbiologic agents (methotrexate, azathioprine, leflunomide) 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 significant 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 [42]. It is an effective steroid-sparing agent [64-67] and in one trial prevented progression and relapses better than oral glucocorticoids when used as initial therapy [68]. It is contraindicated in pregnancy and in patients with nonsarcoidosis hepatic disease, and alcohol use should be minimized. Patient-reported side effects are less common than with oral glucocorticoids [69]. 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 [6,40]. Azathioprine performed similarly to methotrexate in a small trial [67]; leflunomide has also demonstrated effectiveness in small cohorts [70,71]. 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 (PFTs) to assess pulmonary disease burden. 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 sarcoidosis", section on 'Ongoing 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 changes. In this situation, a careful discussion about the relationship of symptoms and granulomatous inflammation may help inform the decision about whether to continue with potentially toxic therapy.

The PFTs that we follow at three- to six-month intervals (depending on disease course) are spirometry and diffusing capacity of the lung for carbon monoxide (DLCO). We reserve ambulatory oximetry for patients with moderate to severe dyspnea, poor exercise tolerance, and severe DLCO impairment.

A favorable response to therapy is defined by:

●A decrease in symptoms, especially dyspnea, cough, or fatigue.

●A reduction in or clearing of radiographic abnormalities.

●Increased efficiency of ventilation or gas exchange (eg, improvement in spirometry, DLCO, or exercise oximetry).

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 who previously exhibited progressive pulmonary deterioration.

Patients who improve and remain stable for more than one year following cessation of therapy have a low rate of relapse [48].

Sarcoidosis 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 [72,73]. Additionally, ACE inhibitor therapy suppresses ACE levels [74].

RELAPSES AND ACUTE BRONCHITIC SYMPTOMS — Relapses may occur during tapering of immunosuppression or after discontinuation of therapy. Clinically, relapses are characterized by two or more of the following:

●Worsening bronchitic symptoms (dyspnea, cough, wheezing, and fatigue)

●A fall of 10 percent or more in forced vital capacity (FVC), total lung capacity (TLC), or diffusing capacity of the lung for carbon monoxide (DLCO)

●Worsening of radiographic opacities

●Decreased gas exchange at rest or with exercise

We use the following therapeutic approach for these relapses of disease activity:

●For patients who relapse during a taper or after discontinuation of therapy – For these patients, therapy can be reinitiated. The dose of choice can range between the lowest prior effective antisarcoidosis dose up to the initial dose required for disease control, depending on the severity of the symptoms. Subsequent tapering of the same agent should be more gradual than the taper that resulted in a relapse. (See 'Stopping glucocorticoid therapy' above.)

●For patients with acute bronchitic symptoms while on maintenance prednisone therapy – Patients frequently describe "flares" of pulmonary sarcoidosis, either after viral syndromes or without an obvious precipitant. The pathologic correlate of these "flares" is unknown, but given the usual rate of granuloma development, they are most likely nongranulomatous bronchitic episodes. In these patients, we suggest a treatment course of prednisone 20 mg/day for two to three weeks followed by an immediate resumption of the prior effective therapeutic regimen. A retrospective study of 36 pulmonary sarcoidosis patients with acute exacerbations of bronchitic symptoms 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 [44]. Following treatment, maintenance therapy can be continued at the prior stable dose.

●For patients with bronchitic symptoms 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 – Patients with pulmonary sarcoidosis who have frequent relapses despite this treatment approach may benefit from the addition or substitution of alternative immunosuppressive agents [36]. (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) [19]. 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 "Chronic pulmonary aspergillosis: Treatment".)

●Extrapulmonary sarcoidosis, including cardiac, neurologic, and hepatic disease.

●Nongranulomatous complications of sarcoidosis therapies, such as excess cardiovascular mortality and infections induced by complications of immunosuppressive therapy.

(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 5^th to 6^th 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 10^th to 12^th 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 (PFTs). (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) (algorithm 1). We monitor symptoms and pulmonary function at three- to six-month intervals, with chest radiography every 6 to 12 months. However, for the subset of asymptomatic patients who present with severe disease, we suggest a trial of 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, a therapeutic trial of low-dose prednisone (5 to 10 mg/day) may be appropriate (algorithm 1). We often assess responsiveness with a moderate dose (20 mg/day) followed by a taper to low doses following the initial response. Administration of moderate- to high-dose inhaled glucocorticoids is a reasonable alternative approach. Most of these patients will undergo spontaneous remission, so observation is safe for patients who prefer to avoid pharmacologic therapy.

•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) (algorithm 1). We typically start prednisone at 20 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 PFTs at four- to six-week intervals during initial therapy and at three- to six-month intervals while on maintenance therapy (algorithm 1). (See 'Assessing response to therapy' above.)

●Relapses and acute bronchitic symptoms – Relapses describe worsening of pulmonary disease during tapering of immunosuppression or after discontinuation of therapy. They are typically managed by increasing immunosuppressant therapy to the last effective dose. Acute bronchitic symptoms while on maintenance therapy may be treated with moderate-dose oral glucocorticoids (eg, 20 mg/day of prednisone) for two to three weeks. (See 'Relapses and acute bronchitic symptoms' 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".)