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Treatment of pulmonary sarcoidosis: Disease refractory to glucocorticoid therapy
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Treatment of pulmonary sarcoidosis: Disease refractory to glucocorticoid therapy
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Literature review current through: Dec 2017. | This topic last updated: Jun 22, 2017.

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 typically present without symptoms, but with an abnormal chest radiograph obtained for an unrelated reason. When symptomatic, patients usually report dyspnea, cough, or nonspecific chest discomfort. Spontaneous resolution of the disease is common, but progressive and disabling organ failure can occur in up to 10 percent of patients.

Glucocorticoids are the most commonly used medication for the treatment of pulmonary sarcoidosis, although no medications have been approved by the US Food and Drug Administration (FDA) for the treatment of sarcoidosis [1-5]. However, some patients with sarcoidosis cannot tolerate or do not respond to glucocorticoids. Several alternative approaches have been proposed, such as the use of immunosuppressive, cytotoxic, and antimalarial drugs [6]. In addition, irradiation has been used for neurosarcoidosis and organ transplantation has been performed successfully for end-stage hepatic, renal, cardiac, or pulmonary disease complicating sarcoidosis. Unfortunately, limited data exist regarding the indications and efficacy of these approaches in the management of pulmonary sarcoidosis.

The treatment of pulmonary sarcoidosis with alternatives to glucocorticoids will be reviewed here. The diagnosis, treatment approach, and use of glucocorticoids for sarcoidosis affecting the lungs and other organs are discussed separately. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Treatment of pulmonary sarcoidosis: Initial therapy with glucocorticoids" and "Neurologic sarcoidosis", section on 'Treatment' and "Sarcoid arthropathy", section on 'Treatment' and "Renal disease in sarcoidosis" and "Gastrointestinal and hepatic sarcoidosis", section on 'Treatment' and "Management and prognosis of cardiac sarcoidosis", section on 'Management of cardiac sarcoidosis'.)

APPROACH — Progressive and disabling respiratory impairment complicates pulmonary sarcoidosis in up to 10 percent of patients. For these patients, intensification of therapy with alternatives to glucocorticoids typically involves immunosuppressive agents. Other patients may be intolerant of glucocorticoids and require immunosuppressive therapy in that basis. Many of these patients may benefit from referral to a sarcoidosis center.

Indications — Patients with sarcoidosis who may benefit from agents other than, or in addition to, glucocorticoids generally have one or more of the following features:

Progression of the disease despite adequate glucocorticoid therapy. An adequate trial of glucocorticoid therapy is considered to be a minimum of 10 mg of prednisone daily (or its equivalent) for at least three months (the usual initial dose is prednisone 20 to 40 mg daily, or its equivalent) [7].

Intolerable glucocorticoid side effects (eg, difficult to control diabetes mellitus, excessive weight gain, myopathy, osteoporosis).

Need for a glucocorticoid-sparing agent in a patient who requires long-term glucocorticoid therapy, has been unable to taper below 10 to 15 mg/day, and has had at least one documented problem with glucocorticoid toxicity.

Patient refusal to take glucocorticoids.

Pretreatment assessment — Prior to intensifying therapy for pulmonary sarcoidosis, we investigate possible reasons for lack of clinical improvement, such as noncompliance with systemic glucocorticoids, comorbid disease, and end-stage fibrosis.

Noncompliance with glucocorticoid therapy is common, due to the numerous side effects of glucocorticoid therapy [5]. Sometimes patients will admit on questioning that they have been missing doses due to fear about the potential side effects. This is helpful information when assessing the likelihood of a response to another potentially toxic agent.

We also assess patients for comorbid diseases that may contribute to their symptoms, pulmonary function impairment, or radiographic abnormalities (eg, infection, heart failure, thromboembolic disease, pulmonary hypertension) [8,9]. Testing typically includes repeat pulmonary function tests (PFTs), a high resolution computed tomography (HRCT) scan, and often an echocardiogram. Dyspnea that is out of proportion to the spirometric findings or a diffusing capacity that is lower than expected based on the amount of interstitial disease on chest imaging might suggest pulmonary hypertension or thromboembolic disease. This is also a good time to ask the patient again about possible occupational exposure to beryllium or any exposures that could cause hypersensitivity pneumonitis. (See "Chronic beryllium disease (berylliosis)", section on 'Exposure' and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

End-stage lung fibrosis is not responsive to immunosuppressive therapy, so it is important to determine whether a patient with apparently refractory disease has end-stage fibrosis or refractory but active inflammation. Chest imaging is not precise enough in most patients to exclude the presence of active disease in a severely scarred lung. On the other hand, PFT abnormalities that have been stable for a few years are more likely due to fibrosis than active inflammation, although the stability of PFT abnormalities does not entirely exclude reversibility. If it is uncertain whether the patient has end-stage fibrosis without active disease, one or two second-line immunosuppressive agents are often tried before deciding that the patient has stable fibrosis and is not in need of ongoing therapy. Patients with advanced lung disease may be candidates for lung transplantation. (See 'Lung transplantation' below.)

Agent selection — The agents that appear to have the greatest likelihood of benefit in pulmonary sarcoidosis with an acceptable side effect profile are methotrexate (MTX), azathioprine, leflunomide, and mycophenolate. Tumor necrosis factor-alpha (TNF-a) antagonists show promise. Randomized trial data to guide selection among the agents are lacking. All of these agents carry substantial risk for toxicity, particularly myelosuppression, hepatotoxicity, and opportunistic infection. The specific toxicities and ways to reduce their impact should be carefully reviewed with the patient.

MTX is the most commonly used second-line agent, although it cannot be used in patients with underlying liver disease. Patients who fail or do not tolerate MTX are commonly transitioned to another second-line immunosuppressive agent. Occasionally, two agents are used in combination, such as MTX and leflunomide.

If none of the second-line agents, alone or in combination, is effective, the next step is often a TNF-a antagonist, usually infliximab or adalimumab. Data are insufficient to determine whether a second-line agent (eg, MTX) should be used during TNF-a antagonist therapy. Combination therapy (eg, TNF-a inhibitor with MTX) has been used in rheumatoid arthritis to improve efficacy and reduce the risk of development of antibodies to the TNF-a inhibitor, but has not been formally evaluated in sarcoidosis and is associated with increased risk of infection and possibly malignancy. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'MTX plus TNF inhibitor' and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

If the TNF-a antagonist is contraindicated (eg, known hepatitis or aspergillus infection) or is unsuccessful, the next steps are less clear, but may include hydroxychloroquine or one of the other agents that has been successful in other types of immunologic lung disease but has not been formally studied in sarcoidosis, such as mycophenolate, cyclophosphamide, or rituximab. (See 'Off-label investigational agents' below.)

Assessing response — The response to therapy with any of the agents described above is evaluated in the same manner as that described for glucocorticoid therapy of pulmonary sarcoidosis and requires ongoing assessment of changes in symptoms (eg, dyspnea, cough, hemoptysis, chest pain, fatigue), PFTs, gas transfer, and radiographic abnormalities. (See "Treatment of pulmonary sarcoidosis: Initial therapy with glucocorticoids", section on 'Assessing the response'.)

The parameters of response are sometimes conflicting and clinical judgment is needed to determine whether changes reflect true worsening or true improvement. Generally, greater weight is attributed to changes in symptoms than to changes in other parameters.

In addition to assessing the response to therapy, patients are monitored for new, extrapulmonary manifestations of sarcoidosis on a regular basis. An approach to monitoring is presented separately. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Monitoring'.)

Opportunistic infection — Opportunistic infectious complications (eg, cryptococcosis, aspergillosis, mycobacterial) are rare in patients with sarcoidosis treated with MTX, azathioprine, leflunomide, and mycophenolate [8,10,11]. However, patients on a combination of glucocorticoids (≥20 mg daily) and another immunosuppressive agent (eg, MTX, azathioprine, leflunomide, TNF-a antagonist) do appear to be at some increased risk and clinicians need to be aware of this possibility. The types of infection associated with these therapies and the indications for preventive therapy are discussed separately. (See "Glucocorticoid effects on the immune system", section on 'Infection risk' and "Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients", section on 'Indications' and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

METHOTREXATE — Methotrexate (MTX), an antimetabolite with both immunosuppressive and antiinflammatory properties, is the most commonly used nonglucocorticoid immunosuppressive agent for sarcoidosis [12]. It is also used for the management of other chronic inflammatory or autoimmune disorders, such as rheumatoid arthritis, psoriasis, and Crohn disease. The mechanism of action of MTX and its use in these other diseases are discussed separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Immunomodulator therapy in Crohn disease", section on 'Methotrexate' and "Treatment of psoriatic arthritis", section on 'Methotrexate' and "Treatment of psoriatic arthritis".)

Efficacy — A small randomized trial, several small series, and case reports suggest that MTX is effective in patients with sarcoidosis affecting the lungs, skin, eyes, and central nervous system [13-22]. As an example, 24 patients with recent-onset pulmonary sarcoidosis were randomly assigned to low-dose MTX plus glucocorticoids or glucocorticoids alone [21]. At 12 months, those in the MTX group had been able to taper prednisone to a lower dose than those without MTX. However, when the study was analyzed including all the patients who had dropped out, the benefit was no longer statistically significant.

Clinical experience suggests a response rate to methotrexate of 40 to 60 percent among patients with pulmonary sarcoidosis [5,20]. A systematic review did not find convincing evidence of benefit, but this was due to insufficient published data, rather than demonstrated lack of benefit [23].

A two-year, retrospective cohort study of 200 patients with sarcoidosis treated with methotrexate or azathioprine found that the daily prednisone dose decreased a mean of 6.32 mg/year, forced expiratory volume in one second (FEV1) increased 52 mL/year, vital capacity increased 95 mL/year, and diffusing capacity (DLCO) increased 1.23 percent/year [24]. No significant differences were noted between the two treatments except for a higher rate of infection with azathioprine (35 versus 18 percent).

Pretreatment preparation and contraindications — Prior to initiating MTX, complete blood counts (CBC), albumin, aminotransferases, alkaline phosphatase, bilirubin, creatinine, and hepatitis B and C viral testing (ie, HBsAg, anti-HBc, anti-HCV) are obtained. Patients with evidence of underlying liver disease (eg, aminotransferase level above two times the upper limit of normal) or chronic infection with hepatitis B or C are not candidates for MTX therapy [25]. A creatinine clearance less than 30 mL/min is considered a contraindication for methotrexate in patients with rheumatoid arthritis [25]. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Patient selection'.)

In addition, ingestion of alcoholic beverages while using MTX is strongly discouraged, and patients who are unwilling to reduce their alcohol consumption to an occasional and minimal level are not treated with MTX.

MTX is contraindicated in pregnancy due to teratogenic effects. It should be discontinued at least three months prior to a planned pregnancy and should not be used during breastfeeding [12]. Women of childbearing age should use a reliable method of contraception while taking MTX. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Methotrexate'.)

Dosage and administration — MTX can be administered either orally or intramuscularly. We typically begin with oral therapy at a dose of 5 to 7.5 mg weekly. The dose is gradually increased (eg, by increments of 2.5 mg every two weeks) until a dose of 10 to 15 mg per week is achieved [12]. We switch to intramuscular MTX when patients have refractory nausea or have not achieved a beneficial effect after three to six months of oral therapy at 15 mg per week. A trial of MTX therapy should last at least six months to allow adequate assessment of effectiveness. (See "Treatment of pulmonary sarcoidosis: Initial therapy with glucocorticoids", section on 'Assessing the response'.)

Folic acid at a dose of 1 mg per day or 5 mg weekly is routinely given to patients on chronic methotrexate therapy to reduce the incidence of myelosuppression [12]. A routine peripheral blood count is obtained every four to eight weeks [25].

The optimal frequency for assessing liver function tests during methotrexate therapy for sarcoidosis is unknown. Alanine aminotransferase (ALT) with or without aspartate aminotransferase (AST), creatinine, and a CBC should be obtained every three to six weeks until a stable dose is reached and then every one to three months [12].

If ALT/AST increases without other clear cause, the methotrexate dose should be decreased or the drug stopped [12].

Because hepatic toxicity may initially be clinically occult, some have advocated liver biopsy when the total dose exceeds one gram or after 18 to 24 months of therapy, even without signs of hepatic injury, or if 6 of 12 serum aminotransferase levels are abnormal in a single year. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Hepatotoxicity'.)

Adverse effects — The most serious side effects of immunosuppressive MTX therapy are hepatic fibrosis (in up to 10 percent of cases when the dose exceeds 5 g), leukopenia, and interstitial pneumonitis, resulting in pulmonary fibrosis [5]. In a study of the long-term use of MTX for sarcoidosis, 50 patients completed two years of therapy; the major adverse effects requiring hospitalization were hepatic toxicity and leukopenia [20]. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease", section on 'Guidelines in other rheumatic diseases' and "Methotrexate-induced lung injury", section on 'Clinical manifestations'.)

The differential diagnosis of abnormal liver function in patients with sarcoidosis receiving MTX is broad and includes drug toxicity and hepatic sarcoidosis. Liver biopsy is frequently required to establish a definitive diagnosis. In a series of 100 liver biopsies performed in 68 patients with sarcoidosis, 14 biopsies demonstrated significant changes related to MTX; however, evidence of sarcoidosis involving the liver was even more common, noted in 47 biopsies [26]. Toxic reactions to MTX eventually developed in 10 percent of patients treated for more than two years. (See "Hepatic granulomas", section on 'Sarcoidosis'.)

MTX-induced interstitial pneumonitis may be difficult to distinguish from progressive interstitial lung changes secondary to sarcoidosis. Characteristic features of MTX-induced lung injury include nonproductive cough, dyspnea, and fever beginning within days to weeks after initiation of MTX therapy. Peripheral blood (but not pulmonary) eosinophilia, when present, is more likely due to MTX than sarcoidosis [27-29]. Typical radiographic findings of MTX-induced lung injury include diffuse or patchy ground glass opacities, centrilobular nodules, and increased reticular opacities; pleural effusion is seen in about 10 percent. Poorly formed granulomas may be seen on lung biopsy. Recovery usually occurs after withdrawal of the drug. (See "Methotrexate-induced lung injury".)

Other toxicities include nausea, alopecia, and skin rash [5]. MTX is known to be teratogenic and may transiently suppress gonadal function. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)

Chronic MTX treatment has been associated with the development of lymphoproliferative disorders, some of which regress after discontinuation of MTX [30,31]. It is not known whether MTX had an etiologic role in the development of the lymphoproliferative disease, or whether the underlying inflammatory condition was the sole contributor. (See "Malignancy and rheumatic disorders", section on 'Antirheumatic medications and risk of malignancy'.)

ALTERNATIVES TO METHOTREXATE — A variety of immunosuppressive agents have been used to treat pulmonary sarcoidosis that is insufficiently controlled with an acceptable dose of glucocorticoids. The evidence in support of individual second-line agents is largely observational [32,33].

Azathioprine — Azathioprine affects synthesis of RNA and DNA, thus inhibiting lymphocyte proliferation. Cellular immunity is suppressed to a greater degree than humoral immunity, but the exact mechanism by which azathioprine might affect sarcoidosis is not clear. Azathioprine is used as second-line therapy for pulmonary sarcoidosis, generally as a supplement to glucocorticoids rather than as a single drug [1,19,34-39]. Due to the greater clinical experience with methotrexate (MTX), azathioprine is usually used in patients who have failed MTX due to side effects or lack of benefit.

Efficacy — No randomized trials have examined the efficacy of azathioprine for pulmonary sarcoidosis. An open-label series examined the effect of azathioprine (2 mg/kg per day) combined with glucocorticoids in 11 patients with chronic or relapsing pulmonary sarcoidosis [38]. All of the patients experienced improvement in symptoms and/or pulmonary function tests. Therapy was continued for a mean of 20 months (range 8 to 26). Three patients, including the one who discontinued therapy after 8 months, sustained relapses at 8, 18, and 22 months. The remaining eight had stable remissions for at least 4 to 73 months after discontinuing therapy.

In a separate series, 7 of 10 patients with pulmonary sarcoidosis exhibited clinical improvement with azathioprine 150 mg per day without concomitant glucocorticoids [36]. In contrast, a retrospective case review found a benefit in only 2 of 10 patients [40].

As noted above, in a two-year cohort study, modest improvements were noted among patients taking either MTX (n = 145) or azathioprine (n = 55) without significant between group differences, except for a higher infection rate with azathioprine (35 versus 18 percent) [24]. (See 'Efficacy' above.)

Pretreatment preparation — The toxicity of azathioprine is largely related to its metabolites and is strongly affected by the presence of genetic polymorphisms of the enzyme thiopurine-S-methyltransferase (TPMT) [41]. TPMT activity can be predicted by genotyping or by measurement of serum TPMT enzyme activity levels. Low TPMT enzyme activity levels are associated with increased toxicity. Pretreatment screening of patients for genetic polymorphisms of TPMT or reduced TPMT enzyme activity is controversial as patients with normal genotypes can still develop myelosuppression and hepatic toxicity. However, many clinicians perform one test or another before initiating azathioprine therapy. It is not known whether a high level of TPMT activity would identify patients who need a higher dose of azathioprine to achieve a therapeutic effect. (See "6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in patients with inflammatory bowel disease", section on 'TPMT enzyme determination' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and TPMT testing'.)

Baseline complete blood counts and serum albumin, aminotransferases, and creatinine are obtained in all patients.

Azathioprine is a teratogen, so women of childbearing age should use a reliable method of contraception during azathioprine therapy. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

Dosage and administration — The usual starting dose of azathioprine is 50 mg per day, given as a single daily oral dose. To reduce the likelihood of gastrointestinal side effects, the dose is slowly increased by 25 mg every two to three weeks until the desired dose is reached. The typical maintenance dose is 2 mg/kg (up to a maximum of 200 mg/day), unless the patient has renal insufficiency or an adverse effect necessitating a lower dose. We monitor the white blood cell count and reduce the azathioprine dose if the count falls to 4000/mm3. A discernible response to therapy may not be evident until the patient has received three to six months of therapy. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

A complete blood count (including hemoglobin, white blood cell count, and platelet count) should be monitored every week during dose escalation, and every 8 to 12 weeks after a stable dose is achieved. There is less consensus on the frequency of liver enzyme testing. A reasonable protocol is to check serum aminotransferases every 8 to 12 weeks during the first several months of AZA therapy and then less often during chronic therapy if prior testing has been normal. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and TPMT testing' and "6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in patients with inflammatory bowel disease", section on 'Summary and recommendations'.)

Adverse effects — Gastrointestinal complaints (eg, nausea, vomiting, and diarrhea), rash, fever, and malaise are the most common side effects. Dyspeptic symptoms can be reduced by taking the medication with meals. Hematologic side effects include depression of all cell lines, which may be difficult to distinguish from the bone marrow suppression associated with sarcoidosis. A small percentage of patients demonstrate an increase in liver function tests, but reports of severe hepatitis are rare. An increased risk of subsequent malignancy has been reported in renal transplant patients who are treated with both azathioprine and prednisone. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

Leflunomide — Leflunomide is an antimetabolite similar to MTX but with less gastrointestinal toxicity.

Efficacy – Evidence in favor of using leflunomide for pulmonary sarcoidosis is limited to case series and to indirect evidence of benefit in a few cases of extrapulmonary sarcoidosis [42-44]. In a retrospective case series, 32 patients received leflunomide with or without concomitant MTX for pulmonary or ocular sarcoidosis [42]. Complete or partial response was seen in 12 of 17 patients who received leflunomide alone. Three patients discontinued leflunomide due to nausea, but no other significant side effects were reported. The combination of leflunomide with MTX resulted in a partial or complete response in 13 of 15 patients. In a case report, a patient with pulmonary, sinus, and cutaneous sarcoidosis that was refractory to azathioprine and hydroxychloroquine responded to leflunomide 20 mg per day [44]. He had been intolerant of MTX, but tolerated leflunomide without side effects.

Pretreatment preparation – Prior to initiating leflunomide therapy, complete blood counts, albumin, aminotransferases, creatinine, and hepatitis B and C viral testing are obtained [25]. Patients with evidence of underlying liver disease (eg, aminotransferase level above two times the upper limit of normal) or chronic infection with hepatitis B or C are not candidates for leflunomide therapy.

Alcohol avoidance is recommended while taking leflunomide.

Both women and men (and/or their female partners) of childbearing age should use a reliable method of contraception during leflunomide therapy and for up to two years afterwards, unless they follow a cholestyramine clearance regimen. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Leflunomide'.)

Dosage and administration – The typical initial leflunomide dose is 20 mg per day, without a loading dose. We do not use a loading dose as a greater incidence of side effects was noted when a loading dose of 100 mg per day for three days was used in the treatment of rheumatoid arthritis. Alternatively, leflunomide can be initiated at 10 mg per day and increased to 20 mg, if the patient is tolerating the medication but has not achieved control of the disease manifestations [42]. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Pharmacokinetics and drug elimination'.)

Extrapolating from the experience with rheumatoid arthritis, it may take 6 to 12 weeks for any improvement in lung function to occur.

Adverse effects – The most common adverse effects of leflunomide are nausea, diarrhea, abdominal pain, hepatotoxicity, rash, and peripheral neuropathy [45,46]. This risk of hepatotoxicity appears higher among patients with underlying liver disease (eg, alcohol abuse, viral hepatitis, autoimmune liver disease) who are taking another hepatotoxic agent. The frequency of adverse effects may be influenced by the patient's genotype at the locus for cytochrome P450, CYP1A2, or for dihydroorotate dehydrogenase, an enzyme inhibited by leflunomide [47,48]. However, testing for these genotypes is not clinically available. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Adverse effects'.)

The American College of Rheumatology suggests that patients taking leflunomide undergo monitoring of serum albumin and serum aspartate and alanine aminotransferase (AST and ALT) levels every two to four weeks for the first three months, followed by monitoring every 8 to 12 weeks for the next three months, and then every 12 weeks thereafter [25]. Alcohol avoidance is recommended during leflunomide therapy. Due to the long half-life of leflunomide, if the ALT increases to two times the upper limit of normal or higher, leflunomide should be stopped and active removal with cholestyramine initiated. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Warnings and monitoring for liver disease'.)

Mycophenolate mofetil — Mycophenolate mofetil (MMF), an inhibitor of lymphocyte proliferation and activity, has been used to treat a variety of interstitial lung diseases associated with rheumatic disease. However, data regarding the use of MMF in sarcoidosis are limited, and its role in pulmonary sarcoid requires further study.

Selection of the initial dose and monitoring of MMF are described separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration'.)

Evidence in favor of a benefit to mycophenolate includes the following studies:

In a retrospective review of 37 patients with pulmonary sarcoidosis who had failed to respond to a prior immunosuppressive agent or had experienced an adverse event necessitating discontinuation of the agent, addition of MMF was associated with a decrement in prednisone dosing (5.6 mg over one year) [49]. MMF was not associated with improvement in pulmonary function in the group as a whole. In a subgroup analysis, a trend towards improvement in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) was noted among patients who were given MMF due to intolerance of a prior immunosuppressive agent, rather than due to therapeutic failure.

In a case series, MMF was added to prednisone in 10 patients with biopsy-proven pulmonary sarcoidosis for a median of 31 months; plasma trough levels of MMF were 1 to 3 mg/dL [50]. Over the course of therapy, symptoms, radiographic abnormalities, and pulmonary function improved in four patients and remained stable in six. The mean improvement in FVC was 8.5 percent (range -2 to 16 percent). Concomitant prednisone was reduced slightly from a mean of 14 to 6 mg/day.

Benefit from MMF has been reported in case series of patients with cutaneous, central nervous system, and renal sarcoidosis [51-54]. In a case report, cutaneous and bone marrow sarcoidosis that were refractory to glucocorticoids and MMF responded to a combination of MMF and methotrexate [55]. (See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment", section on 'Mycophenolate mofetil' and "Neurologic sarcoidosis", section on 'Other immunomodulatory therapies'.)

MMF treatment requires careful dosing and monitoring to avoid toxicity. Neutropenia is less of a problem with MMF than with other immunosuppressive agents, but may occur. Nausea and diarrhea may be dose limiting. The dosing, adverse effects, and monitoring of MMF therapy are discussed in greater detail separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Combination therapy — For patients who have progressive pulmonary sarcoidosis that is refractory to one or two of these second-line immunosuppressive agents taken individually, a common practice is to combine two of the agents, such as methotrexate and leflunomide [56]. As an example, in an open label study, 15 of 17 patients with sarcoidosis affecting various organs responded to a combination of MTX and leflunomide [42].

UNRESPONSIVE DISEASE — For patients whose disease is refractory to the above agents or who are unable to tolerate them at a therapeutic dose, the next step is usually a tumor necrosis factor-alpha (TNF-a) antagonist, although sarcoidosis is not a US Food and Drug Administration (FDA) approved indication for these agents. Other alternatives include entering a clinical trial or using an investigational agent as described below. (See 'Off-label investigational agents' below.)

Tumor necrosis factor-alpha antagonists — For patients whose disease is refractory to the above agents, the next step is typically a TNF-a antagonist. The cytokine TNF-a is thought to accelerate the inflammatory process in sarcoidosis via its role in maintenance of granuloma formation. Thus, using agents that block the effect of TNF-a may be beneficial in treating sarcoidosis. Due to the potential toxicity of these agents, we reserve them for patients who have persistent disease and have failed treatment with glucocorticoids (eg, prednisone ≥15 mg/day) AND at least one second-line immunosuppressive agent (eg, methotrexate [MTX], azathioprine, leflunomide) [4,57,58].

Efficacy of individual agents — Studies of the efficacy of TNF-a antagonists in the treatment of sarcoidosis have yielded mixed results.

Infliximab (ie, Remicade) is a chimeric, humanized monoclonal antibody that neutralizes TNF-a. It has been studied in patients with pulmonary and extrapulmonary sarcoidosis refractory to glucocorticoid therapy [59-65]. In a randomized trial, 138 patients with chronic pulmonary sarcoidosis were assigned to receive infusions of placebo, low-dose infliximab (3 mg/kg), or higher-dose infliximab (5 mg/kg) at baseline and weeks 2, 6, 12, 18, and 24 [63]. At evaluations performed at 24 and 52 weeks, low-dose infliximab increased the percent of predicted forced vital capacity (FVC) compared with baseline, whereas placebo did not. The proportion of patients that reported adverse events was similar among the treatment groups; the most common adverse events were upper respiratory infection, cough, dyspnea, and bronchitis.

The infliximab trial described above has been criticized for its small and clinically insignificant effect size, although it did identify subgroups that may derive greater benefit [63,66]. As an example, 92 patients with extrapulmonary sarcoidosis that was refractory to chronic glucocorticoids were randomly assigned to take infliximab or placebo for 24 weeks [67]. A modest improvement was noted in the infliximab group, although the improvement was not maintained during the 24-month follow-up period. Long-term infliximab treatment has not been well studied. Patients with predominantly extrapulmonary sarcoidosis appear to receive the most benefit from long-term treatment [65].

Preliminary evidence suggests that a subset of patients with sarcoidosis who have peripheral blood CD4+ T cell lymphopenia and resistance to conventional immunosuppressants may be more likely to respond to infliximab [68]. Among five consecutive patients with this phenotype, the CD4+ lymphopenia corrected with infliximab and all reported improvement in at least one clinical disease manifestation of sarcoidosis. Additional studies regarding the cause of the CD4+ lymphopenia in these patients and the use of CD4+ lymphopenia as a biomarker for response to infliximab are needed.

Adalimumab (ie, Humira) is a fully human anti-TNF-a antibody. A few case reports and small case series have described improvement in extrapulmonary sarcoidosis with adalimumab [69-73]. In addition, among 18 patients who switched from infliximab to adalimumab due to intolerance of infliximab (allergic reaction with or without antibodies) or disease progression, seven patients showed improved forced vital capacity, six patients remained stable, and five deteriorated [74]. One patient developed a lupus-like syndrome, three had severe infections, and seven had mild infections.

Etanercept (ie, Enbrel) is a soluble TNF-a receptor fusion protein that binds TNF-a and has a longer half-life than the native soluble receptor. It was assessed in a preliminary clinical trial of patients with progressive stage II or III sarcoidosis. The trial was stopped after the enrollment of 17 patients, when interval assessment noted treatment failure in 11 participants [75]. Treatment failure was defined as progressive clinical deterioration, the need for other immunosuppressive medications, or the development of intolerable side effects. In a separate trial, etanercept was not shown to improve chronic ocular disease [76]. On the basis of these results, larger trials of this agent for progressive pulmonary sarcoidosis do not appear indicated.

Pretreatment preparation — Therapy with TNF-a antagonists has been associated with reactivation of a variety of latent infections including tuberculosis and hepatitis B and C, although the latter occurs less often. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

Prior to initiating therapy with a TNF-a antagonist, patients are asked about risk factors for tuberculosis infection and undergo a tuberculin skin test (PPD) or a peripheral blood interferon release assay. For patients who have been previously vaccinated with Bacille Calmette-Guérin (BCG), the interferon release assay can help to differentiate between tuberculosis infection and BCG vaccination. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections", section on 'Screening and prevention' and "Interferon-gamma release assays for diagnosis of latent tuberculosis infection".)

Flares of hepatitis B have been documented with infliximab therapy; progression of hepatitis C has rarely been reported with TNF-a antagonists. We ask patients about risk factors for hepatitis viral infection and obtain serologic testing for hepatitis B and C. Serologic testing should include assessment of HBsAg, anti-HBc, and anti-HCV. If the HBsAg test is positive, further testing should include HBeAg, anti-HBe, and an HBV DNA level. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Hepatotoxicity' and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Viral infections'.)

Dosage and administration — Infliximab is administered by intravenous infusion 3 to 5 mg/kg at weeks 0, 2, 6, and 12 [62-64,68]. The optimal frequency for subsequent dosing is not known. Among patients with rheumatoid arthritis and Crohn disease, scheduled maintenance therapy (eg, every six to eight weeks) appears more effective than no maintenance therapy. The optimal duration of a therapeutic trial of infliximab in pulmonary sarcoidosis is unknown, but a six-month trial was better than a three-month trial in a group of 244 patients with rheumatoid arthritis [77]. (See "Infliximab in Crohn disease" and "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis", section on 'Infliximab and related agents'.)

Adalimumab is administered by subcutaneous injection. The optimal dose in pulmonary sarcoidosis is not known, but a dose of 40 mg every week or every other week has been used in case reports [69-71,78]. In other inflammatory conditions, the usual dose is 40 mg every other week; sometimes an initial dose of 80 to 160 mg (given as 4 injections over 24 hours) is used. (See "Adalimumab for treatment of Crohn disease in adults", section on 'Dosing'.)

Combination with other agents — The combination of infliximab (or another TNF-a inhibitor) with MTX or azathioprine appears to inhibit antibody formation to the monoclonal antibody and to improve disease control among patients with rheumatoid arthritis or Crohn disease. However, the risks of serious infection and malignancy (lymphoma) in these diseases appear greater with combination therapy than with infliximab alone. Data for sarcoidosis are insufficient to make a clear recommendation between these choices. However, we typically initiate infliximab or adalimumab in combination with a low dose of glucocorticoid or low-dose MTX to prevent antibody formation. (See "Infliximab in Crohn disease", section on 'Combination therapy with an immunomodulator' and "Randomized clinical trials of tumor necrosis factor inhibitors in rheumatoid arthritis", section on 'Infliximab and related agents'.)

Adverse effects — The major adverse effects associated with the TNF-a antagonists are increased susceptibility to infection, particularly mycobacterial and invasive fungal infections, and infusion-reactions. Additional side effects reported in separate studies (in one patient each) include alopecia, oral candidiasis, cellulitis, pneumonia, visual field defect, fatal pulmonary embolism, and development of a hypercoagulable state associated with circulating anticardiolipin antibodies [59-62,64]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

The development of noncaseating granulomas consistent with sarcoidosis has been reported during anti-TNF-a therapy for other diseases [79-82]. Granulomas have occurred in the skin, lungs, and lymph nodes. The sarcoid-like disease manifestations have typically resolved with cessation of anti-TNF-a therapy, although some patients have also received glucocorticoid therapy.

OFF-LABEL INVESTIGATIONAL AGENTS — Several medications have been proposed for use in sarcoidosis based on their mechanism of action, but are not commonly used for pulmonary sarcoidosis due lack of adequate data to support their use or their side effect profile.

Clinical trials — Information about clinical trials of therapies for pulmonary sarcoidosis can be found at Clinicaltrials.gov.

Cyclophosphamide — Cyclophosphamide is used rarely as a glucocorticoid-sparing agent in the treatment of sarcoidosis [83,84]. Due to its toxicity profile, it is reserved for use as a "third-line" drug in patients whose condition is deteriorating despite therapy with glucocorticoids and one of the more commonly used immunosuppressive agents. (See 'Alternatives to methotrexate' above.)

Mechanism of actionCyclophosphamide is an alkylating agent of the nitrogen mustard group. It is an inactive drug that is metabolized by the cytochrome P-450 system into active metabolites. These metabolites decrease lymphocyte numbers and function and may also have antiinflammatory effects. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Dosage and administrationCyclophosphamide is generally given orally as a single daily dose. We usually begin at a dose of 25 to 50 mg/day and increase gradually, by 25 mg increments, aiming to reduce and maintain the white blood cell count (WBC) to between 4000 and 7000/mm3. The WBC count is measured biweekly for the first 6 to 12 weeks and then at least monthly thereafter. We do not exceed a dose of 150 mg/day, even if the leukocyte count remains about 7000/m3, as it is our clinical impression that this dose is associated with a lower rate of side effects without loss of clinical efficacy. There is little experience in sarcoidosis with the intravenous administration of intermittent ("pulse") therapy with cyclophosphamide. It has been used occasionally in patients with refractory or progressive disease. The usual dose is 500 to 1000 mg given intravenously over 30 to 60 minutes once every two or four weeks; the exact dose is calculated based on the patient's age, creatinine clearance, and peripheral leukocyte counts during treatment. Intravenous administration is discussed in greater detail separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)

We do not expect to achieve a favorable response to cyclophosphamide for at least three to six months after initiating therapy, either with or without accompanying low doses of glucocorticoids.

Adverse effects – Reductions in all hematologic cell lines can be seen, and these require an adjustment in dosage. As discussed above, we adjust the cyclophosphamide dose to maintain the WBC count between 4000 and 7000/mm3. Other toxicities include increased risk of infection, hemorrhagic cystitis, stomatitis, nausea, diarrhea, hepatotoxicity (rarely), and carcinoma of the bladder. Strategies to reduce the risk of hemorrhagic cystitis include advising the patient to drink eight or more glasses (eight ounces each) of water daily to create a forced diuresis and monthly monitoring of the urine for red blood cells or other abnormalities. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

Infertility may occur in both men and women. Cyclophosphamide may be teratogenic, so women of childbearing age should use a reliable method of contraception. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Cyclophosphamide'.)

Golimumab and ustekinumab — Golimumab is a humanized tumor necrosis factor-alpha (TNF-a) antibody that has been found effective for rheumatoid arthritis; ustekinumab is a monoclonal antibody to interleukin (IL)-12/IL-23 that is used in psoriasis. In a randomized trial, 132 patients with lung sarcoidosis were assigned to golimumab, ustekinumab, or placebo for 24 weeks [85]. At week 16, the change from baseline in percent predicted forced vital capacity was no different in the active treatment groups compared with placebo.

Rituximab — Rituximab is a monoclonal antibody that targets CD-20 on B lymphocytes, leading to B lymphocyte depletion. As sarcoidosis is associated with hypergammaglobulinemia, it is hypothesized that a B lymphocyte-directed therapy may be of benefit. Several reports describe treatment of refractory sarcoidosis affecting the lungs, heart, and eyes with variable results [86-89]. Further study is needed to determine whether rituximab is beneficial in refractory sarcoidosis.

Hydroxychloroquine and chloroquine — Hydroxychloroquine and chloroquine are antimalarial drugs with immunomodulating properties. Clinical experience with these agents for pulmonary sarcoidosis is limited, and their relative efficacy versus other therapies has not been assessed. Due to the limited benefit and concerns about ocular toxicity, we reserve these medications for circumstances where other options have failed or are contraindicated. Hydroxychloroquine is preferred over chloroquine due to a more favorable adverse effect profile.  

EfficacyChloroquine has been used most often to treat cutaneous sarcoidosis [90,91], but several reports have described its use in patients with pulmonary disease [33,92-98]. (See "Management of cutaneous sarcoidosis", section on 'Antimalarials'.)

As an example, one trial treated 23 symptomatic patients with biopsy-proven pulmonary sarcoidosis for six months with chloroquine, and then randomized patients to either maintenance therapy with chloroquine or observation [98]. Small but statistically significant advantages in forced expiratory volume in one second (FEV1) and relapse rate were observed in the group maintained on chloroquine during a mean follow-up of 20 months. In cutaneous sarcoidosis, chloroquine appears to have a higher response rate than hydroxychloroquine, although hydroxychloroquine is often preferred due to lower ocular toxicity [99]. (See "Management of cutaneous sarcoidosis", section on 'Antimalarials'.)

Dosage and administration – Glucose-6-phosphate dehydrogenase (G6PD) levels must be determined prior to initiating therapy; these agents cannot be given if the patient is G6PD deficient. For patients with a normal G6PD level, the dose of hydroxychloroquine is 5 mg/kg real body weight with the dose not to exceed 400 mg/day; the dose of chloroquine is approximately 250 mg/day (maximum daily dose ≤2.3 mg/kg real body weight). Higher doses have been used based upon an observational study [98], but are now avoided due to the risk of retinopathy associated with higher doses. All patients should undergo a baseline eye examination; the primary tests used in follow-up to screen for retinopathy are automated visual fields plus spectral-domain coherence tomography (SD OCT). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency" and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)

Adverse effects – The major adverse effects of the antimalarial agents are irreversible retinopathy and blindness. Hydroxychloroquine is associated with a lower rate of retinal toxicity than chloroquine even when the dose is adjusted for lean body weight [100]. Thus, eye examination by an ophthalmologist is required at baseline and every 6 to 12 months during therapy to avoid drug-related toxic retinitis and corneal lesions [5]. Alternate day treatment minimizes the risk of ocular toxicity.

Nausea is a frequent dose-limiting problem.

Antimycobacterial therapy — Data suggestive of a role for an unidentified mycobacterium as a cause of some cases of sarcoidosis led to a study of combination levofloxacin, ethambutol, azithromycin, and rifampin for pulmonary sarcoidosis [101]. Improvement in forced vital capacity (FVC) was reported for patients able to complete the eight weeks of therapy. Approximately half of patients were not able to complete the entire the eight-week protocol mainly because of adverse events, including leucopenia, arthralgias, insomnia, and rash.

LUNG TRANSPLANTATION — For patients with advanced pulmonary fibrosis due to pulmonary sarcoidosis and associated pulmonary hypertension, lung transplantation may offer the only hope for long-term survival [9,102,103]. Patients considered for lung transplantation usually have stage IV radiographic disease (ie, advanced fibrotic changes, honeycombing, hilar retraction, and cystic change) and are New York Heart Association III or IV. Survival rates following lung transplantation for pulmonary sarcoidosis are comparable to those for other indications [104-107]. (See "Lung transplantation: An overview".)

Data are limited regarding the optimal timing of lung transplantation for sarcoidosis. Parameters that would favor a lung transplant evaluation include a forced vital capacity (FVC) less than 1.5 L (or less than 50 percent of predicted) and the development of oxygen dependence or pulmonary hypertension due to sarcoidosis, as these features are associated with increased one-year mortality in the absence of transplantation [108,109]. (See "Lung transplantation: General guidelines for recipient selection".)

Bilateral lung transplantation appears to be associated with slightly better survival than single lung transplantation [107]. When deciding between a single or bilateral lung transplantation, the presence of a mycetoma or significant bronchiectasis may necessitate a bilateral lung procedure [104]. In addition, patients with mycetomas may require specific, individualized antifungal therapy [110,111]. The extent of extrapulmonary sarcoidosis must be carefully assessed prior to surgery. In particular, cardiac involvement may indicate a greater risk from lung transplantation alone or the need for a simultaneous heart-lung transplantation. Heart-lung transplantation increases the risk for short-term posttransplant mortality, although long-term outcomes are comparable to double lung transplantation [104,112]. (See "Lung transplantation: General guidelines for recipient selection", section on 'Cystic fibrosis and bronchiectasis' and "Management and prognosis of cardiac sarcoidosis", section on 'Management of cardiac sarcoidosis'.)

Following lung transplantation, asymptomatic foci of noncaseating granulomas, suggestive of recurrent disease, have been identified in the allografts of sarcoidosis patients [113-117]. However, clinically significant organ dysfunction due to recurrent sarcoidosis is rare, and evidence of recurrence usually disappears within three months, without associated clinical sequelae during the follow-up period [102,103,106,115].

The incidence of acute rejection and bronchiolitis obliterans syndrome appear similar after transplantation among patients with sarcoidosis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease, despite observations to the contrary in the older literature [106,114,115,117,118].

AGENTS WITHOUT CLEAR BENEFIT — A number of agents have substantial toxicity and/or insufficient evidence of benefit for pulmonary sarcoidosis and are consequently avoided. These agents include colchicine, chlorambucil, cyclosporine, nonsteroidal antiinflammatory agents, tetracyclines, and thalidomide.  

Colchicine – Colchicine has multiple effects, including the arrest of cell division, inhibition of granulocyte migration, and inhibition of the release of several proteins from cells. It may also interfere with the secretion of collagen from fibroblasts and may increase collagen degradation by enhancing the action of collagenase. Colchicine may be useful for sarcoid arthritis (based on case series), but is not used for pulmonary sarcoidosis.  

Side effects of colchicine include nausea, vomiting, abdominal pain, and diarrhea.

Chlorambucil – Chlorambucil is an alkylating agent that is rarely used for the treatment of refractory pulmonary sarcoidosis [34,119-122]. Clinical experience is limited, and the relative efficacy of chlorambucil versus other therapies has not been assessed. Due to the limited benefit and substantial toxicity, we avoid this medication except in circumstances where other options have failed or are contraindicated. (See "General toxicity of cyclophosphamide in rheumatic diseases".)

The evidence in favor of using chlorambucil for sarcoidosis is limited. In one report, 10 patients with progressive disease were treated with chlorambucil alone or in combination with glucocorticoids [119]. Eight had some degree of improvement that may have been attributable to chlorambucil. The responsive patients showed beneficial effects within three months of starting chlorambucil therapy.

Bone marrow function usually recovers rapidly when the drug is discontinued, but irreversible marrow failure has also been reported. An alarming rate of oncogenesis (leukemia and other tumors) limits its potential use in nonneoplastic diseases. Other side effects include nausea, vomiting, hepatotoxicity, dermatitis, and infertility.

Cyclosporine – Cyclosporine, a fungus-derived cyclic peptide that suppresses cell-mediated and humoral immune responses, is primarily used for the prevention of allograft rejection. In addition, it may be effective in T-cell mediated disorders such as uveitis, psoriasis, rheumatoid arthritis, and primary biliary cholangitis. The use of cyclosporine in the treatment of pulmonary sarcoidosis remains experimental, due to limited clinical experience and known toxicities [123-127].

The limited clinical experience with cyclosporine for pulmonary sarcoidosis has not demonstrated significant improvement in control of the disease. As an example, one study randomly assigned 37 patients with biopsy-proven sarcoidosis and deteriorating respiratory function to treatment with prednisone with or without concomitant, open-label cyclosporine, titrated to trough levels of 100 to 200 ng/mL [127]. Combined outcome measures did not differ significantly between the two treatment groups at 3, 9, or 18 months. It is possible that the small trials in which its use has been studied have had insufficient power to detect beneficial effects of cyclosporine treatment or that only selected subgroups of patients will derive a benefit.

The major adverse reactions are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia [127]. There is apparently no myelotoxicity associated with the therapeutic use of cyclosporine. Many drugs interfere with the metabolism of cyclosporine. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

Nonsteroidal antiinflammatory agentsIbuprofen, indomethacin, or salicylates may help reduce acute inflammatory or constitutional symptoms of sarcoidosis (eg, arthritis and fever) but are not recommended for the treatment of pulmonary sarcoidosis.

Tetracyclines – Antibiotics in the tetracycline family (eg, doxycycline, minocycline) have been used to treat cutaneous sarcoidosis with variable effect [128]. There is insufficient evidence of benefit to use these agents for the treatment of pulmonary sarcoidosis. (See "Cutaneous manifestations of sarcoidosis".)

Thalidomide – Thalidomide has anti-tumor necrosis factor-alpha (TNF-a) activity and has been used to treat cutaneous sarcoidosis in a few patients [129,130]. However, it does not appear to be of benefit in pulmonary sarcoidosis [131]. In an open label study, 10 patients with pulmonary sarcoidosis dependent on glucocorticoids received thalidomide 200 mg/day for 24 weeks [131]. No significant improvement in dyspnea, pulmonary function, or quality of life occurred. A dose reduction was necessary in 9 of 10 patients due to side effects such as excess somnolence, constipation, and peripheral neuropathy.

Pentoxifylline – Pentoxifylline is a xanthine that has hemorheologic activity (improves blood flow), leading to its use in the treatment of vascular insufficiency. In addition, pentoxifylline inhibits the synthesis of TNF-a by alveolar macrophages from patients with sarcoidosis, potentially inhibiting the formation and maintenance of granulomas [132,133]. As a result, it has been postulated that pentoxifylline might have a beneficial clinical effect in patients with sarcoidosis; however, its use for this indication remains experimental.

In a preliminary study, 23 untreated patients with active sarcoidosis were treated with pentoxifylline; improvement was noted in 11 patients, while 7 patients remained stable and none deteriorated [134]. Three patients discontinued therapy because of gastrointestinal side effects. Three patients whose sarcoidosis was refractory to glucocorticoids had improvement following addition of pentoxifylline to the glucocorticoid regimen. In a separate trial, 27 patients with pulmonary sarcoidosis were randomly assigned to pentoxifylline with prednisone or prednisone alone; no benefit was found in pulmonary function parameters or dyspnea, although a post hoc analysis found a diminution in flares of sarcoidosis and in the prednisone usage with pentoxifylline [135].

The primary side effects of pentoxifylline are gastrointestinal, and are similar to those of other xanthine agents [134,135]. (See "Medical management of lower extremity chronic venous disease", section on 'Pentoxifylline'.)

Endothelin receptor antagonists – It has been proposed that the antifibrotic effect of the endothelin receptor antagonists might be beneficial in interstitial lung diseases with a fibrotic component. A trial to assess the efficacy of the endothelin receptor antagonist bosentan in patients with progressive pulmonary sarcoidosis with and without pulmonary hypertension was terminated due to difficulties with recruitment. A separate study of bosentan for sarcoidosis associated pulmonary hypertension is ongoing. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

PATIENT INFORMATION — 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)")


The majority of patients with pulmonary sarcoidosis either do not require treatment at all, or their disease responds well to systemic glucocorticoid therapy. However, progressive and disabling organ failure can occur in up to 10 percent of patients. For these patients, intensification of therapy with alternatives to glucocorticoids typically involves immunosuppressive agents. (See 'Introduction' above.)

Prior to intensifying therapy for pulmonary sarcoidosis, we investigate possible reasons for lack of clinical improvement during therapy with systemic glucocorticoids, such as noncompliance, comorbid disease, and end-stage fibrosis. (See 'Indications' above.)

All of the alternative agents for patients with refractory pulmonary sarcoidosis carry substantial risk for toxicity, particularly myelosuppression, hepatotoxicity, and opportunistic infection. Prior to initiating therapy with methotrexate (MTX), azathioprine, or leflunomide, baseline complete blood counts and serum aminotransferases, albumin, and creatinine are obtained. Assessment of hepatitis B or C infection is performed prior to MTX or leflunomide therapy. (See 'Methotrexate' above and 'Alternatives to methotrexate' above.)

Indications for alternative agents include lack of response to glucocorticoids, intolerable side effects of glucocorticoids, or inability to taper glucocorticoids below 10 to 15 mg/day in a patient with at least one documented adverse effect from glucocorticoid therapy. (See 'Indications' above and "Treatment of pulmonary sarcoidosis: Initial therapy with glucocorticoids".)

For patients with pulmonary sarcoidosis refractory to systemic glucocorticoids, we suggest addition of another immunosuppressive agent (Grade 2B); choices include MTX, azathioprine, leflunomide, and mycophenolate. MTX is usually the first choice due to a greater clinical experience in managing pulmonary sarcoidosis with this agent. If MTX is ineffective or not tolerated, we usually substitute one of the other agents for the methotrexate. In most instances, we continue low-dose glucocorticoids (0.25 mg/kg per day, usually less than 20 mg per day). (See 'Alternatives to methotrexate' above.)

For patients with active pulmonary sarcoidosis who need to discontinue glucocorticoids due to adverse effects, we suggest substitution of a second-line immunosuppressive agent for the glucocorticoid (Grade 2B); choices typically include MTX, azathioprine, leflunomide, and mycophenolate. (See 'Alternatives to methotrexate' above.)

For patients who do not respond to a trial of one or two of the second-line immunosuppressive agents given alone or in combination with glucocorticoids, the next step is either to combine two of the second-line immunosuppressive agents or to add a tumor necrosis factor-alpha (TNF-a) antagonist (eg, infliximab or adalimumab). The choice is usually guided by the individual patient's history of medication-related adverse effects, clinician experience with the agents, and patient preference. (See 'Combination therapy' above and 'Tumor necrosis factor-alpha antagonists' above.)

Prior to initiation of therapy with a TNF-a antagonist, patients are asked about risk factors for tuberculosis and are screened with a tuberculin skin test or peripheral blood interferon release assay. Patients are also asked about risk factors for hepatitis B and C and screened for these infections with testing for hepatitis B antigen (HBsAg), anti-hepatitis B core antibody (anti-HBc), and anti-hepatitis C antibody (anti-HCV). (See 'Tumor necrosis factor-alpha antagonists' above and "Interferon-gamma release assays for diagnosis of latent tuberculosis infection".)

Several medications proposed for pulmonary sarcoidosis are still considered experimental (eg, rituximab, golimumab, ustekinumab, antimycobacterial agents) or are used infrequently due to their side effect profile (eg, cyclophosphamide, hydroxychloroquine, chloroquine). (See 'Off-label investigational agents' above.)

Several medications proposed for use in pulmonary sarcoidosis are now avoided due to the lack of adequate supportive data or their adverse effect profile; these agents include colchicine, chlorambucil, cyclosporine, nonsteroidal antiinflammatory agents, tetracyclines, thalidomide, pentoxifylline, and endothelin receptor antagonists. (See 'Agents without clear benefit' above.)

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