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Treatment of pulmonary sarcoidosis refractory to initial therapy

Treatment of pulmonary sarcoidosis refractory to initial therapy
Author:
Daniel A Culver, DO, FCCP
Section Editor:
Kevin R Flaherty, MD, MS
Deputy Editor:
Paul Dieffenbach, MD
Literature review current through: Apr 2025. | This topic last updated: Jan 22, 2025.

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. Spontaneous resolution of the disease is common, but progressive and disabling organ failure can occur in up to 10 percent of patients.

For patients with sarcoidosis who cannot tolerate or do not respond to initial treatments, other immunosuppressive or immunomodulatory agents may be of benefit [1], although no medications other than prednisone and repository corticotropin have been approved by the US Food and Drug Administration (FDA) for the treatment of sarcoidosis [2-7]. Organ transplantation has been performed successfully for end-stage hepatic, renal, cardiac, and pulmonary sarcoidosis. Unfortunately, limited data exist regarding the indications and efficacy of these approaches in the pulmonary sarcoidosis management.

The conventional initial treatment for pulmonary sarcoidosis is oral glucocorticoid therapy, although patients with poor tolerance of or risk factors for toxicity from glucocorticoids may use an alternative agent, typically methotrexate. The treatment of pulmonary sarcoidosis that cannot be managed with initial therapeutic approaches will be reviewed here. The diagnosis and initial treatment of pulmonary sarcoidosis and the management of sarcoidosis affecting other organs are discussed separately.

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

●(See "Treatment of pulmonary sarcoidosis: Initial approach".)

●(See "Management and prognosis of cardiac sarcoidosis".)

●(See "Neurologic sarcoidosis".)

●(See "Kidney disease in sarcoidosis".)

●(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

●(See "Sarcoid arthritis" and "Sarcoidosis of bone" and "Sarcoid myopathy".)

●(See "Cutaneous sarcoidosis: Management".)

APPROACH — 

Progressive and disabling respiratory impairment complicates pulmonary sarcoidosis despite initial therapy in up to 10 percent of patients. For these patients, we suggest the addition of another immunosuppressive agent. Other patients may be intolerant of glucocorticoids and require glucocorticoid-sparing immunosuppressive therapy. Many of these patients may benefit from referral to a sarcoidosis center.

Typical reasons patients require alteration of therapy — Patients with sarcoidosis who may benefit from next-line therapies generally have one or more of the following features (see "Treatment of pulmonary sarcoidosis: Initial approach"):

●Progression of disease despite adequate initial therapy (eg, at least one month of either prednisone 20 mg daily or several months of methotrexate 10 to 15 mg weekly) [8].

●Intolerable side-effects of initial therapy. Typical glucocorticoid side effects include mood changes, insomnia, diabetes mellitus, weight gain, myopathy, and osteoporosis. Typical methotrexate side effects include nausea, fatigue, hepatic toxicity, and leukopenia.

●Need for a glucocorticoid-sparing agent in a patient who requires long-term glucocorticoid therapy.

Pretreatment assessment for those with progressive disease — Prior to intensifying therapy for pulmonary sarcoidosis, we investigate possible reasons for lack of clinical improvement, such as nonadherence with initial treatment, comorbid disease, and predominant fibrosis.

Nonadherence with glucocorticoid therapy is common due to the numerous side effects of this treatment [6]. Sometimes patients will admit on questioning that they have missed doses due to fear of 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, deconditioning, and weight gain) [9,10]. Testing typically includes repeat pulmonary function tests (PFTs), a noncontrast 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. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis" and "Chronic beryllium disease (berylliosis)", section on 'Risk factors'.)

Predominant lung fibrosis is not very responsive to immunosuppressive therapy, so it is essential 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. 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. Imaging with 18-F-fluorodeoxyglucose positron emission tomography (FDG-PET) can be helpful in differentiating active inflammation from fibrosis, however the published literature on the effect of using PET to make treatment decisions is small [11]. If it is uncertain whether the patient has end-stage fibrosis without active disease, we discuss the risks and benefits of a trial of 30 mg prednisone for a month or infliximab to ensure the patient does not have responsive disease in need of ongoing therapy. Patients with advanced lung disease may be candidates for lung transplantation. (See 'Lung transplantation' below.)

Agent selection — The European Respiratory Society Guideline for the treatment of sarcoidosis suggests using methotrexate, azathioprine, leflunomide, or mycophenolate as second-line therapy [12]. Methotrexate has the widest evidence base and is used most frequently. Still, the data comparing these agents are sparse, so the choice is usually based on specific patient preferences, comorbidities, and tolerance. Biologic antitumor necrosis factor agents, such as infliximab (and its biosimilars) and adalimumab, can be used when the second-line agents are not effective. Infliximab tends to work more quickly and convincingly for pulmonary sarcoidosis than adalimumab. The specific toxicities and ways to reduce their impact should be carefully reviewed with the patient.

MTX is the most frequently used second-line agent, although it cannot be used in patients with underlying liver disease (except for sarcoidosis-related liver enzyme elevations). 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-antagonist, usually infliximab or adalimumab. Combination therapy (eg, TNF inhibitor with MTX) has been used in rheumatoid arthritis and inflammatory bowel disease to improve efficacy and reduce the risk of developing antibodies to the TNF inhibitor, but it has not been formally evaluated in sarcoidosis. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

If a TNF-antagonist is contraindicated (eg, known viral hepatitis or aspergillus infection) or unsuccessful, the next steps are less clear, but may include agents like repository corticotropin, Janus kinase (JAK) inhibitors, rituximab, or interleukin-6 inhibitors [12]. (See 'Less common therapies' below.)

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

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 sarcoidosis", section on 'Ongoing monitoring'.)

Opportunistic infection risk — Opportunistic infectious complications (eg, pneumocystis, cryptococcosis, aspergillosis, mycobacterial) are rare in patients with sarcoidosis treated with MTX, azathioprine, leflunomide, and mycophenolate [9,13,14]. However, patients on a combination of glucocorticoids (≥20 mg daily) and another immunosuppressive agent (eg, MTX, azathioprine, leflunomide, TNF antagonist) do appear to be at some increased risk. 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 patients without HIV", section on 'Indications' and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

PATIENTS WHO PROGRESS ON OR DO NOT TOLERATE GLUCOCORTICOIDS

Preferred option: Methotrexate — Methotrexate (MTX), an antimetabolite with both immunosuppressive and anti-inflammatory properties, is the most commonly used nonglucocorticoid immunosuppressive agent for sarcoidosis [15]. 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 "Chronic plaque psoriasis in adults: Treatment of disease requiring phototherapy or systemic therapy", section on 'Methotrexate'.)

Alternatives to methotrexate, for those who are not candidates or prefer other options, are discussed below. (See 'Patients who progress on or cannot use methotrexate' below.)

Pretreatment preparation and contraindications — Prior to initiating MTX, complete blood counts (CBC), albumin, aminotransferases, alkaline phosphatase, bilirubin, and creatinine should be obtained. Patients with risk factors should undergo testing for hepatitis B and C (ie, HBsAg, anti-HBc, anti-HCV). 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 [16]. Patients with liver enzyme elevations from sarcoidosis can be treated with methotrexate [17]. A creatinine clearance less than 30 mL/min is considered a contraindication for methotrexate in patients with rheumatoid arthritis [16] (see "Use of methotrexate in the treatment of rheumatoid arthritis"). Methotrexate metabolites can accumulate in pleural effusions and ascites, increasing the risk of toxicity. Therefore, the presence of pleural effusions or ascites is considered a relative contraindication to methotrexate therapy.

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 [15]. Reliable contraception is required for anyone taking methotrexate who could become pregnant. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)

Dosage and administration — MTX can be administered either orally or intradermally. We typically begin therapy at a dose of 5 to 7.5 mg weekly. The dose is increased (eg, by increments of 2.5 mg every two weeks) until a dose of 10 to 15 mg per week is achieved [15,17,18]. Parenteral administration achieves more reliable systemic effects with fewer side effects; for this reason, we use parenteral (subcutaneous) dosing in most patients. A trial of MTX therapy should last at least six months to allow adequate assessment of effectiveness. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Assessing response to therapy'.)

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 [15]. A routine peripheral blood count is obtained every four to eight weeks [16] during dose escalation and every three months thereafter.

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 three months [15].

If ALT/AST increases without other clear cause, the methotrexate dose should be decreased or the drug stopped [15]. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

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 [6]. 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 [19]. (See "Major adverse effects of low-dose methotrexate" and "Methotrexate-induced lung injury", section on 'Clinical manifestations' and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

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 [20]. Toxic reactions to MTX eventually developed in 10 percent of patients treated for more than two years. (See "Evaluation of the adult patient with hepatic granuloma", section on 'Sarcoidosis'.)

Methotrexate pulmonary toxicity can occur but is rare; nonetheless, it is important for clinicians prescribing MTX to be aware of the possibility. 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 [21-23]. 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, fatigue, headache, alopecia, and skin rash [6]. MTX is known to be teratogenic and may transiently suppress gonadal function. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Chronic MTX treatment has been associated with the development of lymphoproliferative disorders, some of which regress after discontinuation of MTX [24,25]. It is not known whether MTX had an etiologic role in the development of the lymphoproliferative disease, or whether the underlying inflammatory condition is the sole contributor. (See "Malignancy and rheumatic disorders", section on 'Antirheumatic medications and risk of malignancy'.)

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 [18,19,26-33]. As an example, 24 patients with recent-onset pulmonary sarcoidosis were randomly assigned to low-dose MTX plus glucocorticoids or glucocorticoids alone [18]. 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 in approximately two-thirds of patients with pulmonary sarcoidosis [6,19].

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 [34]. No significant differences in efficacy were noted between the two treatments.

PATIENTS WHO PROGRESS ON OR CANNOT USE METHOTREXATE — 

A variety of immunosuppressive agents have been used to treat pulmonary sarcoidosis that is insufficiently controlled with glucocorticoids. The evidence in support of individual second-line agents is largely observational [35,36].

Azathioprine — Azathioprine is used as second-line therapy for pulmonary sarcoidosis, generally as a supplement to glucocorticoids rather than as a single drug [2,32,37-43]. Due to the greater clinical experience with methotrexate (MTX), azathioprine is usually used in patients who are not appropriate for MTX due to side effects or lack of benefit. The exact mechanism by which azathioprine might affect sarcoidosis is not clear.

●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) [44]. 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 of these tests before initiating azathioprine therapy. In settings where testing is not readily available, an alternative approach is to obtain frequent (eg, every two weeks) complete blood counts (CBCs) during the first months of 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 "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity' and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

Baseline CBCs and serum albumin, aminotransferases, and creatinine should be obtained in all patients.

Although not recommended by the manufacturer for pregnant patients, azathioprine is considered "generally safe" in pregnancy and during breastfeeding. However, adverse events have been reported, including intrahepatic cholestasis. We recommend caution and informed consent regarding azathioprine use in patients who may become pregnant. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine'.)

●Dosing and administration – The usual starting dose of azathioprine is 50 mg per day, given as a single daily oral dose; 25 mg per day may be used initially if TPMT is not assessed. To reduce the likelihood of gastrointestinal side effects, the dose is slowly increased by 50 mg every two to four weeks until the desired dose is reached. The typical maintenance dose is 2 mg/kg per day (up to a maximum of 200 mg/day), unless the patient has renal insufficiency or an adverse effect necessitating a lower dose. We reduce the azathioprine dose if the white blood cell count decreases to ≤4000/microL or the platelet count to ≤150,000/microL. 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", section on 'Dose titration and monitoring'.)

A CBC (including hemoglobin, white blood cell count, and platelet count) should be monitored after the first two weeks, then every two weeks during dose escalation, and every three months 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 azathioprine toxicity' and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults 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. Infection is a known complication of azathioprine therapy [34]. An increased risk of subsequent malignancy has been reported in renal transplant patients who are treated with both azathioprine and prednisone. Azathioprine has also been associated with an increased risk of leukemia and myelodysplasia in older patients [45]. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

●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 [41]. 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 [39]. In contrast, a retrospective case review found a benefit in only 2 of 10 patients [43].

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 [34]. (See 'Efficacy' above.)

Leflunomide — Leflunomide is an antimetabolite that blocks lymphocyte proliferation but exhibits less gastrointestinal toxicity than MTX.

●Pretreatment preparation – Prior to initiating leflunomide therapy, complete blood counts, albumin, aminotransferases, creatinine are obtained [16]. 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.

All patients should use a reliable method of contraception during leflunomide therapy and for up to two years afterwards if they or their partner could become pregnant, unless they follow a cholestyramine clearance regimen. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Leflunomide'.)

●Dosing 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 [46]. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Pharmacokinetics, drug elimination, and genetic factors'.)

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 diarrhea, abdominal pain, hepatotoxicity, hypertension, and peripheral neuropathy [47,48]. This risk of hepatotoxicity appears higher among patients with underlying liver disease (eg, alcohol-associated steatosis or cirrhosis, 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 [49,50]. However, testing for these genotypes is not clinically available. Leflunomide is relatively contraindicated in patients at risk for neuropathy (eg, poorly controlled diabetes). (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 [16]. 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'.)

●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 [46,51,52]. In a retrospective case series, 32 patients received leflunomide with or without concomitant MTX for pulmonary or ocular sarcoidosis [46]. 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 [52]. He had been intolerant of MTX, but tolerated leflunomide without side effects.

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 sarcoidosis 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 [53-55]:

●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) [53]. 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 [54]. 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 [56-59]. In a case report, cutaneous and bone marrow sarcoidosis that were refractory to glucocorticoids and MMF responded to a combination of MMF and methotrexate [60]. (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 it may still 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 [61]. 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 [46]. If the patient’s condition worsens or toxic effects develop, the clinician may introduce a third-choice therapeutic option, as described below [62].

PATIENTS WITH DISEASE REFRACTORY TO THE ABOVE AGENTS — 

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 biologic tumor necrosis factor (TNF) antagonist. Other alternatives include entering a clinical trial or using an investigational agent, as described below. (See 'Less common therapies' below.)

Tumor necrosis factor antagonists — For patients whose disease is refractory to the above agents, the next step is typically a TNF antagonist. The cytokine TNF is critical for granuloma maintenance and is thought to accelerate the inflammatory process in sarcoidosis. Thus, using agents that block the effect of TNF may be beneficial. Due to the potential toxicity of these agents, we reserve them (in pulmonary sarcoidosis) 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) [5,63,64].

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

●Infliximab – Infliximab is a chimeric, humanized monoclonal antibody that neutralizes TNF. It has been studied in patients with pulmonary and extrapulmonary sarcoidosis refractory to glucocorticoid therapy [65-71]. 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 [69]. 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 [69,72]. 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 [73]. 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 [71]. Because steroids were not tapered during this trial, the steroid-sparing capacity of IFX was not analyzed, but it is likely more meaningful than the small median change in FVC suggests.

●Adalimumab – Adalimumab is a fully human anti-TNF antibody. A few case reports and small case series have described improvement in extrapulmonary sarcoidosis with adalimumab [74-78]. 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 [79]. One patient developed a lupus-like syndrome, three had severe infections, and seven had mild infections. Overall, the effect of adalimumab on pulmonary sarcoidosis is less noticeable and slower than that for infliximab. However, it has the advantage of subcutaneous, rather than intravenous, administration and a lower propensity to develop antidrug antibodies.

●Etanercept – Etanercept is a soluble TNF-a receptor fusion protein that binds TNF 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 pulmonary sarcoidosis (table 1). The trial was stopped after the enrollment of 17 patients, when interval assessment noted treatment failure in 11 participants [80]. 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 [81]. On the basis of these results, larger trials of this agent for progressive pulmonary sarcoidosis do not appear indicated.

Pretreatment preparation — Therapy with TNF 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 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), an interferon release assay can help to differentiate between tuberculosis infection and BCG vaccination. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors", section on 'Screening' and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

Flares of hepatitis B have been documented with infliximab therapy; progression of hepatitis C has rarely been reported with TNF 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'.)

Dosing and administration — Infliximab is administered by intravenous infusion of 3 to 5 mg/kg at weeks 0, 2, 6, and 10 [68-70,82]. The bulk of physiologic benefits for pulmonary sarcoidosis are seen within the first three months [70]. The optimal frequency for subsequent dosing in those with a positive response is not known; in clinical practice, we usually dose patients every four to six weeks, with attempts to space out infusions in those with stability. 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 [83]. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

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 published in case reports [74-76,84]. In other inflammatory conditions, the usual dose is 40 mg every other week; sometimes an initial dose of 80 to 160 mg (given as four injections over 24 hours) is used.

Combination with other agents — The combination of infliximab (or another TNF inhibitor) with MTX, azathioprine, or leflunomide 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 second-line agent to prevent antibody formation. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Adverse effects — The major adverse effects associated with the TNF 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 [65-68,70]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

The development of noncaseating granulomas consistent with sarcoidosis has been reported during anti-TNF therapy for other diseases [85-88]. Granulomas have occurred in the skin, lungs, and lymph nodes. The sarcoid-like disease manifestations have typically resolved with cessation of anti-TNF therapy, although some patients have also received glucocorticoid therapy.

LESS COMMON THERAPIES — 

Several medications have been proposed for use in pulmonary sarcoidosis based on their mechanism of action and small case series but are not commonly used due to lack of adequate data or their side effect profile.

Repository corticotropin — Repository corticotrophin (RCI) was approved by the FDA for symptomatic pulmonary sarcoidosis in 1952 but was not subjected to randomized placebo-controlled trials prior to approval, so the relative benefit of RCI remains unclear. RCI formulations target melanocortin receptors (MCR), found on multiple immune cells, as well as the adrenal cortex, but only MCR2 stimulates cortisol production. The relative contributions of other MCR (nonglucocorticoid receptor agonists) to the anti-inflammatory properties of RCI in sarcoidosis are unknown.

In a phase 4 trial, RCI 80 units or placebo was administered to 55 participants with steroid-requiring pulmonary sarcoidosis twice weekly [89]. Treatment with RCI was associated with a nonsignificant trend toward improvement of the Sarcoidosis Therapeutic Score, an amalgam of pulmonary function tests, patient-reported outcomes, change in CT scan, and ability to taper steroids. The trends favoring RCI were not maintained over the 24-week open-label extension period. The incremental benefit from RCI compared with conventional glucocorticoids is uncertain based on these data. A trial of RCI may be considered in patients refractory to other agents. Besides the typical side effects that can be seen with glucocorticoids, RCI therapy is associated with fluid retention through its effect on the adrenal cortex; aldosterone receptor antagonists like spironolactone are effective in managing this complication.

JAK inhibitors — Janus kinase (JAK) inhibitors, such as tofacitinib, have been reported in case series for patients with refractory pulmonary, neurologic, and cutaneous sarcoidosis. Inhibition of JAK-activated STAT signaling is theoretically attractive, since interferon-mediated immunity through the JAK-STAT pathway is a central feature of sarcoidosis inflammation [90-95]. The risks of side effects and infections appear to be similar to other nonsteroid immunosuppressive medications, but there are some data suggesting an increased risk of venous thromboembolism [96].

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 [97-100]. Further study is needed to determine whether rituximab is beneficial in refractory sarcoidosis.

Tocilizumab — Tocilizumab is a humanized interleukin (IL)-6 receptor antibody approved for use in rheumatoid arthritis. In a case series of four patients with pulmonary sarcoidosis refractory to prednisone and other immunosuppressive agents, tocilizumab was associated with improvement in symptoms and, in some cases, pulmonary function tests [101]. Of note, development of sarcoidosis (mediastinal and hilar lymphadenopathy and cutaneous nodules) has been reported in patients with rheumatoid arthritis being treated with tocilizumab [102,103].

mTOR inhibitors — Myeloid-specific conditional deletion of TSC2, which leads to unchecked mammalian target of rapamycin (mTOR) activity, triggers a multisystem granulomatous disorder in mice, and mTOR-downstream pathways are upregulated in patients with progressive sarcoidosis [104]. A single-center cross-over trial of 16 patients with chronic refractory cutaneous sarcoidosis suggested durable benefits from oral but not topical sirolimus [105]. The efficacy of mTOR inhibitors for pulmonary and other forms of sarcoidosis has not yet been carefully evaluated. Given the toxicities of systemic mTOR inhibitors, we suggest use of them should be restricted to experienced centers and only for patients who have failed multiple other agents.

Antifibrotic therapies — Nintedanib reduces disease progression in fibrotic interstitial lung disease when immunosuppressive agents have failed [106]. The major trial assessing this, INBUILD, did not separately evaluate sarcoidosis patients, but the "other" category included a minority of sarcoidosis patients. Outcomes of nintedanib were similar across diagnostic subgroups, including "other" [107]. The effectiveness of nintedanib for preventing progressive fibrosis is uncertain in sarcoidosis. In some patients, disease progression is very indolent, even when fibrosis is extensive; these patients typically do not meet criteria for progressive pulmonary fibrosis (see "Overview of the management of adults with interstitial lung disease", section on 'Patients with progressive fibrotic changes or worsening restriction'). In others, there is residual underlying inflammation that should be targeted prior to considering antifibrotic therapy. In our practice, we reserve a trial of nintedanib for patients with predominantly fibrotic disease that is progressive despite attempts to control it with immunosuppression. Initiating nintedanib is done in the context of a patient-centered discussion about the uncertainties of benefit and the prospects for toxicity. Dosing and administration are similar to that used in idiopathic pulmonary fibrosis. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration'.)

Pirfenidone has been studied in a small (n = 15) randomized-controlled trial [108] which was too under-enrolled to have adequate power to comment on the role of pirfenidone in sarcoidosis.

Clinical trials — Patients with disease refractory to multiple agents are appropriate for enrollment in clinical trials. Information about clinical trials of therapies for pulmonary sarcoidosis can be found at Clinicaltrials.gov.

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 [10,109,110]. 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 [111-114]. (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 [115,116]. (See "Lung transplantation: General guidelines for recipient selection".)

Bilateral lung transplantation appears to be associated with slightly better survival than single lung transplantation [114]. When deciding between a single or bilateral lung transplantation, the presence of a mycetoma or significant bronchiectasis may necessitate a bilateral lung procedure [111]. In addition, patients with mycetomas may require specific, individualized antifungal therapy [117,118]. 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 [111,119]. (See "Lung transplantation: General guidelines for recipient selection", section on 'Cystic fibrosis and bronchiectasis' and "Management and prognosis of cardiac sarcoidosis", section on 'Approach to management'.)

Following lung transplantation, asymptomatic foci of noncaseating granulomas, suggestive of recurrent disease, have been identified in the allografts of sarcoidosis patients [120-124]. 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 [109,110,113,122].

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 [113,121,122,124,125].

AGENTS WITHOUT CLEAR BENEFIT — 

Several medications have been historically proposed for use in pulmonary sarcoidosis, but are not currently suggested as fourth-line therapy in modern guidelines. Examples include cyclophosphamide, chlorambucil, thalidomide, antimalarial agents, cyclosporine, and pentoxifylline.

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".)

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)")

SUMMARY AND RECOMMENDATIONS

●Indications for altering therapy – 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 despite initial therapy can occur in up to 10 percent of patients, and some patients do not tolerate initial immunosuppressant regimens. Additionally, the long-term toxicity of chronic steroid use is increasingly recognized as an indication to use other agents. For these patients, changes in treatment approach are needed. (See 'Introduction' above and 'Typical reasons patients require alteration of therapy' above.)

●Pretreatment assessment – Prior to intensifying therapy for progression of pulmonary sarcoidosis, we investigate possible reasons for lack of clinical improvement during initial therapy, such as nonadherence, comorbid disease, and end-stage fibrosis. (See 'Pretreatment assessment for those with progressive disease' above.)

●Patients who progress on or do not tolerate glucocorticoids

•For patients with pulmonary sarcoidosis refractory to systemic glucocorticoids, we suggest the addition of methotrexate (Grade 2C). In most instances, we initially continue low-dose glucocorticoids (0.25 mg/kg per day, usually less than 20 mg per day). (See 'Patients who progress on or do not tolerate glucocorticoids' above.)

•For patients with active pulmonary sarcoidosis who need to discontinue glucocorticoids due to adverse effects, we suggest substitution with methotrexate (Grade 2C). (See 'Patients who progress on or do not tolerate glucocorticoids' above.)

●Patients who progress on or are not candidates for methotrexate – For patients who progress on or cannot use methotrexate, we suggest azathioprine, leflunomide, or mycophenolate rather than other options (Grade 2C). The choice of therapy should include thiopurine methyltransferase (TPMT) level and other individual patient factors associated with potential toxicities of these agents. (See 'Patients who progress on or cannot use methotrexate' above.)

●Later line therapy

•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 (TNF) 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 antagonists' above.)

•Several additional immunosuppressants have been used to treat sarcoidosis refractory to other agents, but clinical experience is limited (eg, repository corticotropin, Janus kinase [JAK] inhibitors, rituximab, tocilizumab, mammalian target of rapamycin [mTOR] antagonists, nintedanib).(See 'Less common therapies' above.)

•Patients with advanced pulmonary fibrosis or severe pulmonary hypertension associated with sarcoidosis may be appropriate candidates for lung transplantation. We refer patients with stage IV radiographic disease (table 1) or World Health Organization class III or IV pulmonary hypertension (table 2). (See 'Lung transplantation' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Talmadge E King, Jr, MD, who contributed to earlier versions of this topic review.

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  87. Daïen CI, Monnier A, Claudepierre P, et al. Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford) 2009; 48:883.
  88. Toussirot E, Berthelot JM, Pertuiset E, et al. Pulmonary nodulosis and aseptic granulomatous lung disease occurring in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha-blocking agent: a case series. J Rheumatol 2009; 36:2421.
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  117. Hadjiliadis D, Sporn TA, Perfect JR, et al. Outcome of lung transplantation in patients with mycetomas. Chest 2002; 121:128.
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Topic 4325 Version 36.0

References

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2 : Pulmonary sarcoidosis.

3 : Pulmonary sarcoidosis and corticosteroids.

4 : Corticosteroids in sarcoidosis: friend or foe?

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8 : Refractory pulmonary sarcoidosis - proposal of a definition and recommendations for the diagnostic and therapeutic approach.

9 : Fungal infections as a complication of therapy for sarcoidosis.

10 : Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation.

11 : 18F-FDG PET as a predictor of pulmonary function in sarcoidosis.

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13 : [Opportunistic infections and sarcoidosis].

14 : The spectrum of opportunistic diseases complicating sarcoidosis.

15 : Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide.

16 : American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.

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18 : Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.

19 : Prolonged use of methotrexate for sarcoidosis.

20 : Role of liver function tests in detecting methotrexate-induced liver damage in sarcoidosis.

21 : Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis.

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23 : Variation of immunological response in methotrexate-induced pneumonitis.

24 : Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate.

25 : Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication.

26 : Spontaneous remission or response to methotrexate in sarcoidosis.

27 : Invasive nasal sarcoidosis treated with methotrexate.

28 : The use of low dose methotrexate in refractory sarcoidosis.

29 : Weekly low-dose methotrexate therapy for sarcoidosis.

30 : Laryngeal and cutaneous sarcoidosis treated with methotrexate.

31 : Low-dose methotrexate: an effective corticosteroid-sparing agent in the musculoskeletal manifestations of sarcoidosis.

32 : Therapeutic considerations in patients with refractory neurosarcoidosis.

33 : The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis.

34 : Methotrexate vs azathioprine in second-line therapy of sarcoidosis.

35 : Immunosuppressive and cytotoxic therapy for pulmonary sarcoidosis.

36 : Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.

37 : Sarcoidosis of the anterior visual pathway: successes and failures.

38 : Neurosarcoidosis. A report of 5 cases.

39 : Azathioprine treatment of chronic pulmonary sarcoidosis.

40 : VIIIth cranial nerve involvement in sarcoidosis.

41 : Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen.

42 : Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society.

43 : Efficacy of azathioprine as second-line treatment in pulmonary sarcoidosis.

44 : Relevance of pharmacogenetic aspects of mercaptopurine metabolism in the treatment of interstitial lung disease.

45 : Increased risk of acute myeloid leukemias and myelodysplastic syndromes in patients who received thiopurine treatment for inflammatory bowel disease.

46 : Leflunomide for chronic sarcoidosis.

47 : A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.

48 : Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports.

49 : Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients.

50 : Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis.

51 : A 50-year-old man with stage 2 sarcoidosis with pleural involvement.

52 : Successful treatment of sarcoidosis with leflunomide.

53 : Efficacy of mycophenolate mofetil in sarcoidosis.

54 : Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study.

55 : Mycophenolate mofetil as an alternative treatment in sarcoidosis.

56 : Successful steroid-sparing treatment of renal limited sarcoidosis with mycophenolate mofetil.

57 : Mycophenolate mofetil may serve as a steroid-sparing agent for sarcoidosis.

58 : Presentations and outcomes of neurosarcoidosis: a study of 54 cases.

59 : Experience of mycophenolate mofetil in 10 patients with autoimmune-related interstitial lung disease demonstrates promising effects.

60 : Sarcoidal anemia and leukopenia treated with methotrexate and mycophenolate mofetil.

61 : Combination therapy for sarcoidosis.

62 : Knowing when to use steroids, immunosuppressants or biologics for the treatment of sarcoidosis.

63 : Inhibitors of tumor necrosis factor (TNF) in sarcoidosis: who, what, and how to use them.

64 : Cytokine modulators in the treatment of sarcoidosis.

65 : Tumour necrosis factor alpha inhibitor treatment for sarcoidosis refractory to conventional treatments: a report of five patients.

66 : Successful tumor necrosis factor alpha blockade treatment in therapy-resistant sarcoidosis.

67 : Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy.

68 : Infliximab for refractory sarcoidosis.

69 : Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.

70 : A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis.

71 : Long-term treatment with infliximab in patients with sarcoidosis.

72 : Infliximab in sarcoidosis: more answers or more questions?

73 : Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial.

74 : Recalcitrant cutaneous sarcoidosis responding to adalimumab but not to etanercept.

75 : Systemic sarcoidosis with bone marrow involvement responding to therapy with adalimumab: a case report.

76 : Adalimumab for treatment of cutaneous sarcoidosis.

77 : Using TNF-alpha antagonist adalimumab for treatment for multisystem sarcoidosis: a case study.

78 : Effect of the TNF-αinhibitor adalimumab in patients with recalcitrant sarcoidosis: a prospective observational study using FDG-PET.

79 : Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab.

80 : Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis.

81 : Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial.

82 : The CD4+ lymphopenic sarcoidosis phenotype is highly responsive to anti-tumor necrosis factor-{alpha} therapy.

83 : Assessment of anti-TNF-alpha efficacy in rheumatoid arthritis: is 3 months sufficient?

84 : Adalimumab for refractory pulmonary sarcoidosis.

85 : Development of sarcoidosis following etanercept treatment: a report of three cases.

86 : Cutaneous sarcoidosis occurring during anti-TNF-alpha treatment: report of two cases.

87 : Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases.

88 : Pulmonary nodulosis and aseptic granulomatous lung disease occurring in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha-blocking agent: a case series.

89 : Results From a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Repository Corticotropin Injection for the Treatment of Pulmonary Sarcoidosis.

90 : Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.

91 : Tofacitinib for cutaneous and pulmonary sarcoidosis: A case series.

92 : Tofacitinib as a Steroid-Sparing Therapy in Pulmonary Sarcoidosis, an Open-Label Prospective Proof-of-Concept Study.

93 : Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis.

94 : Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis.

95 : Hypothesis: sarcoidosis is a STAT1-mediated disease.

96 : Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

97 : Successful use of rituximab in refractory cardiac sarcoidosis.

98 : Rituximab in refractory sarcoidosis: a single centre experience.

99 : Rituximab in the treatment of refractory pulmonary sarcoidosis.

100 : Successful treatment of ocular sarcoidosis with rituximab.

101 : Tocilizumab in sarcoidosis patients failing steroid sparing therapies and anti-TNF agents.

102 : Sarcoidosis induced by tocilizumab: a paradoxical event?

103 : Cutaneous sarcoidosis in a patient with rheumatoid arthritis receiving tocilizumab.

104 : Principles and descriptions of design of skin flaps for use on the lower extremity.

105 : Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial.

106 : Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.

107 : Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.

108 : Pirfenidone for Progressive Fibrotic Sarcoidosis (PIRFS): Results of a Double Blind Placebo Controlled Pilot Study

109 : Lung transplantation for pulmonary sarcoidosis.

110 : Lung transplantation for end-stage pulmonary sarcoidosis: outcome in a series of seven consecutive patients.

111 : Sarcoidosis, race, and short-term outcomes following lung transplantation.

112 : Lung transplantation in sarcoidosis.

113 : Bronchiolitis obliterans syndrome and survival following lung transplantation for patients with sarcoidosis.

114 : Lung transplantation for pulmonary sarcoidosis. Twenty-five years of experience in the USA.

115 : Predicting mortality in patients with sarcoidosis awaiting lung transplantation.

116 : Predicting respiratory failure in sarcoidosis patients.

117 : Outcome of lung transplantation in patients with mycetomas.

118 : Impact of mold infections in explanted lungs on outcomes of lung transplantation.

119 : Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients.

120 : Transplantation of the lungs and heart and lung for patients with severe pulmonary complications from sarcoidosis.

121 : Recurrence of sarcoidosis in pulmonary allograft recipients.

122 : Single lung transplantation as treatment for end-stage pulmonary sarcoidosis: recurrence of sarcoidosis in two different lung allografts in one patient.

123 : Recurrence of sarcoidosis in a human lung allograft.

124 : Sarcoidosis: recurrence of primary disease in transplanted lungs.

125 : Lung transplant outcomes in white and African American recipients: special focus on acute and chronic rejection.