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Corticosteroid refractory sarcoidosis

Open ArchivePublished:July 03, 2020DOI:https://doi.org/10.1016/j.rmed.2020.106081

      Highlights

      • True corticosteroid failure is a rare occurrence. True corticosteroid failure is extremely rare with pulmonary sarcoidosis and is most commonly seen with cardiac sarcoidosis, neurosarcoidosis and the lupus pernio form of skin sarcoidosis.
      • Corticosteroid failure most commonly is the result of corticosteroid toxicity or concern of the risk of developing corticosteroid toxicity. The clinician should carefully monitor for the development of corticosteroid toxicity in all patients receiving these medications.
      • Corticosteroid failure commonly occurs when the sarcoidosis patient's symptoms or organ dysfunction is unrelated to granulomatous inflammation from sarcoidosis. This may occur from parasarcoidosis syndromes that do not typically respond to corticosteroids such as small fiber neuropathy, fibrosis from previously active sarcoidosis, or medical conditions completely unrelated to sarcoidosis.

      Abstract

      A sarcoidosis patient may be refractory to corticosteroid therapy. This may be because corticosteroids are ineffective in relieving the sarcoidosis patient's symptoms/dysfunction or because the clinician has determined that the risks of corticosteroids outweigh their benefits. Interestingly, when corticosteroids truly fail to improve a sarcoidosis patient's condition, it is very rarely because of failure of the drug as an anti-granulomatous agent; rather, it is usually because the patient's symptoms were unrelated to active sarcoid granulomas. In this manuscript, we review the causes of corticosteroid refractory sarcoidosis. The clinician should consider these causes when confronted with a sarcoidosis patient who is either not responding to corticosteroids, developing corticosteroid side-effects, or is at significant risk of developing such side-effects. We believe that determining the cause of corticosteroid refractory sarcoidosis may aid the clinicians in optimizing the care of sarcoidosis patients and clinical researchers in appropriately stratifying patients for clinical trials.

      Keywords

      1. Introduction

      Sarcoidosis is a granulomatous disease of unknown cause that may affect any organ. The course of the disease is variable, ranging from an asymptomatic state to a potentially life-threatening condition. Treatment of sarcoidosis is not universally indicated because the disease may not cause symptoms, significant quality of life impairment or permanent organ injury. The indications for sarcoidosis treatment can usually be distilled down to two: a) of potential or actual danger or b) significant quality of life impairment [
      • Baughman R.P.
      • Judson M.A.
      • Wells A.U.
      The indications for the treatment of sarcoidosis : well's Law.
      ]. When therapy for sarcoidosis is indicated, corticosteroids are usually the initial drugs of choice because they work more reliably and more rapidly than all other alterative agents [
      • Judson M.A.
      Corticosteroids in sarcoidosis.
      ]. However, because corticosteroids are associated with numerous impactful side-effects, alternative therapies that are corticosteroid-sparing or corticosteroid-replacing are often required. In this manuscript, we will explore the various criteria that clinicians have used to define sarcoidosis as “refractory to corticosteroids” such that additional or alternative medications should be considered. Understanding these criteria will provide the clinician with insight concerning when treatment of sarcoidosis solely with corticosteroids may be inappropriate or inadequate.

      2. True corticosteroid failure

      Refractory sarcoidosis may imply true corticosteroid failure where the granulomatous inflammation of sarcoidosis is unresponsive to corticosteroid therapy. True corticosteroid failure is rare with sarcoidosis. At daily prednisone doses of greater than 30 mg, it is unusual to observe evidence of appreciable granulomatous inflammation. This is particularly true for pulmonary sarcoidosis, where in one series, all 36 patients with an acute exacerbation of pulmonary sarcoidosis had a return of spirometry and symptoms to baseline after a median of 3 weeks of prednisone at a dose of 20 mg/day [
      • McKinzie B.P.
      • Bullington W.M.
      • Mazur J.E.
      • et al.
      Efficacy of short-course, low-dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations.
      ]. True corticosteroid failure is more common with the lupus pernio form of skin sarcoidosis [
      • Stagaki E.
      • Mountford W.K.
      • Lackland D.T.
      • et al.
      The treatment of lupus pernio: results of 116 treatment courses in 54 patients.
      ], neurosarcoidosis [
      • Sodhi M.
      • Pearson K.
      • White E.S.
      • et al.
      Infliximab therapy rescues cyclophosphamide failure in severe central nervous system sarcoidosis.
      ,
      • Lower E.E.
      • Broderick J.P.
      • Brott T.G.
      • et al.
      Diagnosis and management of neurological sarcoidosis.
      ], and cardiac sarcoidosis [
      • Kikuchi N.
      • Nunoda S.
      • Serizawa N.
      • et al.
      Combination therapy with corticosteroid and mycophenolate mofetil in a case of refractory cardiac sarcoidosis.
      ,
      • Theodore J.
      • Saggu D.K.
      • Yalagudri S.
      • et al.
      Management of refractory ventricular tachycardia due to cardiac sarcoidosis-A biologic approach.
      ,
      • Okada D.R.
      • Assis F.R.
      • Gilotra N.A.
      • et al.
      Cardiac sympathectomy for refractory ventricular arrhythmias in cardiac sarcoidosis.
      ,
      • Shelke A.B.
      • Aurangabadkar H.U.
      • Bradfield J.S.
      • et al.
      Serial FDG-PET scans help to identify steroid resistance in cardiac sarcoidosis.
      ].
      As is implied above, true corticosteroid failure appears to be somewhat organ dependent. It is unknown if this is because the immune mechanisms involved in sarcoidosis in various organs are different, which has been previously suggested [
      • Monast C.S.
      • Li K.
      • Judson M.A.
      • et al.
      Sarcoidosis extent relates to molecular variability.
      ], or if this relates to differences in the local concentration of corticosteroid drug in various organs [
      • Ramamoorthy S.
      • Cidlowski J.A.
      Corticosteroids: mechanisms of action in health and disease.
      ]. True corticosteroid failure may also be the result of molecular mechanisms that lead to corticosteroid resistance that has been demonstrated in asthma and chronic obstructive disease patients who have been found to be refractory to corticosteroid therapy [
      • Barnes P.J.
      Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.
      ]. However, a molecular basis for corticosteroid resistance has yet to be demonstrated in sarcoidosis patients.
      True corticosteroid failure could be confirmed by demonstrating active granulomatous inflammation from sarcoidosis causing symptoms or significant organ dysfunction in a patient on at least 30 mg/day of daily prednisone equivalent. Demonstration of granulomatous inflammation could be determined on a tissue biopsy or via a biomarker of granulomatous inflammation (Table 1). Confirmation of true corticosteroid failure in a sarcoidosis patient is clinically relevant, as it mandates a trial of other interventions to control the disease. We believe that in patients receiving at least 30 mg/day of prednisone, the presence of granulomatous inflammation alone without the presence of significant symptoms or organ dysfunction is inadequate to be classified as corticosteroid failure, as subclinical granulomatous inflammation may cause no symptoms, worsening organ dysfunction, or fibrosis. Admittedly, such a patient would be at risk of developing symptomatic sarcoidosis as the corticosteroid dose is tapered.
      Table 1Evidence of active granulomatous inflammation from sarcoidosis.
      EvidenceReliability in reflecting active granulomatous inflammation from sarcoidosisPositive featuresNegative features
      The presence of symptoms of sarcoidosis organ involvement - cough, dyspnea, eye symptoms, worsening skin lesions++Focuses on issues important to patientsSymptoms are not highly sensitive or specific for acute sarcoidosis. They may represent alternative conditions or permanent fibrotic change from previously active sarcoidosis.
      Serum biomarkers (angiotensin-converting enzyme; serum IL-2 receptor; chitotriosidase)++Quantifiable. Directly reflect the total body granuloma burdenNot highly specific or sensitive
      Tissue biopsy demonstrating granulomatous inflammation++++Highly specificCumbersome and relatively invasive; although highly specific granulomas could be from an alternative cause
      Changes in imaging consistent with worsening granulomatous inflammation++Certain radiographic findings are highly specific for active lung inflammation.Often insensitive to significant change, especially in the case of chest radiographs. Chest CT scans pose a significant radiation risk
      Positive FDG uptake on PET scan+++Specifically reflects active lung inflammationMay be alternative causes for the positive findings besides sarcoidosis
      ++: good; +++: very good: ++++excellent; CT: computed tomography; PET: positron emission tomography scan; FDG: fluorodeoxyglucose.

      3. Corticosteroid failure because of corticosteroid side effects

      Corticosteroids are associated with numerous significant side effects including weight gain, edema, diabetes, hypertension, cataract formation, glaucoma, acne, osteoporosis, increased risk of infection, and mood changes. Because a large percentage of sarcoidosis patients have chronic disease [
      • Baughman R.P.
      • Nagai S.
      • Balter M.
      • et al.
      Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
      ], corticosteroid therapy is often prolonged [
      • Baughman R.P.
      • Nagai S.
      • Balter M.
      • et al.
      Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
      ], which increases the risk and severity of these potential side effects. Therefore, it is not unexpected that clinicians must often discontinue or decrease the maintenance dose of corticosteroids in sarcoidosis patients because of the development of corticosteroid toxicity. Such patients are not truly refractory to corticosteroids in terms of failure of the drug as an anti-granulomatous agent. Nevertheless, complications of corticosteroid therapy are extremely common in sarcoidosis patients [
      • Khan N.A.
      • Donatelli C.V.
      • Tonelli A.R.
      • et al.
      Toxicity risk from glucocorticoids in sarcoidosis patients.
      ], and they have a major impact on quality of life. Sarcoidosis patients receiving a minimal dose or no corticosteroids (≤500 mg prednisone/year) were found to have a significantly better quality of life than those receiving a significant dose of corticosteroids (>500 mg prednisone/year), even after adjusting for the severity of illness [
      • Judson M.A.
      • Chaudhry H.
      • Louis A.
      • et al.
      The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis.
      ]. Greater corticosteroid use in sarcoidosis cohorts has also been associated with increased health care utilization [
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      ].
      Sarcoidosis patients receiving chronic corticosteroids should be monitored for the development of significant toxicity (vide infra). If corticosteroid toxicity develops, consideration should be given to discontinuing corticosteroids depending on the risks and potential consequences of the patient developing worsening disease. If the risks of worsening sarcoidosis by discontinuing corticosteroids are too great and the corticosteroid toxicity is minor, corticosteroid-sparing agents should be considered as the corticosteroid dose is concomitantly lowered. Because several corticosteroid sparing agents such as anti-metabolites (methotrexate, leflunomide, and azathioprine) and anti-malarials often take months to reach maximum efficacy [
      • Baughman R.P.
      • Winget D.B.
      • Lower E.E.
      Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.
      ,
      • Sahoo D.H.
      • Bandyopadhyay D.
      • Xu M.
      • et al.
      Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis.
      ,
      • Jones E.
      • Callen J.P.
      Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas.
      ], it may be prudent to add the corticosteroid-sparing drug for weeks to months before lowering the corticosteroid dose if the corticosteroid toxicity is minor.

      4. Corticosteroid failure because of concern for corticosteroid side effects

      Clinicians often taper or discontinue corticosteroids because of a concern for potential drug toxicity although side effects have not yet occurred. The decision to taper or discontinue corticosteroids depends on the patient's risk for specific adverse events as well as the dose and duration of therapy. The probability of some corticosteroid toxicities increases in a dose-dependent manner. Other corticosteroid toxicities occur with a “threshold pattern,” where once a corticosteroid dose or duration threshold is reached, the probability of toxicity dose not increase further with higher doses [
      • Huscher D.
      • Thiele K.
      • Gromnica-Ihle E.
      • et al.
      Dose-related patterns of glucocorticoid-induced side effects.
      ].
      Infectious complications of corticosteroid therapy are common and impactful. Corticosteroids are powerful anti-inflammatory drugs, modulating the immune system by multiple mechanisms [
      • Rhen T.
      • Cidlowski J.A.
      Antiinflammatory action of glucocorticoids--new mechanisms for old drugs.
      ]. Such dampening of the immune response by corticosteroids may expose the patient to infections from common pathogens as well as from organisms that are not pathogenic in normal hosts (“opportunistic pathogens”). An increased risk of serious bacterial infections and pneumonia begins at the lowest corticosteroid doses and continues to rise in a dose-dependent fashion. Opportunistic infections are less well-studied, but they appear to become a concern at a corticosteroid dose thresholds of 7.5 mg of prednisone day.23 24 Although the impact of corticosteroid use on the outcome of COVID-19 infections is currently unknown, the risk is thought to be substantial and rigorous efforts should be made to reduce corticosteroids to the lowest effective dose during the current pandemic [
      • Sweiss N.J.
      • Korsten P.
      • Syed H.
      • et al.
      When the game changes: guidance to adjust sarcoidosis management during the COVID-19 pandemic.
      ].
      Non-infectious toxicities also may occur at very low corticosteroid doses. Cushingoid appearance and leg edema occur at the lowest corticosteroid doses and exhibit a dose-dependent increase in frequency. Weight gain occurs above a threshold of 5 mg/day [
      • Huscher D.
      • Thiele K.
      • Gromnica-Ihle E.
      • et al.
      Dose-related patterns of glucocorticoid-induced side effects.
      ]. Osteoporosis and diabetes occur at a somewhat higher thresholds, beyond which there is a dose-dependent increase in risk. The data on the risk of corticosteroid-induced adrenal insufficiency are inconsistent, but a meta-analysis concluded that there is essentially no threshold below which this risk can be excluded, and it is both dose and duration-dependent [
      • Broersen L.H.
      • Pereira A.M.
      • Jorgensen J.O.
      • et al.
      Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis.
      ]; although at least three weeks of corticosteroid use is usually required to develop this complication [
      • Ahmet A.
      • Kim H.
      • Spier S.
      Adrenal suppression: a practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy.
      ].
      Corticosteroids are associated with development of a wide range of affective, psychotic, and cognitive disorders. Risk factors for these side effects include the corticosteroid dose and female sex [
      • Warrington T.P.
      • Bostwick J.M.
      Psychiatric adverse effects of corticosteroids.
      ]. A prior history of depression or suicide attempt is associated with a higher risk of recurrence when the patient is exposed to corticosteroids, with a treatment hazard ratio of 10 [
      • Fardet L.
      • Petersen I.
      • Nazareth I.
      Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care.
      ]. There does not seem to be such an association for other chronic psychiatric illnesses [
      • Stiefel F.C.
      • Breitbart W.S.
      • Holland J.C.
      Corticosteroids in cancer: neuropsychiatric complications.
      ]. The overall incidence of psychiatric toxicity occurs in one-quarter of patients, with severe toxicity in approximately 6% [
      • Lewis D.A.
      • Smith R.E.
      Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature.
      ]. Depression and mania/euphoria are the most commonly reported psychiatric conditions.29 31 In the elderly, delirium and cognitive dysfunction are very common, and have a treatment hazard ratio (for corticosteroids vs no corticosteroids) of 10 at age ≥71 years. The literature concerning the effect of the corticosteroid dose on the development of psychiatric toxicities is inconsistent. The incidence of psychiatric toxicity below 20 mg/day of prednisone seems to be negligible and limited to anxiety and cognitive dysfunction [
      • Fardet L.
      • Petersen I.
      • Nazareth I.
      Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care.
      ]. The incidence is substantially higher at a dose of 20–40 mg, with reports as high as to 23% [
      • Lewis D.A.
      • Smith R.E.
      Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature.
      ]. At dose of ≥40 mg, there seems to be a sharp rise in the frequency of psychiatric toxicity of up to 77% [
      • Lewis D.A.
      • Smith R.E.
      Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature.
      ].
      Table 2 shows the risk of various corticosteroid toxicities in relation to dose. These data are not robust but suggest that the various corticosteroid toxicities occur at a wide range of doses. Thus, the threshold chronic corticosteroid dose that would be considered unacceptable must be individualized. In a Delphi study of 36 sarcoidosis experts, a consensus was reached that a maintenance dose of less than prednisone 10 mg/day is considered a successful taper [
      • Schutt A.C.
      • Bullington W.M.
      • Judson M.A.
      Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.
      ]. This implies that, at least amongst sarcoidosis experts, the risk for adverse effects is unacceptable at or above a daily prednisone dose of 10 mg.
      Table 2The risk of various corticosteroid toxicities related to corticosteroid dose.
      ToxicityDoseϮRiskRef.
      Infection
       Serious bacterial infection≥5+[
      • Dixon W.G.
      • Abrahamowicz M.
      • Beauchamp M.E.
      • et al.
      Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis.
      ]
      ≥30+++[
      • Dixon W.G.
      • Abrahamowicz M.
      • Beauchamp M.E.
      • et al.
      Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis.
      ]
       Pneumonia≤5+[
      • Wolfe F.
      • Caplan L.
      • Michaud K.
      Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy.
      ]
      ≥10++[
      • Wolfe F.
      • Caplan L.
      • Michaud K.
      Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy.
      ]
       Herpes Zoster (Shingles)≥7.5+[
      • Pappas D.A.
      • Hooper M.M.
      • Kremer J.M.
      • et al.
      Herpes Zoster reactivation in patients with rheumatoid arthritis: analysis of disease characteristics and disease-modifying antirheumatic drugs.
      ]
       Tuberculosis≥7.5+++[
      • Jick S.S.
      • Lieberman E.S.
      • Rahman M.U.
      • et al.
      Glucocorticoid use, other associated factors, and the risk of tuberculosis.
      ]
       PJ Pneumonia≥20NA[
      • Sepkowitz K.A.
      • Brown A.E.
      • Telzak E.E.
      • et al.
      Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.
      ]
      Osteoporosis≥10+[
      • Wilson J.C.
      • Sarsour K.
      • Collinson N.
      • et al.
      Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): a nested case-control analysis.
      ]
      Diabetes≥20++[
      • Wilson J.C.
      • Sarsour K.
      • Collinson N.
      • et al.
      Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): a nested case-control analysis.
      ]
      Weight gain≥5++[
      • Huscher D.
      • Thiele K.
      • Gromnica-Ihle E.
      • et al.
      Dose-related patterns of glucocorticoid-induced side effects.
      ]
      Hypertension≥7.5++[
      • Panoulas V.F.
      • Douglas K.M.
      • Stavropoulos-Kalinoglou A.
      • et al.
      Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis.
      ]
      Ϯ: daily prednisone equivalent, mg; +: risk ratio of 1–2; ++: risk ratio of 2–4; +++: risk ratio of >4; NA: not available; PJ: Pneumocystis jirovecii.
      Indeed, expert guidelines recommend consideration of steroid-sparing agents when a patient is unable to be weaned below 10 mg [
      • West S.G.
      Current management of sarcoidosis I: pulmonary, cardiac, and neurologic manifestations.
      ]. This recommendation is consistent with the entry criteria for participation in most clinical sarcoidosis trials of corticosteroid-sparing agents (Table 3) of a chronic prednisone dose of ≥10 mg/day. This implies that there is a consensus that corticosteroid-sparing drugs are warranted at this dose threshold.
      Table 3Minimum prednisone dose for entry into a sarcoidosis drug treatment trial.
      Study drugSarcoidosis organ(s) treatedMinimum daily prednisone equivalent for entryReference
      Ustekinumab Golimumablung/skin≥10[
      • Judson M.A.
      • Baughman R.P.
      • Costabel U.
      • et al.
      Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.
      ]
      Adalimumablung≥7.5[
      • Sweiss N.J.
      • Noth I.
      • Mirsaeidi M.
      • et al.
      Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis.
      ]
      rituximablung≥10[
      • Sweiss N.J.
      • Lower E.E.
      • Mirsaeidi M.
      • et al.
      Rituximab in the treatment of refractory pulmonary sarcoidosis.
      ]
      infliximablung≥10[
      • Baughman R.P.
      • Drent M.
      • Kavuru M.
      • et al.
      Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
      ]
      It is important to note that the toxicities of corticosteroids not only relate to the dose but also the duration of therapy. Many of the toxicities of corticosteroids are cumulative such as weight gain, osteoporosis and cataracts. Patients receiving corticosteroids for more than 6–12 months are at high risk of developing significant corticosteroid side effect and corticosteroid sparring agents should be considered in this situation.

      5. Monitoring for corticosteroid toxicity

      Because the long-term use of corticosteroids is associated with significant toxicities, adequate monitoring is essential to prevent and manage these complications. Before initiating potentially long term corticosteroid therapy, a detailed history and physical examination should be performed to assess for risk factors or pre-existing conditions that may be exacerbated by corticosteroid use such as the presence of chronic and/or untreated infections, dyslipidemia, diabetes, cardiovascular disease, psychological/psychiatric disorders, cataracts/glaucoma, and osteoporosis [
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      ]. Baseline measurements of weight, height, blood pressure should be obtained. Laboratory assessment should include a complete blood count, serum glucose, lipid profile and bone mineral density [
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      ]. Patients should educated on healthy dietary habits to avoid weight gain. They should be educated about the common signs and symptoms of hyperglycemia and instructed to seek medical attention if these occur. All of these risk factors and measurements should also be monitored regularly while the patient is receiving corticosteroids.
      In terms of monitoring bone mineral density and fracture risk, annual height measurements should be performed, and patients should be questioned regularly concerning incident fragility fractures [
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      ]. The detailed approach to monitoring and treatment of corticosteroid-induced osteoporosis is quite complex and beyond the scope of this manuscript and it is available elsewhere [
      • Buckley L.
      • Guyatt G.
      • Fink H.A.
      • et al.
      American college of rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis.
      ]. Basically, in patients receiving ≥ 5 mg/day of prednisone for more than 3 months, serial bone density measurements and assessment of the fracture risk by use of the World Health Organization Fracture Risk Assessment Tool (FRAX) should be performed at regular intervals determined by the patient's age and risk factors for osteoporosis [
      • Buckley L.
      • Guyatt G.
      • Fink H.A.
      • et al.
      American college of rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis.
      ]. Complaints of joint pain at each visit should be seriously scrutinized, as they may suggest the development of osteonecrosis [
      • Moghadam-Kia S.
      • Werth V.P.
      Prevention and treatment of systemic glucocorticoid side effects.
      ].
      Adrenal suppression should be considered in any patient who develops significant fatigue or other symptoms of adrenal insufficiency as the corticosteroid dose is lowered or discontinued. Adrenal insufficiency can occur in any individual receiving more than three weeks of corticosteroids in the previous 6 months [
      • Ahmet A.
      • Kim H.
      • Spier S.
      Adrenal suppression: a practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy.
      ]. Although the specificity of a low first morning serum cortisol level (<85 nmol/L) is very specific for adrenal insufficiency, this test only has approximately a 60% sensitivity [
      • Erturk E.
      • Jaffe C.A.
      • Barkan A.L.
      Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.
      ], and a low-dose adrenocorticotropic hormone (ACTH) stimulation test may needed to confirm this diagnosis.
      Although there are no established guidelines for the monitoring of dyslipidemia and cardiovascular risk in those receiving corticosteroids, it has been recommend to perform a lipid profile at baseline, one month after initiating corticosteroids, and then every 6–12 months [
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      ]. Patients receiving corticosteroids should be regularly questioned concerning anginal symptoms and other symptoms of vascular insufficiency. Established guidelines for monitoring and assessing cardiovascular risk should also be used [
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American college of cardiology/American heart association task force on practice guidelines.
      ].
      To monitor for hyperglycemia and diabetes, some have advocated regular measurement of glycated hemoglobin (A1C) [
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      ]. Others have recommended that serum glucose levels be determined within 48 h [
      • Cheng A.Y.
      Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Introduction.
      ] or even 8 h [
      • Burt M.G.
      • Roberts G.W.
      • Aguilar-Loza N.R.
      • et al.
      Continuous monitoring of circadian glycemic patterns in patients receiving prednisolone for COPD.
      ] of the first corticosteroid dose.
      Patients receiving corticosteroids for more than 6 months should undergo ophthalmology evaluations at least annually. These patients should be evaluated for the development of cataracts and glaucoma [
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      ]. Patients with previous histories or risk factors for these ocular disorders should be seen by an ophthalmologist within a few months of initiating corticosteroids and probably be reevaluated more frequently than yearly. Because active eye sarcoidosis may result in cataracts and glaucoma [
      • Ohara K.
      • Judson M.A.
      • Baughman R.P.
      Clinical aspects of ocular sarcoidosis.
      ], it is often problematic for the ophthalmologist to distinguish corticosteroid eye toxicity from active sarcoid eye disease.

      6. Corticosteroid failure due to poor adherence to medication

      Some corticosteroid treatment failures may be related to poor medication adherence. Poor medication adherence takes several forms including failure to take medications, missing doses, taking insufficient dosages and taking medication erratically [
      • Osterberg L.
      • Blaschke T.
      Adherence to medication.
      ]. Even in clinical trials, average medication adherence rates have varied from 43% to 78% [
      • Osterberg L.
      • Blaschke T.
      Adherence to medication.
      ,
      • Waeber B.
      • Leonetti G.
      • Kolloch R.
      • et al.
      Compliance with aspirin or placebo in the hypertension optimal treatment (HOT) study.
      ,
      • Claxton A.J.
      • Cramer J.
      • Pierce C.
      A systematic review of the associations between dose regimens and medication compliance.
      ,
      • Cramer J.
      • Rosenheck R.
      • Kirk G.
      • et al.
      Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes.
      ]. The causes of non-adherence to medications include forgetfulness, emotional factors, a conscious decision to omit doses, the complexity of dosage regimens, the development or concern of medication side-effects, poor patient-clinician communication the lack of medication efficacy and medication cost.42 46 47
      Of all these factors associated with non-adherence, suboptimal communication between the patient and the clinician is probably the major one. In order to maximize medication adherence, the clinician needs to be aware of the patient's psychosocial mental capacity issues that might be barriers to adherence. An open line of communication needs to be developed between the patient and the clinician whereby with the treatment plan can be explained, the medication side effects are explained, the wishes of the patient can be freely expressed and the patient feels free to voice concerns about the medications and the treatment approach.
      Significant corticosteroid non-adherence has been demonstrated in patients with asthma [
      • Hatton M.Q.
      • Allen M.B.
      • Vathenen S.V.
      • et al.
      Compliance with oral corticosteroids during steroid trials in chronic airways obstruction.
      ,
      • Cooper V.
      • Metcalf L.
      • Versnel J.
      • et al.
      Patient-reported side effects, concerns and adherence to corticosteroid treatment for asthma, and comparison with physician estimates of side-effect prevalence: a UK-wide, cross-sectional study.
      ], adrenal insufficiency [
      • Chapman S.C.
      • Llahana S.
      • Carroll P.
      • et al.
      Glucocorticoid therapy for adrenal insufficiency: nonadherence, concerns and dissatisfaction with information.
      ], rheumatologic diseases [
      • Arena C.
      • Morin A.S.
      • Blanchon T.
      • et al.
      Impact of glucocorticoid-induced adverse events on adherence in patients receiving long-term systemic glucocorticoid therapy.
      ,
      • Nived O.
      • Andersson M.
      • Lindgren M.
      • et al.
      Adherence with advice and prescriptions in SLE is mostly good, but better follow up is needed: a study with a questionnaire.
      ], inflammatory bowel disease [
      • Mountifield R.
      • Andrews J.M.
      • Mikocka-Walus A.
      • et al.
      Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
      ], and nephrotic syndrome [
      • Ulinski T.
      • Carlier-Legris A.
      • Schlecht D.
      • et al.
      Triamcinolone acetonide: a new management of noncompliance in nephrotic children.
      ]. Non-adherence rates for corticosteroids in these cohorts have varied from 20% to 80% [
      • Arena C.
      • Morin A.S.
      • Blanchon T.
      • et al.
      Impact of glucocorticoid-induced adverse events on adherence in patients receiving long-term systemic glucocorticoid therapy.
      ,
      • Mountifield R.
      • Andrews J.M.
      • Mikocka-Walus A.
      • et al.
      Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
      ,
      • Hatton M.Q.
      • Allen M.B.
      • Vathenen S.V.
      • et al.
      Compliance with oral corticosteroids during steroid trials in chronic airways obstruction.
      ,
      • Chapman S.C.
      • Llahana S.
      • Carroll P.
      • et al.
      Glucocorticoid therapy for adrenal insufficiency: nonadherence, concerns and dissatisfaction with information.
      ]. Specific common causes of non-adherence with corticosteroid therapy have included a) development of corticosteroid-related adverse events [
      • Cooper V.
      • Metcalf L.
      • Versnel J.
      • et al.
      Patient-reported side effects, concerns and adherence to corticosteroid treatment for asthma, and comparison with physician estimates of side-effect prevalence: a UK-wide, cross-sectional study.
      ], particularly epigastric pain and weight gain [
      • Arena C.
      • Morin A.S.
      • Blanchon T.
      • et al.
      Impact of glucocorticoid-induced adverse events on adherence in patients receiving long-term systemic glucocorticoid therapy.
      ,
      • Chapman S.C.
      • Llahana S.
      • Carroll P.
      • et al.
      Glucocorticoid therapy for adrenal insufficiency: nonadherence, concerns and dissatisfaction with information.
      ], dissatisfaction with the doctor-patient relationship [
      • Mountifield R.
      • Andrews J.M.
      • Mikocka-Walus A.
      • et al.
      Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
      ], depression [
      • Mountifield R.
      • Andrews J.M.
      • Mikocka-Walus A.
      • et al.
      Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
      ], anxiety [
      • Mountifield R.
      • Andrews J.M.
      • Mikocka-Walus A.
      • et al.
      Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
      ], and negative views about medication efficacy [
      • Mountifield R.
      • Andrews J.M.
      • Mikocka-Walus A.
      • et al.
      Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
      ].
      The clinician should consider non-adherence as a cause of corticosteroid treatment failure in sarcoidosis patients, especially in patients with any of the aforementioned risk factors for non-adherence with corticosteroid therapy. When non-adherence with corticosteroid therapy is suspected, the clinician should question the patient about this possibility. This may be the start of a communication whereby the clinician learns that the proposed medication regimen is not in the best interests of the patient. In some patients who may have cognitive or psychosocial barriers to adhering to oral corticosteroid regimens, successful outcomes have been achieved with intramuscular triamcinolone injections [
      • Ulinski T.
      • Carlier-Legris A.
      • Schlecht D.
      • et al.
      Triamcinolone acetonide: a new management of noncompliance in nephrotic children.
      ]. The use of 360 mg of intramuscular triamcinolone injections every three months was shown to be useful in a cohort of 5 sarcoidosis patients in a previous abstract [
      • Kravitz J.N.
      • Bullington W.
      • Judson M.A.
      Depot Intramuscular Triamcinolone for the Treatment of Sarcoidosis.
      ].

      7. Corticosteroid failure because symptoms and/or dysfunction is related to fibrosis

      Fibrotic pulmonary sarcoidosis is the most common cause of significant morbidity and mortality from sarcoidosis [
      • Walsh S.L.
      • Wells A.U.
      • Sverzellati N.
      • et al.
      An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study.
      ,
      • Kirkil G.
      • Lower E.E.
      • Baughman R.P.
      Predictors of mortality in pulmonary sarcoidosis.
      ]. The fibrosis is caused from active granulomatous inflammation, [
      • Xu L.
      • Kligerman S.
      • Burke A.
      End-stage sarcoid lung disease is distinct from usual interstitial pneumonia.
      ,
      • Judson M.A.
      Strategies for identifying pulmonary sarcoidosis patients at risk for severe or chronic disease.
      ] and many of these patients do not have “burnt out” disease but rather active granulomatous inflammation that is leading to continued fibrosis [
      • Mostard R.L.
      • Prompers L.
      • Weijers R.E.
      • et al.
      F-18 FDG PET/CT for detecting bone and bone marrow involvement in sarcoidosis patients.
      ]. However, as true corticosteroid failure is unlikely with sarcoidosis, failure to respond to corticosteroids suggests that the patient has developed worsening fibrosis or a complication of pulmonary fibrosis. These complications include a) pulmonary hypertension from fibrotic distortion of the pulmonary vasculature; [
      • Baughman R.P.
      • Shlobin O.A.
      • Wells A.U.
      • et al.
      Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry.
      ,
      • Handa T.
      • Nagai S.
      • Miki S.
      • et al.
      Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis.
      ] b) bronchiectasis and/or airway obstruction from fibrotic distortion of airways; [
      • Lewis M.M.
      • Mortelliti M.P.
      • Yeager Jr., H.
      • et al.
      Clinical bronchiectasis complicating pulmonary sarcoidosis: case series of seven patients.
      ,
      • Baughman R.P.
      • Lower E.E.
      Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients.
      ] c) growth of mycetoma and chronic fungal infection in devitalized areas of fibrotic lung. [
      • Kravitz J.N.
      • Berry M.W.
      • Schabel S.I.
      • et al.
      A modern series of percutaneous intracavitary instillation of amphotericin B for the treatment of severe hemoptysis from pulmonary aspergilloma.
      ,
      • Uzunhan Y.
      • Nunes H.
      • Jeny F.
      • et al.
      Chronic pulmonary aspergillosis complicating sarcoidosis.
      ] All these manifestations of fibrotic pulmonary sarcoidosis will not respond to corticosteroid therapy and should be searched for in corticosteroid refractory fibrotic pulmonary sarcoidosis patients.

      8. Corticosteroid failure from conditions unrelated to sarcoidosis

      Sarcoidosis patient may not benefit from corticosteroid therapy because the cause of their symptoms or dysfunction is unrelated to sarcoidosis. The potential alternative causes are endless, but several important ones are highlighted here. Sarcoidosis patients may develop significant corticosteroids side effects that may be confused with manifestations of the disease. These include the development of ischemic heart disease and obesity that may cause dyspnea, infections from corticosteroid-induced immunosuppression, and a corticosteroid myopathy that may lead to weakness and fatigue [
      • Judson M.A.
      • Baughman R.P.
      Worsening of pulmonary sarcoidosis.
      ]. The weight gain from corticosteroid use may also result in obstructive sleep apnea that may cause fatigue and cognitive impairment [
      • Lal C.
      • Medarov B.I.
      • Judson M.A.
      Interrelationship between sleep-disordered breathing and sarcoidosis.
      ]. Corticosteroids may also exacerbate gastroesophageal reflux causing cough [
      • Lazenby J.P.
      • Guzzo M.R.
      • Harding S.M.
      • et al.
      Oral corticosteroids increase esophageal acid contact times in patients with stable asthma.
      ]. Parasarcoidosis syndromes are sarcoidosis-associated conditions that are not directly related to the deposition of granulomas into tissues or the development of fibrosis [
      • Judson M.A.
      The three tiers of screening for sarcoidosis organ involvement.
      ]. Most parasarcoidosis syndromes are thought to result from release of a systemic release of inflammatory mediators. Parasarcoidosis syndromes include small fiber neuropathy [
      • Tavee J.O.
      • Karwa K.
      • Ahmed Z.
      • et al.
      Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment.
      ] and other pain syndromes [
      • Kersting-Sommerhoff B.
      • Hof N.
      • Golder W.
      • et al.
      MRI of the wrist joint: "granulomatous tenovaginitis of the sarcoidosis type"--a rare cause of carpal tunnel syndrome.
      ], fatigue syndromes [
      • Drent M.
      • Lower E.E.
      • De Vries J.
      Sarcoidosis-associated fatigue.
      ], depression [
      • Chang B.
      • Steimel J.
      • Moller D.R.
      • et al.
      Depression in sarcoidosis.
      ], and possibly cognitive impairment [
      • Elfferich M.D.
      • Nelemans P.J.
      • Ponds R.W.
      • et al.
      Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-alpha treatment.
      ]. Corticosteroid therapy is often not effective for parasarcoidosis syndromes. It is also our experience that because sarcoidosis has the potential to involve any organ, any symptom pertaining to any part of the body may be attributed to sarcoidosis solely on the basis that the patient has been diagnosed with sarcoidosis. It is imperative that the clinician maintain an objective approach in evaluating new symptoms in a sarcoidosis patient. General principles that should be kept in mind when assessing the likelihood that a new symptom representing a manifestation of sarcoidosis are a) sarcoidosis-related symptoms usually develop slowly over many weeks to months [
      • Moller D.R.
      Negative clinical trials in sarcoidosis: failed therapies or flawed study design?.
      ]; therefore, it is unlikely that symptoms of very acute onset are attributable to sarcoidosis; b) the growth and regression of sarcoidosis granulomata tend to be concordant in different organs; therefore, it is somewhat unusual for symptoms attributable to sarcoidosis to improve in one organ while they simultaneously worsen in another organ.

      9. Treatment of corticosteroid refractory sarcoidosis

      A major motivation to classify the cause of corticosteroid refractory sarcoidosis is to determine adequate therapy. Although specific details of therapy are complex and beyond the scope of this manuscript, a general approach is outlined here. Because corticosteroids have anti-inflammatory effects by numerous mechanisms, it is possible that patients with true corticosteroid failure will not to respond to other sarcoidosis medications. Nevertheless, a trial of alternative sarcoidosis drugs should be considered. Corticosteroid failure because of side effects or concern for developing side effects should be managed by lowering the corticosteroid dose to the lowest tolerable level and adding a corticosteroid sparing agent. Corticosteroids may need to be completely discontinued If the corticosteroid side effects are severe. Poor corticosteroid adherence is best managed by improving patient-clinician communication such the goals of therapy can be mutually agreed upon and the patient can voice concerns. Corticosteroid failure related to fibrosis should be treated by reducing or eliminating anti-granulomatous therapy to minimize medication side effects and considering anti-fibrotic therapy if it is available. Corticosteroid failure because the sarcoidosis patient's symptoms or dysfunction relate to another condition suggest that this condition should be treated. The clinician must be constantly vigilant for the presence of alternative conditions that could cause illness in sarcoidosis patients.

      10. Other definitions of corticosteroid refractory sarcoidosis

      Other definitions of corticosteroid refractory sarcoidosis have been proposed. One proposed definition of refractory sarcoidosis that it fulfills the following two criteria: 1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for disease-modifying anti-sarcoidosis drugs due to lack of efficacy, drug toxicity or intolerability; and 2) treatment started for significant impairment of life due to progressive pulmonary symptoms [
      • Korsten P.
      • Strohmayer K.
      • Baughman R.P.
      • et al.
      Refractory pulmonary sarcoidosis - proposal of a definition and recommendations for the diagnostic and therapeutic approach.
      ]. This definition combines many of the individual causes of corticosteroid refractory disease discussed in this manuscript. Although we believe that this proposed definition is useful, we feel that there is value in the clinician determining the cause of corticosteroid failure so that the proper intervention can be initiated.

      11. Summary

      Corticosteroid refractory sarcoidosis has many causes, and true corticosteroid failure is a very uncommon one. Determining the cause of corticosteroid refractoriness will likely lead to better patient outcomes including optimizing the corticosteroid dose, considering alternative anti-sarcoidosis therapies, and considering alternative diagnoses that require alternative treatments. Furthermore, determining the cause of corticosteroid refractory sarcoidosis may allow the clinical researcher to appropriately stratify patients for clinical trials. Table 4 summaries the cause of corticosteroid refractory sarcoidosis and the general approaches to management.
      Table 4Causes and conditions of corticosteroid refractory sarcoidosis.
      Cause/ConditionFrequencyComments
      True corticosteroid failurerareUsually requires evidence of active granulomatous inflammation causing symptoms while receiving greater than 30 mg/day of prednisone
      Development of significant corticosteroid side effectcommonMonitor for corticosteroid side effect
      Concern for potential corticosteroid side effectcommonCorticosteroid side effects commonly occur in patient receiving greater than 10 mg of prednisone or corticosteroid therapy for greater than 6 months
      Poor corticosteroid adherencecommonMany potential causes including poor patient-clinician communication, forgetfulness, drug toxicity, lack of drug efficacy
      Lack of granulomatous inflammation
       from sarcoidosis-related fibrosisuncommonEvidence of fibrosis usually present
       from a condition unrelated to sarcoidosiscommonAlways consider other conditions when evaluating a symptomatic sarcoidosis patient

      CRediT authorship contribution statement

      Chananya Goldman: Data curation, Formal analysis, Investigation, Resources, Software, Writing - original draft. Marc A. Judson: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing.

      Declaration of competing interest

      The authors (CG, MAJ) have no conflicts of interest concerning the publication of this manuscript.

      Acknowledgement

      The authors wish to acknowledge the assistance of Sooyeon Kwon, PhD who assisted in the construction of the tables contained in this manuscript.

      References

        • Baughman R.P.
        • Judson M.A.
        • Wells A.U.
        The indications for the treatment of sarcoidosis : well's Law.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2017; 34: 280-282
        • Judson M.A.
        Corticosteroids in sarcoidosis.
        Rheum. Dis. Clin. N. Am. 2016; 42 ([published Online First: 2015/11/28]): 119-135https://doi.org/10.1016/j.rdc.2015.08.012
        • McKinzie B.P.
        • Bullington W.M.
        • Mazur J.E.
        • et al.
        Efficacy of short-course, low-dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations.
        Am. J. Med. Sci. 2010; 339 ([published Online First: 2009/12/10]): 1-4https://doi.org/10.1097/MAJ.0b013e3181b97635
        • Stagaki E.
        • Mountford W.K.
        • Lackland D.T.
        • et al.
        The treatment of lupus pernio: results of 116 treatment courses in 54 patients.
        Chest. 2009; 135: 468-476
        • Sodhi M.
        • Pearson K.
        • White E.S.
        • et al.
        Infliximab therapy rescues cyclophosphamide failure in severe central nervous system sarcoidosis.
        Respir. Med. 2009; 103: 268-273
        • Lower E.E.
        • Broderick J.P.
        • Brott T.G.
        • et al.
        Diagnosis and management of neurological sarcoidosis.
        Arch. Intern. Med. 1997; 157: 1864-1868
        • Kikuchi N.
        • Nunoda S.
        • Serizawa N.
        • et al.
        Combination therapy with corticosteroid and mycophenolate mofetil in a case of refractory cardiac sarcoidosis.
        J. Cardiol. Cases. 2016; 13 ([published Online First: 2016/03/06]): 125-128https://doi.org/10.1016/j.jccase.2015.12.008
        • Theodore J.
        • Saggu D.K.
        • Yalagudri S.
        • et al.
        Management of refractory ventricular tachycardia due to cardiac sarcoidosis-A biologic approach.
        Heart Rhythm Case Rep. 2019; 5 ([published Online First: 2019/03/02]): 97-100https://doi.org/10.1016/j.hrcr.2018.11.004
        • Okada D.R.
        • Assis F.R.
        • Gilotra N.A.
        • et al.
        Cardiac sympathectomy for refractory ventricular arrhythmias in cardiac sarcoidosis.
        Heart Rhythm. 2019; ([published Online First: 2019/03/01])https://doi.org/10.1016/j.hrthm.2019.02.025
        • Shelke A.B.
        • Aurangabadkar H.U.
        • Bradfield J.S.
        • et al.
        Serial FDG-PET scans help to identify steroid resistance in cardiac sarcoidosis.
        Int. J. Cardiol. 2017; 228 ([published Online First: 2016/11/26]): 717-722https://doi.org/10.1016/j.ijcard.2016.11.142
        • Monast C.S.
        • Li K.
        • Judson M.A.
        • et al.
        Sarcoidosis extent relates to molecular variability.
        Clin. Exp. Immunol. 2017; 188 ([published Online First: 2017/02/17]): 444-454https://doi.org/10.1111/cei.12942
        • Ramamoorthy S.
        • Cidlowski J.A.
        Corticosteroids: mechanisms of action in health and disease.
        Rheum. Dis. Clin. N. Am. 2016; 42 (vii) ([published Online First: 2015/11/28]): 15-31https://doi.org/10.1016/j.rdc.2015.08.002
        • Barnes P.J.
        Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.
        J. Allergy Clin. Immunol. 2013; 131 ([published Online First: 2013/01/31]): 636-645https://doi.org/10.1016/j.jaci.2012.12.1564
        • Baughman R.P.
        • Nagai S.
        • Balter M.
        • et al.
        Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2011; 28 ([published Online First: 2011/07/30]): 56-64
        • Khan N.A.
        • Donatelli C.V.
        • Tonelli A.R.
        • et al.
        Toxicity risk from glucocorticoids in sarcoidosis patients.
        Respir. Med. 2017; 132 ([published Online First: 2017/12/13]): 9-14https://doi.org/10.1016/j.rmed.2017.09.003
        • Judson M.A.
        • Chaudhry H.
        • Louis A.
        • et al.
        The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis.
        Respir. Med. 2015; 109 ([published Online First: 2015/02/24]): 526-531https://doi.org/10.1016/j.rmed.2015.01.019
        • Ligon C.B.
        • Judson M.A.
        Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
        Am. J. Med. Sci. 2011; 341 ([published Online First: 2011/03/30]): 196-201
        • Baughman R.P.
        • Winget D.B.
        • Lower E.E.
        Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2000; 17: 60-66
        • Sahoo D.H.
        • Bandyopadhyay D.
        • Xu M.
        • et al.
        Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis.
        Eur. Respir. J. 2011; ([published Online First: 2011/05/14])https://doi.org/10.1183/09031936.00195010
        • Jones E.
        • Callen J.P.
        Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas.
        J. Am. Acad. Dermatol. 1990; 23: 487-489
        • Huscher D.
        • Thiele K.
        • Gromnica-Ihle E.
        • et al.
        Dose-related patterns of glucocorticoid-induced side effects.
        Ann. Rheum. Dis. 2009; 68 ([published Online First: 2008/08/08]): 1119-1124https://doi.org/10.1136/ard.2008.092163
        • Rhen T.
        • Cidlowski J.A.
        Antiinflammatory action of glucocorticoids--new mechanisms for old drugs.
        N. Engl. J. Med. 2005; 353 ([published Online First: 2005/10/21]): 1711-1723https://doi.org/10.1056/NEJMra050541
        • Jick S.S.
        • Lieberman E.S.
        • Rahman M.U.
        • et al.
        Glucocorticoid use, other associated factors, and the risk of tuberculosis.
        Arthritis Rheum. 2006; 55 ([published Online First: 2006/02/08]): 19-26https://doi.org/10.1002/art.21705
        • Pappas D.A.
        • Hooper M.M.
        • Kremer J.M.
        • et al.
        Herpes Zoster reactivation in patients with rheumatoid arthritis: analysis of disease characteristics and disease-modifying antirheumatic drugs.
        Arthritis Care Res. (Hoboken). 2015; 67 ([published Online First: 2015/05/29]): 1671-1678https://doi.org/10.1002/acr.22628
        • Sweiss N.J.
        • Korsten P.
        • Syed H.
        • et al.
        When the game changes: guidance to adjust sarcoidosis management during the COVID-19 pandemic.
        Chest. 2020; ([published Online First: 2020/05/04])https://doi.org/10.1016/j.chest.2020.04.033
        • Broersen L.H.
        • Pereira A.M.
        • Jorgensen J.O.
        • et al.
        Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis.
        J. Clin. Endocrinol. Metab. 2015; 100 ([published Online First: 2015/04/07]): 2171-2180https://doi.org/10.1210/jc.2015-1218
        • Ahmet A.
        • Kim H.
        • Spier S.
        Adrenal suppression: a practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy.
        Allergy Asthma Clin. Immunol. 2011; 7 ([published Online First: 2011/08/27]): 13https://doi.org/10.1186/1710-1492-7-13
        • Warrington T.P.
        • Bostwick J.M.
        Psychiatric adverse effects of corticosteroids.
        Mayo Clin. Proc. 2006; 81 ([published Online First: 2006/10/14]): 1361-1367https://doi.org/10.4065/81.10.1361
        • Fardet L.
        • Petersen I.
        • Nazareth I.
        Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care.
        Am. J. Psychiatr. 2012; 169 ([published Online First: 2012/07/06]): 491-497https://doi.org/10.1176/appi.ajp.2011.11071009
        • Stiefel F.C.
        • Breitbart W.S.
        • Holland J.C.
        Corticosteroids in cancer: neuropsychiatric complications.
        Canc. Invest. 1989; 7 ([published Online First: 1989/01/01]): 479-491https://doi.org/10.3109/07357908909041378
        • Lewis D.A.
        • Smith R.E.
        Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature.
        J. Affect. Disord. 1983; 5 ([published Online First: 1983/11/01]): 319-332https://doi.org/10.1016/0165-0327(83)90022-8
        • Schutt A.C.
        • Bullington W.M.
        • Judson M.A.
        Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.
        Respir. Med. 2010; 104 ([published Online First: 2010/01/22]): 717-723https://doi.org/10.1016/j.rmed.2009.12.009
        • West S.G.
        Current management of sarcoidosis I: pulmonary, cardiac, and neurologic manifestations.
        Curr. Opin. Rheumatol. 2018; 30 ([published Online First: 2018/02/02]): 243-248https://doi.org/10.1097/bor.0000000000000489
        • Liu D.
        • Ahmet A.
        • Ward L.
        • et al.
        A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
        Allergy Asthma Clin. Immunol. 2013; 9 ([published Online First: 2013/08/21]): 30https://doi.org/10.1186/1710-1492-9-30
        • Buckley L.
        • Guyatt G.
        • Fink H.A.
        • et al.
        American college of rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis.
        Arthritis Care Res. (Hoboken). 2017; 69 ([published Online First: 2017/06/07]): 1095-1110https://doi.org/10.1002/acr.23279
        • Moghadam-Kia S.
        • Werth V.P.
        Prevention and treatment of systemic glucocorticoid side effects.
        Int. J. Dermatol. 2010; 49 ([published Online First: 2010/05/15]): 239-248https://doi.org/10.1111/j.1365-4632.2009.04322.x
        • Erturk E.
        • Jaffe C.A.
        • Barkan A.L.
        Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.
        J. Clin. Endocrinol. Metab. 1998; 83 ([published Online First: 1998/07/14]): 2350-2354https://doi.org/10.1210/jcem.83.7.4980
        • Goff Jr., D.C.
        • Lloyd-Jones D.M.
        • Bennett G.
        • et al.
        ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American college of cardiology/American heart association task force on practice guidelines.
        Circulation. 2013; 129 ([published Online First: 2013/11/14]): S49-S73https://doi.org/10.1161/01.cir.0000437741.48606.98
        • Cheng A.Y.
        Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Introduction.
        Can. J. Diabetes. 2013; 37 ([published Online First: 2014/05/16]): S1-S3https://doi.org/10.1016/j.jcjd.2013.01.009
        • Burt M.G.
        • Roberts G.W.
        • Aguilar-Loza N.R.
        • et al.
        Continuous monitoring of circadian glycemic patterns in patients receiving prednisolone for COPD.
        J. Clin. Endocrinol. Metab. 2011; 96 ([published Online First: 2011/03/18]): 1789-1796https://doi.org/10.1210/jc.2010-2729
        • Ohara K.
        • Judson M.A.
        • Baughman R.P.
        Clinical aspects of ocular sarcoidosis.
        Eur. Respir. J. Monogr. 2005; 10: 188-209
        • Osterberg L.
        • Blaschke T.
        Adherence to medication.
        N. Engl. J. Med. 2005; 353 ([published Online First: 2005/08/05]): 487-497https://doi.org/10.1056/NEJMra050100
        • Waeber B.
        • Leonetti G.
        • Kolloch R.
        • et al.
        Compliance with aspirin or placebo in the hypertension optimal treatment (HOT) study.
        J. Hypertens. 1999; 17 ([published Online First: 1999/07/27]): 1041-1045https://doi.org/10.1097/00004872-199917070-00022
        • Claxton A.J.
        • Cramer J.
        • Pierce C.
        A systematic review of the associations between dose regimens and medication compliance.
        Clin. Therapeut. 2001; 23 ([published Online First: 2001/09/18]): 1296-1310https://doi.org/10.1016/s0149-2918(01)80109-0
        • Cramer J.
        • Rosenheck R.
        • Kirk G.
        • et al.
        Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes.
        Value Health. 2003; 6 ([published Online First: 2003/11/25]): 566-573https://doi.org/10.1046/j.1524-4733.2003.65269.x
        • Arena C.
        • Morin A.S.
        • Blanchon T.
        • et al.
        Impact of glucocorticoid-induced adverse events on adherence in patients receiving long-term systemic glucocorticoid therapy.
        Br. J. Dermatol. 2010; 163 ([published Online First: 2010/06/04]): 832-837https://doi.org/10.1111/j.1365-2133.2010.09877.x
        • Mountifield R.
        • Andrews J.M.
        • Mikocka-Walus A.
        • et al.
        Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.
        J. Crohns Colitis. 2014; 8 ([published Online First: 2014/09/30]): 1723-1729https://doi.org/10.1016/j.crohns.2014.08.013
        • Hatton M.Q.
        • Allen M.B.
        • Vathenen S.V.
        • et al.
        Compliance with oral corticosteroids during steroid trials in chronic airways obstruction.
        Thorax. 1996; 51 ([published Online First: 1996/03/01]): 323-324https://doi.org/10.1136/thx.51.3.323
        • Cooper V.
        • Metcalf L.
        • Versnel J.
        • et al.
        Patient-reported side effects, concerns and adherence to corticosteroid treatment for asthma, and comparison with physician estimates of side-effect prevalence: a UK-wide, cross-sectional study.
        NPJ Prim. Care Respir. Med. 2015; 25 ([published Online First: 2015/07/15]): 15026https://doi.org/10.1038/npjpcrm.2015.26
        • Chapman S.C.
        • Llahana S.
        • Carroll P.
        • et al.
        Glucocorticoid therapy for adrenal insufficiency: nonadherence, concerns and dissatisfaction with information.
        Clin. Endocrinol. 2016; 84 ([published Online First: 2015/12/08]): 664-671https://doi.org/10.1111/cen.12991
        • Nived O.
        • Andersson M.
        • Lindgren M.
        • et al.
        Adherence with advice and prescriptions in SLE is mostly good, but better follow up is needed: a study with a questionnaire.
        Lupus. 2007; 16 ([published Online First: 2007/08/31]): 701-706https://doi.org/10.1177/0961203307080635
        • Ulinski T.
        • Carlier-Legris A.
        • Schlecht D.
        • et al.
        Triamcinolone acetonide: a new management of noncompliance in nephrotic children.
        Pediatr. Nephrol. 2005; 20 ([published Online First: 2005/04/22]): 759-762https://doi.org/10.1007/s00467-004-1791-7
        • Kravitz J.N.
        • Bullington W.
        • Judson M.A.
        Depot Intramuscular Triamcinolone for the Treatment of Sarcoidosis.
        American Thoracic Society Annual Meeting, Denver, Colorado2011
        • Walsh S.L.
        • Wells A.U.
        • Sverzellati N.
        • et al.
        An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study.
        Lancet Respir. Med. 2014; 2 ([published Online First: 2014/02/08]): 123-130https://doi.org/10.1016/s2213-2600(13)70276-5
        • Kirkil G.
        • Lower E.E.
        • Baughman R.P.
        Predictors of mortality in pulmonary sarcoidosis.
        Chest. 2018; 153 ([published Online First: 2017/07/22]): 105-113https://doi.org/10.1016/j.chest.2017.07.008
        • Xu L.
        • Kligerman S.
        • Burke A.
        End-stage sarcoid lung disease is distinct from usual interstitial pneumonia.
        Am. J. Surg. Pathol. 2013; 37 ([published Online First: 2013/02/22]): 593-600https://doi.org/10.1097/PAS.0b013e3182785a2d
        • Judson M.A.
        Strategies for identifying pulmonary sarcoidosis patients at risk for severe or chronic disease.
        Expet Rev. Respir. Med. 2017; 11 ([published Online First: 2017/01/13]): 111-118https://doi.org/10.1080/17476348.2017.1281745
        • Mostard R.L.
        • Prompers L.
        • Weijers R.E.
        • et al.
        F-18 FDG PET/CT for detecting bone and bone marrow involvement in sarcoidosis patients.
        Clin. Nucl. Med. 2012; 37 ([published Online First: 2011/12/14]): 21-25https://doi.org/10.1097/RLU.0b013e3182335f9b
        • Baughman R.P.
        • Shlobin O.A.
        • Wells A.U.
        • et al.
        Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry.
        Respir. Med. 2018; 139 ([published Online First: 2018/06/03]): 72-78https://doi.org/10.1016/j.rmed.2018.04.015
        • Handa T.
        • Nagai S.
        • Miki S.
        • et al.
        Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis.
        Chest. 2006; 129: 1246-1252
        • Lewis M.M.
        • Mortelliti M.P.
        • Yeager Jr., H.
        • et al.
        Clinical bronchiectasis complicating pulmonary sarcoidosis: case series of seven patients.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2002; 19 ([published Online First: 2002/07/10]): 154-159
        • Baughman R.P.
        • Lower E.E.
        Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients.
        Respir. Med. 2013; 107 ([published Online First: 2013/11/12]): 2009-2013https://doi.org/10.1016/j.rmed.2013.10.014
        • Kravitz J.N.
        • Berry M.W.
        • Schabel S.I.
        • et al.
        A modern series of percutaneous intracavitary instillation of amphotericin B for the treatment of severe hemoptysis from pulmonary aspergilloma.
        Chest. 2013; 143 ([published Online First: 2012/11/03]): 1414-1421https://doi.org/10.1378/chest.12-1784
        • Uzunhan Y.
        • Nunes H.
        • Jeny F.
        • et al.
        Chronic pulmonary aspergillosis complicating sarcoidosis.
        Eur. Respir. J. 2017; 49 ([published Online First: 2017/06/18])https://doi.org/10.1183/13993003.02396-2016
        • Judson M.A.
        • Baughman R.P.
        Worsening of pulmonary sarcoidosis.
        Curr. Opin. Pulm. Med. 2014; 20 ([published Online First: 2014/07/16]): 508-516https://doi.org/10.1097/mcp.0000000000000082
        • Lal C.
        • Medarov B.I.
        • Judson M.A.
        Interrelationship between sleep-disordered breathing and sarcoidosis.
        Chest. 2015; 148 ([published Online First: 2015/05/23]): 1105-1114https://doi.org/10.1378/chest.15-0584
        • Lazenby J.P.
        • Guzzo M.R.
        • Harding S.M.
        • et al.
        Oral corticosteroids increase esophageal acid contact times in patients with stable asthma.
        Chest. 2002; 121 ([published Online First: 2002/02/09]): 625-634https://doi.org/10.1378/chest.121.2.625
        • Judson M.A.
        The three tiers of screening for sarcoidosis organ involvement.
        Respir. Med. 2016; 113 ([published Online First: 2016/03/30]): 42-49https://doi.org/10.1016/j.rmed.2016.02.011
        • Tavee J.O.
        • Karwa K.
        • Ahmed Z.
        • et al.
        Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment.
        Respir. Med. 2017; 126 ([published Online First: 2017/03/21]): 135-138https://doi.org/10.1016/j.rmed.2017.03.011
        • Kersting-Sommerhoff B.
        • Hof N.
        • Golder W.
        • et al.
        MRI of the wrist joint: "granulomatous tenovaginitis of the sarcoidosis type"--a rare cause of carpal tunnel syndrome.
        Rontgenpraxis. 1995; 48 ([published Online First: 1995/07/01]): 206-208
        • Drent M.
        • Lower E.E.
        • De Vries J.
        Sarcoidosis-associated fatigue.
        Eur. Respir. J. 2012; 40 ([published Online First: 2012/03/24]): 255-263https://doi.org/10.1183/09031936.00002512
        • Chang B.
        • Steimel J.
        • Moller D.R.
        • et al.
        Depression in sarcoidosis.
        Am. J. Respir. Crit. Care Med. 2001; 163: 329-334
        • Elfferich M.D.
        • Nelemans P.J.
        • Ponds R.W.
        • et al.
        Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-alpha treatment.
        Respiration. 2010; 80 ([published Online First: 2010/05/01]): 212-219https://doi.org/10.1159/000314225
        • Moller D.R.
        Negative clinical trials in sarcoidosis: failed therapies or flawed study design?.
        Eur. Respir. J. 2014; 44 ([published Online First: 2014/11/02]): 1123-1126https://doi.org/10.1183/09031936.00156314
        • Korsten P.
        • Strohmayer K.
        • Baughman R.P.
        • et al.
        Refractory pulmonary sarcoidosis - proposal of a definition and recommendations for the diagnostic and therapeutic approach.
        Clin. Pulm. Med. 2016; 23 ([published Online First: 2016/03/15]): 67-75https://doi.org/10.1097/cpm.0000000000000136
        • Dixon W.G.
        • Abrahamowicz M.
        • Beauchamp M.E.
        • et al.
        Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis.
        Ann. Rheum. Dis. 2012; 71 ([published Online First: 2012/01/14]): 1128-1133https://doi.org/10.1136/annrheumdis-2011-200702
        • Wolfe F.
        • Caplan L.
        • Michaud K.
        Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy.
        Arthritis Rheum. 2006; 54 ([published Online First: 2006/02/01]): 628-634https://doi.org/10.1002/art.21568
        • Sepkowitz K.A.
        • Brown A.E.
        • Telzak E.E.
        • et al.
        Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.
        JAMA. 1992; 267 ([published Online First: 1992/02/12]): 832-837
        • Wilson J.C.
        • Sarsour K.
        • Collinson N.
        • et al.
        Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): a nested case-control analysis.
        Semin. Arthritis Rheum. 2017; 46 ([published Online First: 2017/01/04]): 819-827https://doi.org/10.1016/j.semarthrit.2016.11.006
        • Panoulas V.F.
        • Douglas K.M.
        • Stavropoulos-Kalinoglou A.
        • et al.
        Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis.
        Rheumatology. 2008; 47 ([published Online First: 2007/12/14]): 72-75https://doi.org/10.1093/rheumatology/kem311
        • Judson M.A.
        • Baughman R.P.
        • Costabel U.
        • et al.
        Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.
        Eur. Respir. J. 2014; 44 ([published Online First: 2014/07/19]): 1296-1307https://doi.org/10.1183/09031936.00000914
        • Sweiss N.J.
        • Noth I.
        • Mirsaeidi M.
        • et al.
        Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis.
        Sarcoidosis Vasc. Diffuse Lung Dis. 2014; 31 ([published Online First: 2014/04/23]): 46-54
        • Sweiss N.J.
        • Lower E.E.
        • Mirsaeidi M.
        • et al.
        Rituximab in the treatment of refractory pulmonary sarcoidosis.
        Eur. Respir. J. 2014; 43 ([published Online First: 2014/02/04]): 1525-1528https://doi.org/10.1183/09031936.00224513
        • Baughman R.P.
        • Drent M.
        • Kavuru M.
        • et al.
        Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
        Am. J. Respir. Crit. Care Med. 2006; 174: 795-802