Introduction
Sarcoidosis is a granulomatous inflammatory disease of unknown etiology that affects the entire body and characteristically forms non-caseating granulomas. It mainly affects young people, particularly the lungs, eyes, and skin. It can also occur in the liver, spleen, lymph nodes, salivary glands, heart, nervous system, muscles, and bones [1,2]. Skin lesion associated with sarcoidosis was first described by a dermatologist Jonathan Hutchinson in 1877, and it was given the name ‘sarcoid’ by Caesar Boeck for its pathological similarity to sarcoma [3].
Prevalence and incidence rates of sarcoidosis vary by gender, race, and region. Lung sarcoidosis is prevalent among the ages of 30 and 60, and according to a study conducted in Europe from 1976 to 2015, the average age of symptom onset for this disease was 43 years [4]. Similarly, a Japanese study conducted from 2002 to 2011 reported an average age for this symptom onset as 54 years, which showed a bimodal distribution [5]. For female subjects, in particular, the first peak is known to be between the ages of 30 and 40, and the second peak is known to be around 50 years of age. According to a study in the United States, the incidence rate of sarcoidosis in women was reported to be 11 per 100,000 on average, and the incidence was higher in African Americans than in Caucasians [6].
In Korea, two studies reporting the prevalence of sarcoidosis as of 2015 showed that the prevalence was 9.37 and 3.24 per 100,000 people, respectively, and that the prevalence increased over time [7,8]. According to medical statistics from the Korea Health Insurance Review and Assessment Service, the number of cases has increased by approximately 200 per year over the past 10 years, and 3,765 pulmonary sarcoidosis patients were registered in 2022 (Figure 1). According to rare disease registration statistics from the Korea Disease Control and Prevention Agency, the crude incidence rate of sarcoidosis for 2019 to 2020 was confirmed to be 0.62 and 0.51 per 100,000 people. Notably, the incidence of pulmonary sarcoidosis was higher in women than in men.
Etiology and Pathogenesis Etiology
1. Possible causative agents
Causative agents of sarcoidosis include microorganisms such as mycobacteria and propionibacteria [9]. These microorganisms have a particularly high lipid content in their cell membranes, which allows them to resist degradation within the phagosomes of macrophages and to endure for a long time. Several studies verified evidences that pathogen-associated molecular patterns for these antigens cause or amplify sarcoidosis inflammation [10-13].
Environmental and occupational exposure to beryllium, zirconium, aluminum, silica, pesticides, and mold are also associated with the development of sarcoidosis [14-17]. Some workers exposed to dust during rescue and recovery after the collapse of the World Trade Center on September 11, 2001 experienced sarcoidosis or a sarcoidosis-like disease [18]. In addition, there was a recent report that autoimmune response to vimentin, one of the structural proteins, plays a role in the development of sarcoidosis [19].
2. Genetic factors
Immune response of sarcoidosis patients is determined by genetic susceptibility. Several studies have reported that major histocompatibility complex 2 (MHC-2) gene mutations are associated with susceptibility, phenotype, and prognosis of sarcoidosis. In particular, specific MHC-2 alleles could determine disease progression (HLADRB1* 03; spontaneous healing vs. HLA-DRB1*14 or HLA-DRB1*15; chronic disease) [20]. However, this pattern varies depending on the ethnic and racial composition of the study population, and the correlation is relatively weak [21-24]. In addition, several genes involved in the regulation of immune responses, such as Toll-like receptors and MHC-2 transactivators, are believed to be involved in the development of sarcoidosis [25-27].
3. Inflammatory reaction
Complex interactions between immune cells and their mediators play an important role in granuloma formation in sarcoidosis. Granuloma formation begins when monocytes differentiate into antigen-presenting cells, such as macrophages or dendritic cells, by stimulation of an unidentified external antigen. Macrophages or dendritic cells phagocytose antigens and present them on the cell surface [28,29]. In addition to presenting antigens, alveolar macrophages are also believed to play an important role in determining the course of the disease, that is, whether it will heal naturally or cause chronic inflammation [30].
CD4+ T lymphocytes recognize antigens presented by macrophages and secrete Th1 immune response cytokines such as interferon-γ and interleukin-2 (IL-2) to amplify the immune response. Analysis of the bronchoalveolar lavage (BAL) fluid of patients with sarcoidosis reveals significant increase of CD4+ T lymphocytes, whereas CD4+ T lymphocytes in blood are decreased. Reduced antagonism of regulatory T cells (Treg) also contributes to amplification of the Th1 immune response.
CD4+ T lymphocytes are closely related to the course of the disease. In cases of spontaneous remission, CD4+ Th1 and Treg lymphocyte functions are also restored, whereas in cases of persistent T lymphocyte anergy, the disease progresses [31]. In sarcoidosis, IL-17 production increases and number of Th17 lymphocytes also increases, but their roles are not yet well known [32].
4. Granuloma formation
Granulomas are formed as a result of a long-term, chronic inflammatory response. When macrophages react to antigen and aggregate, they evolve into epithelioid cells, and further stimulation by inflammatory mediators causes macrophages and dendritic cells to fuse into multinucleated giant cells. As the granuloma matures, macrophages, epithelioid cells, and a few multinucleated giant cells form a tight central cluster [28,29]. Most of the lymphocytes in the granuloma are CD4+ Th1 lymphocytes, and the periphery of the granuloma is composed of CD4+ and CD8+ T lymphocytes. Granulomas in sarcoidosis may disappear without sequelae or undergo necrotic fibrosis, which may result in interstitial fibrosis [33]. Patients undergoing spontaneous healing process show increased secretion of transforming growth factor-β, an immunosuppressive cytokine [34].
Clinical Manifestations
1. Pulmonary manifestations
Sarcoidosis is most commonly manifested as an interstitial lung disease accompanied by pulmonary and mediastinal lymphadenopathy or perilymphatic nodules that mainly appear in the upper lobes, but pneumothorax, pleural thickening, and chylothorax may also develop. More than 80% of patients show abnormalities on chest X-ray [25], and even if lung involvement is severe, physical examination is often normal and therefore crackles or clubbing are rare. Respiratory symptoms appear in approximately 30% to 53% of patients at the time of diagnosis, and include coughing, difficulty breathing, and chest pain [2,4]. Approximately 10% of patients visit hospital with chronic dyspnea mainly due to lung fibrosis. Pulmonary hypertension and cor pulmonale may also occur, which is caused by pulmonary fibrosis or vascular occlusion.
In approximately 10% to 15% of patients, the upper respiratory tract is involved. Sarcoidosis can also occur in the larynx, salivary glands, pharynx, nose, and paranasal sinuses, and the most common finding is lymphadenopathy in the head and neck. Laryngeal involvement in sarcoidosis mainly occurs in the supraglottic area, and vocal cord involvement is rare. Symptoms include dysphagia, difficulty on breathing, and hoarseness. When the nose and paranasal sinuses are involved, nasal congestion is the most common symptom, but other manifestations include rhinorrhea, dried nasal mucosa, anosmia, nasal polyps, and facial pain [35].
2. Extrapulmonary manifestations
Sarcoidosis most commonly involves the respiratory system, but it can basically affect any organ (Table 1). Systemic symptoms such as fatigue, general weakness, weight loss, and decreased appetite are reported in up to 70% of cases [36], and are especially common in elderly patients. Fever may also occur, but when a patient with granulomatous inflammation develops fever, an infectious disease such as tuberculosis should be excluded. Löfgren syndrome is a distinct phenotype of sarcoidosis, which is characterized by bilateral hilar lymphadenopathy accompanied by fever, erythema nodosum, and bilateral ankle arthritis or periarthritis [2].
Eye involvements are common to be found in about 25% of sarcoidosis patients, therefore the recently published American Thoracic Society (ATS) practice guidelines recommended an ophthalmological examination even if there are no eye symptoms [37]. Uveitis, especially anterior uveitis, is the most frequent manifestation, and common symptoms are dry eyes, decreased vision, glare, and redness. Skin symptoms may include erythema multiforme, papules, plaques, erythema nodosum, subcutaneous nodules, and lupus pernio. Erythema nodosum is the most common lesion, reported in up to 25% of patients [38].
Symptomatic cardiac sarcoidosis is rarely reported, but there are reports that it is observed in 25% to 70% of autopsies of subjects with systemic sarcoidosis. Arrhythmias, heart failure, valve abnormalities, myocardial infarction, and pericardial disease may occur [2], and the most common arrhythmia is atrioventricular block (45%) [39]. It may be asymptomatic, but some patients may present with tachycardia, syncope, dizziness, or chest pain, and may manifest as sudden death due to arrhythmia. Having cardiovascular symptoms or abnormal electrocardiogram findings on diagnosis is an important risk factor for cardiac sarcoidosis. Cardiac sarcoidosis is very rare in patients with no cardiac symptoms and normal electrocardiogram findings.
On the urinary system, symptoms related to calcium metabolism are the most common manifestations. Calcium metabolism abnormalities are due to activated macrophages producing calcitriol (1,25-dihydroxycholecalciferol), which increases calcium absorption in the intestines and causes hypercalcemia, hypercalciuria, nephrocalcinosis, and urinary stones. Other renal complications include granulomatous interstitial nephritis, immunoglobulin A glomerulonephritis, membranous glomerulonephritis, proliferative or crescentic glomerulonephritis, and focal segmental glomerulosclerosis [40]. Liver or spleen involvement is observed in 80% of patients at autopsy [41], but it is rare in clinical practice and is often discovered as asymptomatic liver function abnormality or spleen enlargement [2]. Enlarged lymph nodes in the abdomen are seen in about 30% of patients, and if they are large, other diseases such as lymphoma should be differentiated. In addition, sarcoidosis can occur in all organs, including joints, nerves, endocrine and exocrine glands, and male and female reproductive organs [2].
Diagnosis
1. Radiologic diagnosis
Sarcoidosis affects the thoracic organs in more than 80% to 90% of the cases [42]. Therefore, the most important radiological test in diagnosing sarcoidosis is chest imaging, and it is better confirmed by computed tomography (CT) than by simple chest X-ray. Nuclear medicine tests such as fluorodeoxyglucose-positron emission tomography can also be helpful, but it is difficult to adopt in actual Korean clinical settings [43].
1) Chest X-ray
In cases suspicious of having sarcoidosis, a chest X-ray is a mandatory study. The most classic and representative finding seen in chest X-ray is bilateral hilar and mediastinal lymph node enlargement. When the lung parenchyma is involved, it is mainly observed as a micronodular infiltration, but it is difficult to clearly observe the lesion on a chest X-ray. Lung parenchymal involvement is less common than hilar and mediastinal lymph node enlargement. According to the chest X-ray findings, sarcoidosis is classified into stages 1 to 4 as follows [44] (Table 2 and Figure 2).
2) Chest CT
Chest CT scan can examine changes in lung parenchyma in more detail than a chest X-ray, and can identify which lymph nodes are involved. The role of chest CT is essential for the exclusion of other diseases and determination of an approach for histological confirmation.
In cases of lymph node enlargement, paratracheal and hilar lymph nodes are most commonly involved (Figure 3). It is mainly affected bilaterally but also in a unilateral fashion, and calcification of lymph nodes is observed in 40% to 50% of cases. When lymph node enlargement is observed, it cannot be completely differentiated radiologically from hemato-oncological diseases such as lymphoma, so unless there are clinical findings that strongly suggest sarcoidosis (e.g., typical symptoms of Löfgren syndrome), the diagnosis of sarcoidosis cannot be confirmed. Histological confirmation therefore should be mandatory.
Lung parenchymal involvement can appear in a variety of forms, including micronodules, ground-glass opacity, reticulation, and fibrosis. The most common pattern is micronodules, in which small nodules of about 2 to 5 mm showing characteristic perilymphatic distribution in sites such as bronchovascular bundle, fissure, and subpleural area. Small nodules can fuse to form a nodule or mass measuring 1 to 4 cm, and may show the so-called sarcoid galaxy sign (Figure 4). Therefore, differentiation from lymphangitic metastasis is essential. Additionally, the prevalence of tuberculosis is high in Korea, and micronodule-shaped lesions are sometimes difficult to distinguish from pulmonary tuberculosis, which shows a more centrilobular distribution (Figure 5). As the disease progresses, micronodules and ground-glass opacities generally decrease, and reticular opacities and fibrosis of the lung parenchyma progress, leading to irreversible destruction of the lung parenchyma.
2. Histopathologic diagnosis
1) Histopathologic approach
If there are signs of sarcoidosis involvement in sites other than the chest that are more easily accessible for biopsy (e.g., skin lesions, cervical lymph nodes, etc.), a biopsy in those easily accessible areas are attempted. Since most cases of sarcoidosis involve the chest, tissue examination from the thoracic organs is often necessary, and bronchoscopy is an important tool for this purpose. However, when clinical findings strongly suggest sarcoidosis (e.g., typical symptoms of Löfgren syndrome), diagnosis is possible without histological diagnosis. There is still controversy as to whether histological examination must be performed to diagnose sarcoidosis when hilar and mediastinal lymphadenopathy is incidentally identified without any symptoms [45].
When planning histological diagnosis, the approach method is determined based on chest imaging findings. If lymphadenopathy is observed, lymph node biopsy should be considered, and if only the lung parenchyma is involved without lymphadenopathy, lung biopsy is considered. When abnormal mucosal findings such as redness or changes in the form of nodules are observed in the bronchial mucosa through bronchoscopy, tissue can be obtained by performing a direct endobronchial biopsy of the mucosa.
In the case of lymph node biopsy, mediastinoscopy was performed in the past, but currently diagnosis can be made more non-invasively through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The accuracy of the EBUS-TBNA in diagnosing sarcoidosis is high, approximately 80% to 90%, and complications such as bleeding and pneumothorax are rare, less than 1% [46]. Therefore, when considering lymph node biopsy, biopsy using EBUS-TBNA is attempted first.
When there are no lymphadenopathy findings that justifies EBUS-TBNA, lung biopsy can be considered. Traditionally, the transbronchial lung biopsy (TBLB) method has been used, but the diagnostic accuracy differs between 40% and 90% [47]. This is not only because the amount of tissue that can be obtained through TBLB is small, but also because the amount of tissue obtained varies depending on the operator, and when the tissue is obtained, it is often accompanied by crush artifacts. In cases where diagnosis is difficult with TBLB alone, transbronchial lung cryobiopsy (TBLC), which was recently introduced and is being actively studied in the diagnosis of interstitial lung disease, is expected to play an additional role [48]. The use of surgical lung biopsy (SLB) for diagnosing sarcoidosis has decreased significantly due to the development of bronchoscopy technology, but SLB may be necessary on cases where TBLB or TBLC are not feasible. Diagnosis of sarcoidosis through bronchoscopy can be summarized as the following approach (Figure 6).
2) Histopathology
The histopathological findings of sarcoidosis are characterized by non-caseating, non-necrotizing granulomas (Figure 7). Under the microscope, it is characterized by clusters of epithelioid histiocytes crowded together, and multinucleated giant cells are often observed together. As seen in imaging findings, this granulomatous inflammation mainly occurs along the vascular bundles and around lymphatics.
Occasionally caseation necrosis may be observed, and the possibility of tuberculosis must be considered first. In particular, as the prevalence of tuberculosis is high in Korea, a definitive diagnosis of sarcoidosis cannot be made immediately when granulomas are observed in tissue examination. After tuberculosis, non-tuberculous mycobacteria, or fungal infection are excluded through additional tests, a diagnosis of sarcoidosis can be made at last.
3. Others
1) Blood test
In the process of diagnosing patients with sarcoidosis, in addition to basic blood tests such as complete blood counts, liver function, and renal function tests, serum angiotensin converting enzyme (ACE) has traditionally been widely used [49]. However, there is still controversy regarding the diagnostic value of the serum ACE in confirming the diagnosis of sarcoidosis in actual clinical settings, as false negatives or positives may result [50]. For example, if an ACE inhibitor is taken as a blood pressure lowering agent, a false negative result may occur, and, conversely, a false positive result may occur in pulmonary tuberculosis. Therefore, in the diagnosis of sarcoidosis itself, histological diagnosis should be prioritized, and the serum ACE test should be understood as providing additional auxiliary information.
2) Pulmonary function test
Since sarcoidosis frequently involves the lungs, pulmonary function test is often used to assess and monitor the severity of lung involvement. However, there are cases where pulmonary function test is good despite definite lung involvement; hence, clinical symptoms, radiological tests, and pulmonary function test results should be comprehensively considered when evaluating a patient in a clinical setting.
When pulmonary sarcoidosis has progressed to a certain degree, pulmonary function test finding is a usually restrictive ventilatory defect patten with a decrease in effort vital capacity, lung volume, and diffusing capacity. However, if there are bronchial distortions due to pulmonary fibrosis, primarily involvement of the bronchial trees, or the bronchial trees compressed by enlarged lymph nodes, obstructive pattern may appear. If diffusing capacity is significantly reduced compared to the degree of restrictive ventilatory defect, pulmonary hypertension should be evaluated.
Treatment
Recommendation
For patients with first-diagnosed pulmonary sarcoidosis with clinically significant disease, oral steroid treatment is recommended to alleviate or prevent disease progression. (Level of evidence: moderate; and recommendation grade: strongly recommended) (Voting result: Strongly recommended 7/7)
1. Indications for treatment
The most important factors determining the treatment of patients with sarcoidosis are whether there is a risk of death, organ failure, or loss of quality of life [51-55]. Approximately 5% of sarcoidosis patients die from the disease, and lung or heart involvement is the most common cause of death from sarcoidosis [56]. Death from pulmonary sarcoidosis is associated with decreased lung function due to pulmonary hypertension and pulmonary fibrosis [56-59].
Anti-inflammatory drugs, including steroids, can prevent the progression of the disease. However, various concomitant diseases found with sarcoidosis (coronary artery disease, stroke, arthritis, depression, diabetes, high blood pressure, osteoporosis, and fractures) are likely to worsen with sarcoidosis treatment, and the risk of developing infectious diseases also increases with long-term treatment. Therefore, taking these factors into consideration, treatment should be initiated in cases where there is a potential risk of death or permanent disability due to sarcoidosis or loss of quality of life.
2. Pharmacological treatment
As said before, treatment for sarcoidosis must be determined by verifying whether there is a risk of death or serious pulmonary dysfunction or loss of quality of life, while taking into account the patient’s opinion. In fact, cases of severe lung involvement are often accompanied by other organ involvement and debilitating symptoms, so treatment is often necessary.
Disease-modifying drugs can be broadly divided into three categories: (1) Steroids (e.g., prednisolone); (2) Immunosuppressants (methotrexate, azathioprine, mycophenolate, leflunomide, and hydroxychloroquine); (3) Biologics (e.g., infliximab).
The first-line treatment attempted is steroid and treatment should be carried out in a multidisciplinary approach by integrating various variables observed in the patient.
1) Steroid therapy
Initiating steroid treatment should be decided considering patient’s symptoms, imaging findings, and pulmonary function. However, the use of steroids is not helpful in cases of already advanced pulmonary fibrosis. Improvement after treatment is evaluated based on the subject’s symptoms, chest radiology, and lung function.
As part of this research, a systematic literature review on the effects of steroids was conducted. A total of four randomized clinical trials and one observational study were identified, and we found that steroids were more effective than the control group without treatment on meta-analysis. It was confirmed that steroid treatment improved the disease or at least prevented its aggravation.
However, when using steroids in real clinical practice, the exact dosage of prednisolone varies depending on the clinical setting. If the disease has persisted for a long time and progresses slowly, a low-dose of prednisolone of 10 mg/day may be sufficient for treatment, while aggressive treatment using high-dose methylprednisolone therapy is rarely recommended for very rapidly progressing extrapulmonary diseases (e.g., cardiac sarcoidosis, neurosarcoidosis, and severe optic neuritis). Even if the physician does not start an immediate management and monitor the progress, starting treatment is considered if there is evidence of disease progression, such as symptom aggravation.
In general, if there is no life-threatening disease, initial treatment begins with 20 to 40 mg/day of prednisolone for 4 to 6 weeks, then slowly tapered to 5 to 10 mg/day for 6 to 12 months, and consider discontinuation when the disease goes into remission. All patients using steroids for a long period of time should be aware of side effects and take appropriate preventive treatment.
If the illness relapses on discontinuing steroids or reducing its dose, it is appropriate to restart on a higher dose and then taper slowly. If side effects of steroids occur or it is difficult to reduce because of recurrence, consider coadministration of other second- or third-line drugs is an alternative way of treatment.
Löfgren’s syndrome, which is reported in up to 30% of sarcoidosis patients, may be treated with non-steroidal anti-inflammatory drugs alone for arthralgia. But systemic symptoms (especially severe arthralgia) often require steroid therapy with a treatment period of less than 3 months in general. A high-dose of 30 to 40 mg of prednisolone for 1 to 2 weeks and then reducing the dose is recommended.
2) Secondary immunosuppressants
Before introducing second-line drugs, it is necessary to carefully check the diagnosis of sarcoidosis and patients’ compliance with the treatment. If second-line medication is required, referral to a tertiary hospital should be considered.
Indications for second-line drugs are as follows: (1) progression of lung disease, or severe symptom despite appropriate steroid treatment; (2) severe steroid side effects; (3) unable to taper prednisolone to less than 10 to 15 mg per day [62-65]; (4) major comorbidities that can be aggravated by steroid treatment (severe obesity, diabetes, osteoporosis, and hypertension); (5) patient having a strong aversion to steroid use.
Second-line treatments include methotrexate, azathioprine, mycophenolate mofetil (MMF), and leflunomide. These drugs have side effects including myelosuppression, hepatotoxicity, and opportunistic infections, so blood test monitoring is required. Glomerular filtration rate of less than 30, abnormal liver function (more than twice the upper limit of normal liver function) without liver involvement due to sarcoidosis, hepatitis B, and hepatitis C are common conditions requiring caution on administration.
Methotrexate is an antimetabolite and one of the most widely used second-line drugs for pulmonary sarcoidosis, but there are no reports of its superiority over azathioprine. Methotrexate is administered orally, starting at 5 to 10 mg/week and increasing the dose every 2 weeks, up to 15 to 20 mg per week. If there are symptoms such as nausea or the response is insufficient even after 6 months, it can be administered by subcutaneous injection. Simultaneously, folic acid should be administered to prevent bone marrow suppression. Methotrexate-induced pneumonitis is rare, but it is difficult to differentiate it from the progression of interstitial pulmonary fibrosis caused by sarcoidosis. Generally, symptoms such as dry cough, shortness of breath, and fever occur acutely within a few days to several weeks of starting treatment, but in some cases, they develop slowly, and their incidence is about 0.2% [66]. A new ground-glass opacities with a different pattern from the preexistent imaging abnormality found on a chest X-ray or CT may raise suspicion, and most cases recover after discontinuation of the drug. Other important complications include liver fibrosis, which occurs in approximately 10% of patients when the cumulative dose exceeds 5 g or when treated for approximately 2 years with standard doses. Other symptoms include leukopenia, nausea, alopecia, and skin rash [67].
Azathioprine is a drug that inhibits lymphocyte proliferation, a key characteristic of sarcoidosis, by affecting RNA and DNA synthesis. Its mechanism of action in sarcoidosis is not clear [68]. Its starting dose is 50 mg per day, then increase by 25 mg every 2 to 3 weeks to maintain 2 mg/kg. Side effects of this drug include nausea, vomiting, diarrhea, rash, fever, pancytopenia, abnormal liver function, and risk of malignant tumor. Before starting treatment, it should be confirmed that the thiopurine methyltransferase serum concentration is normal. According to a study directly comparing methotrexate and azathioprine, there was no difference in treatment effect, and the infection rate was higher in the patient group treated with azathioprine (35% vs. 18%), which was interpreted to be due to the use of prophylactic antibiotics in the methotrexate treated patient group [69].
MMF is an inhibitor of lymphocyte proliferation and activity, and is used to treat interstitial lung disease associated with various connective tissue diseases with a fair drug tolerance [70]. Since data on the use of MMF in sarcoidosis are limited, it should not be used before methotrexate or azathioprine unless there is a specific reason not to do so. One retrospective analysis showed that MMF was effective in patients who failed initial second-line treatment [71]. Usual dosage of MMF is 1 to 1.5 g twice a day. There is less neutropenia than other immunosuppressants. Nausea and diarrhea may occur, and like other second-line drugs, it has the potential to cause teratogenic effects in women of childbearing age [72].
Leflunomide is an antimetabolite resembling methotrexate, but has less gastrointestinal toxicity and can be used as monotherapy or in combination with methotrexate. Side effects include nausea, diarrhea, abdominal pain, hypertension, hepatotoxicity, rash, and peripheral neuritis.
Hydroxychloroquine is primarily used for fatigue, joint and skin sarcoidosis, but can be used as an adjunct for discontinuing high-dose prednisolone. Typically, 200 mg of hydroxychloroquine is taken once or twice a day. In rare cases, retinal and cardiac toxicity may occur, and if treatment is required for more than 5 years, an ophthalmological examination is recommended at the start of treatment (or within 12 months of starting treatment) and annually after treatment, and an electrocardiogram (long QT) should also be checked.
All patients with long-term immunosuppression should be aware of the risk of infection and, if necessary, be able to prevent Pneumocystis jiroveci pneumonia. When administering any form of immunosuppressant, the possibility of drug interaction with existing drugs should be reviewed, and the dose should be reduced if there is liver or kidney disease.
However, among the above-mentioned immunosuppressants, methotrexate and azathioprine are mainly used in Korea, and as of June 2023, MMF and leflunomide are not approved for use in sarcoidosis.
3) Biological agents and antifibrotic agents
Biological agents are third-line treatments and are used only when second-line treatment fails. Tumor necrosis factor (TNF), one of the inflammatory cytokines, is known to promote the inflammatory process in sarcoidosis by maintaining granuloma formation. Therefore, the use of drugs that block the effects of TNF may be helpful in the treatment of sarcoidosis, especially in the treatment of sarcoidosis patients with decreased CD4+ lymphocytes [73].
Infliximab can be beneficial in disease control when administered in combination with methotraxate or azathioprine [73-75]. Major side effects include increased risk of infection, infusion reaction, alopecia, oral candidiasis, visual field defects, and pulmonary embolism. In particular, patients should be tested for latent tuberculosis infection before treatment due to increased susceptibility to mycobacterial and invasive fungal infections [76]. If latent tuberculosis is discovered, anti-tuberculosis treatment should be administered according to guidelines before starting biologic agent. Paradoxically, the occurrence of non-proliferative granulomas similar to sarcoidosis has been reported during anti-TNF treatment for other diseases [77]. Infliximab is administered twice every 2 weeks for the first time and then every 4 to 8 weeks as maintenance therapy. However, infliximab has not been approved for pulmonary sarcoidosis in Korea.
3. Lung transplantation
In cases with advanced pulmonary fibrosis and accompanying pulmonary hypertension, lung transplantation may be considered. After lung transplantation, asymptomatic foci of nonproliferative granulomas have been identified in the allograft, but recurrence rarely progresses to a clinically significant organ dysfunction [80-82].
4. Fatigue treatment
Anemia, vitamin D deficiency, iron deficiency, thyroid dysfunction or hypercalcemia, and sleep disorders associated with sarcoidosis can all cause fatigue, so if a patient complains of fatigue, other causes should be ruled out. If vitamin D is administered as needed, it must be administered with caution as there is a risk of fatal hypercalcemia, renal stones, and renal failure. If fatigue is not caused by other diseases, steroid treatment can be attempted. There are no clear guidelines for treatment dosage, but in most cases, low-dose maintenance therapy (e.g., prednisolone 5 to 10 mg/day) is sufficient. Although evidence is lacking, combination therapy with hydroxychloroquine and steroids may be helpful [83]. In addition to pharmaceutical treatment, symptom diaries or exercise can be recommended. Notably, it is important to combine various treatment strategies, discuss various treatment options with the patient, set treatment goals, and regularly follow-up on symptoms.
5. Discontinuation of treatment and monitoring
In patients with sarcoidosis, particularly with patient’s symptoms, pulmonary function tests, and chest radiographs, the following parameters should be evaluated. (1) If recently diagnosed, will it be cured naturally? (2) If untreated, will it progress or show improvement? (3) Is anti-inflammatory treatment effective? (4) Whether the treatment will relapse if the treatment is reduced or treatment is discontinued.
1) Symptoms
The patient’s symptoms are evaluated on every hospital visit. As evaluation of symptoms may be difficult due to side effects of steroid treatment or accompanying respiratory infections, confirmation through chest X-ray and pulmonary function tests is necessary if worsening is suspected. In particular, if breathing difficulty deteriorates, it is important to keep in mind whether cardiac sarcoidosis, pulmonary embolism, or pulmonary hypertension has occurred.
2) Pulmonary function test
Pulmonary function tests track the changes in obstructive, restrictive ventilation defect, and diffusing capacity. There is no standard threshold for changes in pulmonary function tests in sarcoidosis, but generally, a 10% decrease in forced vital capacity and a 15% decrease in diffusing capacity for carbon monoxide (DLCO) compared to baseline is considered a meaningful reduction. However, in sarcoidosis, the pulmonary function test results alone do not determine the course of the disease.
3) Chest X-ray
When pulmonary sarcoidosis worsens, an increase of infiltration is seen on chest X-ray, associated with worsening of the patient’s symptoms. In particular, aggravation of chest radiographs after discontinuation of steroid treatment may appear before deterioration of symptoms and is therefore a major tool of detecting early recurrence [84].
4) Chest CT
Regular CT follow-up is not recommended, but it may be useful in assessing disease progression when the patient’s symptoms, chest X-ray, and physiological findings do not match each other. In particular, changes in lung parenchyma are important in evaluating disease progression [85], and lymph node enlargement alone is not an indicator of disease progression.
5) Serum ACE and disease activity indicators
Serum ACE activity, BAL lymphocytes, and gallium scanning have poor correlation with disease progression and are of little value in monitoring sarcoidosis or assessing response to its treatment. Serum calcium concentration should be monitored as there is a risk of hypercalcemia, but high cholecalciferol levels due to ultraviolet rays are high in summer.
6) Discontinuation of medication
Discontinuation of steroid therapy is attempted when 6 to 12 months elapsed after sarcoidosis is well controlled. To date, the optimal period of use of steroids is unknown, and according to the ATS/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement proposed in 1999, treatment for at least 1 year was recommended. However, long-term oral steroids administration may entail side effects such as weight gain, diabetes, and osteoporosis. A systematic literature review was attempted to find evidence on the period of use on making this guideline, but no suitable study that could serve as evidence was found. Therefore, recommendations regarding the treatment period for patients with pulmonary sarcoidosis could not be proposed.
The most important aspect for observation after reducing or discontinuing treatment is the recurrence of disease. The risk of recurrence is higher in patients receiving steroids than in patients not receiving treatment. The frequency of recurrence after discontinuation of treatment is reported to be about 13% to 75% [86], and most recurrences occur within 1 year after discontinuation of treatment, rare after 3 years [87].
7) Follow-up
For Löfgren syndrome or stage 1 sarcoidosis, follow-up is conducted at 6-month intervals for 2 years, and for stages 2 to 4 sarcoidosis, follow-up is conducted for 2 years at 3- to 6-month intervals, and thereafter at 1-year intervals. Sarcoidosis of major organs originating outside the lungs is followed up for a longer period of time at 3- to 6-month intervals. After discontinuing steroid treatment, follow-up is performed at 2- to 3-month intervals for the first year and then at 3- to 6-month intervals for at least 3 years [88].
Natural History and Prognosis
The natural history of sarcoidosis is very variable. Approximately two-thirds of patients show spontaneous remission, and only 10% to 30% of patients show chronic or progressive form. The response to steroid treatment is good, with most patients being stabilized or improved [44].
Among sarcoidosis patients, those with Löfgren syndrome, including erythema nodosum and acute inflammatory reactions (fever, arthritis, etc.), are known to have a high probability of spontaneous remission and a good prognosis. On the other hand, extrapulmonary organ involvement, onset after an age of 40 years, progressive pulmonary sarcoidosis, pulmonary hypertension, and black are factors that suggest a poor prognosis. In addition, there are reports on genetic factors regarding the natural history and BAL fluid results, but these are not clearly established, therefore additional research is needed [1].
In patients with pulmonary sarcoidosis, radiological stage is highly correlated with prognosis and mortality. In several cohort studies, radiological improvement based on radiological stages was 49%-82% in stage 1 patients, 31%-68% in stage 2, 10%-38% in stage 3, and 0 in stage 4. Mortality rate is also highly correlated with the stage, with the mortality rate reported to be 0%-9% for stage 1 patients, 5%-11% for stage 2 patients, 12%-18% for stage 3 patients, and 16%-17% for stage 4 patients [52,89-91].
The overall mortality rate is low at 3% to 5%, and progressive respiratory failure due to pulmonary sarcoidosis is reported to be the main cause, but cardiac involvement is reported to be the most common cause in Japan [92-94]. A study using data from the Korean Health Insurance Review and Assessment Service reported that the mortality rate of sarcoidosis patients was 1.7 times higher compared to the general population [7].
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