Review

Sarcoidosis: Causes, Diagnosis, Clinical Features,

and Treatments
Rashi Jain 1,† , Dhananjay Yadav 2,† , Nidhi Puranik 3,† , Randeep Guleria 1 and Jun-O Jin 2,4, *
1 Department of Pulmonary Critical Care and Sleep Medicine, AIIMS, New Delhi 110029, India;
[email protected] (R.J.); [email protected] (R.G.)
2 Department of Medical Biotechnology, Yeungnam University, Gyeongsan 712-749, Korea;
[email protected]
3 Department of Biological Science, Bharathiar University, Coimbatore, Tamil Nadu-641046, India;
[email protected]
4 Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College,
Fudan University, Shanghai 201508, China
* Correspondence: [email protected]; Tel.: +82-53-810-3033; Fax: +82-53-810-4769
† These authors contributed equally to this work.


Received: 5 March 2020; Accepted: 8 April 2020; Published: 10 April 2020

Abstract: Sarcoidosis is a multisystem granulomatous disease with nonspecific clinical manifestations

that commonly affects the pulmonary system and other organs including the eyes, skin, liver,
spleen, and lymph nodes. Sarcoidosis usually presents with persistent dry cough, eye and skin
manifestations, weight loss, fatigue, night sweats, and erythema nodosum. Sarcoidosis is not
influenced by sex or age, although it is more common in adults (< 50 years) of African-American
or Scandinavians decent. Diagnosis can be difficult because of nonspecific symptoms and can only
be verified following histopathological examination. Various factors, including infection, genetic
predisposition, and environmental factors, are involved in the pathology of sarcoidosis. Exposures
to insecticides, herbicides, bioaerosols, and agricultural employment are also associated with an
increased risk for sarcoidosis. Due to its unknown etiology, early diagnosis and detection are difficult;
however, the advent of advanced technologies, such as endobronchial ultrasound-guided biopsy,
high-resolution computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose
positron emission tomography has improved our ability to reliably diagnose this condition and
accurately forecast its prognosis. This review discusses the causes and clinical features of sarcoidosis,
and the improvements made in its prognosis, therapeutic management, and the recent discovery of
potential biomarkers associated with the diagnostic assay used for sarcoidosis confirmation.

Keywords: sarcoidosis; biomarkers; diagnosis; cause; management

1. Introduction
Sarcoidosis is a systemic multisystem inflammatory disorder of unknown etiology characterized
by the presence of non-caseating granulomas. The first case of sarcoidosis was reported in 1877 by
Jonathan Hutchinson at the King’s College Hospital in London (United Kingdom) [1]. In 1889, Ernest
Besnier described the cutaneous hallmarks of chronic sarcoidosis as lupus pernio. Later, Caesar Boeck
used the term sarkoid (sarcoid) for the first time when he assumed that these lesions were similar to
sarcoma, but benign. In India, the first case of sarcoid was published in the Journal of the School of
Tropical Medicine, Calcutta in 1956, while in 1923 the first case of Familial sarcoidosis was recorded in
two affected sisters [2].
Despite its long history, this disease remains enigmatic. Unidentified etiology and the
multisystemic nature of the disease have made it more complex. Previous data suggested that

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at least 90% of sarcoidosis patients have manifestations in the lungs [3,4]. In addition to the lungs,
the skin, liver, spleen, lymph nodes, upper respiratory tract, heart, and nervous system have all been
shown to be affected by this disease and account for between 10 and 30 % [5]. Sarcoidosis occurs
worldwide and has been reported in all racial and ethnic groups; no race, sex, or age is immune to it [4,6].
The clinical presentation of sarcoidosis varies depending on the specific organ involved. Sarcoidosis
may present with a wide range of clinical assignations ranging from asymptomatic to fatal. The etiology
of the disease is still unknown but some studies have reported that an unidentified antigen processed
by activated macrophages instigates an immune response regulated by T-cells and macrophages. These
activated cells discharge various mediators, including cytokines, chemokines, and reactive oxygen
species that may be involved in the progression of sarcoidosis [7,8]. Many studies suggest that not
only unknown antigens are responsible for this disease but also genetic susceptibility, environmental
factors, and in some instances, this disease may be result from autoimmune activation [9,10].
To identify the studies included in this review, we performed an intensive search of the electronic
databases, PubMed and MEDLINE, for relevant studies published between 1980 and the present
using the following terms: sarcoidosis, pulmonary sarcoidosis, and extrapulmonary sarcoidosis.
Bibliographies of all selected articles were reviewed, and we also included any relevant information
from our personal files. More than 100 articles were extensively reviewed for the purpose of this review.

2. Epidemiology
The prevalence and incidence of sarcoidosis are not well known worldwide owing to the challenges
associated with ascertaining the number of asymptomatic patients. Sarcoidosis affects individuals of
all ages irrespective of race or ethnicity, with maximum incidence among people aged 20–39 years, and
quite more prevalent in women, non-smokers, and in rural communities [11]. In Europe, a higher onset
of the disease has been recorded in the northern part (around 60 per 100,000) than in southern European
countries, including Italy (<10 per 100,000) [12,13]. In addition, the global incidence for sarcoidosis
is the highest in Sweden (64/100,000) [14], 20/100 000 in the United Kingdom [15], 4.4–6.3/100,000
in Australia [16], 10/100,000 in France, 9/100,000 in Germany, 1.4/100,000 in Spain, 7/100,000 in
Greece, 1.4/100,000 in Japan. Approximately 10–14/100,000 and 35.5–64/100,000 of Caucasian and in
African-Americans develop sarcoidosis, respectively [17–20]. In India, the prevalence of sarcoidosis
is 10–12 cases/1000 new registrations yearly, as reported by a respiratory unit in western India and
61.2/100,000 as reported by the respiratory unit of a hospital in the capital region [21,22]. Evaluation of
sarcoidosis in the Indian population is still in the very early stages, and accordingly, we can assume
that its prevalence is being underreported in this region. The most common comorbidities encountered
in sarcoidosis patients are hyperlipidemia, obesity, thyroid disease, diabetes, osteoporosis, coronary
heart disease, asthma, hypertension, chronic renal disease, and chronic obstructive pulmonary disease
(COPD) [23,24]. Sarcoidosis is also often reported in patients with certain autoimmune diseases
including autoimmune thyroid disease, Sjogren’s syndrome ankylosing spondylitis [25], and systemic
sclerosis [26].

3. Causes
The exact cause of sarcoidosis is not known. Many researchers have hypothesized the role of
genetic susceptibility, environmental factors, putative antigens, and autoimmunity in the development
of this disease, but no single cause has been identified to date.

3.1. Genetic Factors

Various studies suggest that genetic factors could play a crucial role in establishing the risk and
clinical development of sarcoidosis [27]. Eleven sarcoidosis risk loci (BTNL2, HLA-B, HLA-DPB1,
ANXA11, IL23R, SH2B3/ATXN2, IL12B, NFKB1/MANBA, FAM177B, chromosome 11q13.1, and RAB23)
have been identified to date [28]. A previous study reported that familial sarcoidosis occurred in 17% of
African-Americans [29], while only 1.4% of Spanish people exhibited this same risk [30]. According to
J. Clin. Med. 2020, 9, 1081 3 of 21

A Case-Control Etiologic Sarcoidosis Study (ACCESS) the chance of developing sarcoidosis is five-fold
among siblings [31]. Monozygotic siblings with sarcoidosis had an 80-fold higher risk of developing
the condition, although the estimated risk of developing sarcoidosis in dizygotic twins was only
seven-fold [32].
Genome wide association studies have demonstrated that several HLA and non-HLA alleles are
associated with the development of this disease [33]. HLA-DRB1*0301/ DQB1*0201 [34], transforming
growth factor β (TGF-β) [35], tumor necrosis factor α (TNF-α) [36], and Toll-like receptor 4 (TLR-4) [37]
are all considered significant indicators for susceptibility to sarcoidosis [38,39].

3.2. Environmental Risk Factors

Various environmental factors, including exposure to wood stoves, soil, tree pollen, inorganic
particulates, insecticides, and nanoparticles, have been associated with an increased risk for developing
sarcoidosis. In addition to these factors, some workers, such as those involved in hardware, gardening
materials, building supplies, and metal work as well as ship servicemen in the navy, fire workers,
and educators, are prone to sarcoidosis [40–42]. It has been suggested that silica exposure also triggers
the risk of sarcoidosis [43]. The underlying hypothesis for this association is that the environment is
an important risk factor for the development of sarcoidosis, which has been further strengthened by
reports that US World Trade Center workers exposed to the crash debris, in particular firefighters;
all experienced an increased risk for developing sarcoidosis or “sarcoid-like” disease [44].

3.3. Infection
In addition to all of the factors mentioned above, infectious agents such as mycobacteria, have been
suggested to be associated with the development of sarcoidosis, because the production of granulomas
is a key factor in the immune defense response against these agents. Studies have identified numerous
microbial agents as a potential eliciting agents of the immune response in sarcoidosis including Leptospira
species, Mycoplasma species, herpes virus, retrovirus, Chlamydia pneumoniae, Borrelia burgdorferi [45],
Pneumocystis jirovecii [46], Mycobacterium (M.tb) [47], and Propionibacterium species [48]. Isolation of
M.tb. DNA, from tissue specimens collected from sarcoidosis patients, with sequences specific to
mycobacterial proteins, such as ESAT-6, Kat G, and SoD A, illustrate that Mycobacterium is the strongest
candidate for infection-mediated sarcoidosis [49–51]. It has been reported that patients treated with
interferon α therapy for hepatitis C infection developed sarcoidosis [52,53]. A few studies have
suggested that hepatitis C infection on its own could increase the risk of developing sarcoidosis.
However, it seems more likely that therapy with interferon α increases interferon-γ and interleukin-2
expression, stimulating granuloma formation and thus sarcoidosis [54,55].

3.4. Autoimmunity
Autoimmunity has not been studied as extensively but given the underlying pathological
mechanism of sarcoidosis there is certainly potential for these conditions to play a contributing role in
disease development. Although no disease-specific auto-antibodies have been observed, it has been
shown that the major histocompatibility complex (MHC) class II molecules on antigen-presenting
cells possess an autoantigen that is recognized by the T-cell receptor (TCR) of the responding T-cells
in sarcoidosis patients [56,57]. Vimentin-derived peptides are the most plausible candidate for the
activation of both T-cells and B-cells in the lung [58]. Autoimmunity presents a as a novel spectrum for
sarcoidosis immunopathogenesis and may help elucidate sarcoid etiology [59–61].
Another important aspect of autoimmunity is the imbalanced gut microbiome.
Gianchecchi et al. reported the associations between the presence of microbiome dysbiosis and the
development of autoimmune conditions [62]. Sarcoidosis overlaps with other autoimmune diseases,
including rheumatoid arthritis, autoimmune thyroid disease, Sjogren’s syndrome, and ankylosing
spondylitis [63]. The role of the microbiota in these autoimmune diseases has been evaluated in
previous studies and been shown to lay a significant role in their pathogenesis [64]; thus, study of the
J. Clin. Med. 2020, 9, 1081 4 of 21

microbiome of sarcoidosis patients and its correlation with other diseases could open new avenues for
investigating the underlying causes of this disease [65,66].

4. Immunopathogenesis
Many etiological agents, including infectious microbes, as well as organic and inorganic
compounds, contribute to the development of sarcoidosis. These antigens are first cleared by the
immune system, but this is not infallible and some undegraded antigens may remain in the cells, which
can initiate an immune feedback loop. In response to this feedback loop, the antigen-presenting cells
(APCs), such as dendritic cells (DCs), alveolar macrophages (AMs), and alveolar epithelial cells, produce
high levels of TNF-α, and secrete interleukins-12, -15, and -18, macrophage inflammatory protein-1
(MIP-1), monocyte chemoattractant protein-1 (MCP-1), and granulocyte macrophage colony-stimulating
factor (GM-CSF) [67]. These APCs also present antigens to CD4+ T-cells initiating granuloma
construction, a critical feature of sarcoidosis. The growth of these granulomas establishes the primary
abnormality in most cases of sarcoidosis. Sarcoid granulomas are ordered, structured masses comprised
of macrophages and their derivatives, epithelioid cells, giant cells, and T-cells.
Activated CD4+ T-cells can differentiate into two distinct subsets, namely, T helper 1 (Th1) and T
helper 2 (Th2) cells, based on their cytokines profile. Th1 cells predominantly secrete interleukin-2 (IL-2)
and interferon-gamma (IFN-γ), while IL-4 and IL-13 are the major secretions of Th2 cells. Resolution
or maintenance of granuloma is determined by the proportion of Th1 and Th2 cells, respectively.
Alveolar macrophages are activated in the Th2 milieu and stimulate fibroblast and collagen proliferation
culminating in progressive fibrosis [68].
Incapacitation of Tregs is also a key feature of granuloma maintenance. It is presumed that
infiltrating Tregs fail to reduce the exaggerated inflammatory response, thereby contributing to
granuloma persistence and integrity. Tregs also release transforming growth factor β (TGF-β) that may
contribute to fibrosis and granuloma organization [69].
Th17 and Th17.1 cells have only recently been linked to the pathogenesis of sarcoidosis [70].
These cells are recruited to the disease site and are involved in the construction of the granuloma. The
balance between Th17 and Treg cells is thought to be disrupted in sarcoidosis [71] and is an important
factor in its prognosis [72]. The regulation of antigen processing, antigen presentation to the APCs,
and cytokine release are all controlled through genetic elements and may link the various causal factors
of sarcoidosis together [73–75].

5. Clinical Features
Sarcoidosis is often diagnosed when aberrations are identified on a chest radiograph (up to
50% of patients) during a routine examination. Based on the presence of lung infiltration and/or
lymphadenopathies on the radiograph, different stages of sarcoidosis have been described [3] (Box 1)
Symptoms are usually negligible and nonspecific including cough, labored breathing, chest discomfort,
dyspnea, and low-grade fever [76,77]. Systemic symptoms such as tiredness, weight reduction,
and night sweats, are common. Hemoptysis is rare. Sarcoidosis may be acute, sub-acute, or chronic;
however, in a majority of cases, it is entirely asymptomatic. Lofgren syndrome, where erythema
nodosum and bilateral hilar adenopathy are both present, is one of the classic and acute presentation
of sarcoidosis. Individuals suffering from sub-acute sarcoidosis have nonspecific signs comprising
frailty, fever, weight reduction, arthralgia, and peripheral lymphadenopathy [9,78]. Chronic sarcoidosis
is identified following serious persistent lung engagement, with a slow onset and a high degree of
individual variability.
The multisystemic nature of sarcoidosis leads to organ specific manifestations (Table 1).
Symptoms may differ from patient to patient. According to ACCESS, 95% of patients had
thoracic engagement, 50% had extra thoracic symptoms, and 2% had unaccompanied extra thoracic
sarcoidosis [4]. In a study that used 18F-fluorodeoxyglucose positron emission tomography/computed
tomography (18 FDG-PET/CT), the following four sarcoidosis phenotypes were identified and evaluated:
J. Clin. Med. 2020, 9, 1081 5 of 21

thoracic nodal hilar-mediastinal, thoracic nodal hilar-mediastinal and lungs, extended thoracic and
extra-thoracic only nodal phenotype including inguinal-abdominal-supraclavicular stations, and all
of the above plus systemic organs and tissues such as muscles-bones-spleen and skin [79]. Most
clinical studies agree that owing to the multi-organ and system granulomatous potential of sarcoidosis,
a multifaceted approach is necessary to evaluate the possibility of extrapulmonary localizations of
this disease.

Table 1. List of organs involved in sarcoidosis.

Prevalence of Organ
Organ Involvement Manifestations References
Involvement
Dry cough, wheezing, dysponea,
fatigue
more than 90% Acute: Pleural effusion, pericardial
Lung involvement (With hilar and effusion, pneumothorax, and [80–82]
mediastinal lymph node) lymph-node
Chronic: lung fibrosis and respiratory
failure
Peripheral lymphadenopathy, affected
Lymph node
20% of patients lymph nodes are moderately swollen, [83–85]
involvement
and are usually not painful.
Thyroid glands and Thyroid dysfunction (5%), Parotid
Endocrine and exocrine parotid glands are enlargement (5%–10%),
[86,87]
involvement usually affected in hypothalamic-pituitary effects (for
20%–50% of cases example, diabetes insipidus),
Erythema nodosum (most common),
Skin involvement 20%–30% of patients profuse sweating, nodules, papules and [88,89]
plaques.
pain, photophobia, and hyperaemia,
more than 40% of
Eye involvement sometimes associated with the Löfgren [90–92]
patients
syndrome
Osteoporosis and osteopenia are
common, Nodular lesions, cystic lesions
Bone involvement 1%–13% of patients [93–95]
involving the joints, arthritis and
arthralgia
In most patients with Larynx, nasopharynx and nose are
Upper respiratory tract [96–98]
systemic sarcoidosis affected
Renal calculi, nephrocalcinosis,
Renal involvement 5% [99,100]
interstitial nephritis, and kidney failure
Cardiac involvement 20%–27% of sarcoidosis Heart failure, arrhythmias, syncope [101,102]
Neurological Facial palsy, Meningeal inflammation,
involvement or less than 10% of patients encephalopathy, vasculopathy, seizures, [103,104]
neurosarcoidosis hydrocephalus, and mass lesions
Hepatosplenomegaly, intrahepatic
Liver and spleen
18% cholestasis, and portal hypertension [105–107]
involvement
and altered liver function
J. Clin. Med. 2020, 9, 1081 6 of 21

Box 1. Scadding’s staging of sarcoidosis.

Radiographic Type Radiographic Characteristics

0 No visible findings
I Bilateral hilar lymphadenopathy
II Bilateral hilar lymphadenopathy and parenchymal infiltration
III Parenchymal infiltration without hilar adenopathy in regular chest radiography
Advanced fibrosis with severe distortion of the normal lung architecture
IV predominately in the middle and upper lobes with evidence of bronchiectasis,
hilar retraction, bulla, cysts and more rarely “honeycombing”

6. Screening and Diagnosis

Diagnosis of sarcoidosis always poses a challenge to clinicians. Owing to its multisystemic nature
and unidentified etiology, the diagnosis of this condition can be difficult and is often delayed; however,
early diagnosis is indispensable for patient management. Sarcoidosis is usually diagnosed when
radiological and typical clinical data are reinforced by histological confirmation of non-necrotic
granulomas. To establish any confirmed diagnosis, patients should undergo multiple clinical
examinations, depending on organ involvement, as a specific diagnostic assay is still lacking (Table 2).

Table 2. A list of conventional diagnostic tests for sarcoidosis.

Test Indication for Sarcoidosis References

fever, fatigue, malaise, weight loss, and erythema
Physical examination [108]
nodosum
Routine ophthalmologic
orbital and eyelid granulomas [109]
examination
Peripheral blood count Lymphopenia [110]
Renal function tests High level of calcium, urea, and creatinine [111]
Urine analysis Hypercalciurea [112]
Pulmonary function Tests Assess pulmonary involvement and disease severity [113]
For the presence of granuloma
Tissue biopsy [114]
(Lungs, lymph node, skin, salivary gland, conjunctiva)
Detect pulmonary involvement, (Endobronchial
Bronchial Biopsy ultrasound-guided transbronchial needle aspirate [115,116]
[EBUS-TBNA], Trans and endobronchial Biopsy)
Tuberculin skin test (Mantoux) Negative in the most sarcoidosis patients [117]
Bilateral hilar lymphadenopathy, Disseminated nodules
Chest X-ray [118,119]
in the lungs
Differentiation of sarcoidosis from other pulmonary
HRCT [120,121]
conditions
Highly sensitive to detect cardiac and pulmonary
FDG-PET [122]
involvement
Repolarization disturbances, Ectopic beats, Rhythm
Electrocardiogram (ECG) [123,124]
abnormalities
Detect neurological involvement, spinal cord, meninges,
MRI [125,126]
skull vault, and pituitary lesions.

Numerous imaging techniques have also been assessed for their diagnostic utility in the
identification of sarcoidosis, but their utility is mostly restricted to specific organs. Despite these
limitations, high-resolution computed tomography (HRCT), magnetic resonance imaging (MRI),
 J. Clin. Med. 2020, 9, 1081 7 of 21

and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) have improved the diagnosis
of sarcoidosis. These techniques are equally effective in evaluating a patient’s response to treatment.
All examinations mentioned in Table 2 can be used to identify sarcoidosis in different organs;
however, no assay has been established as the gold standard. One or more tests can be performed
in combination to confirm the presence of sarcoidosis, but patients’ history, symptoms, clinical signs,
and particularly, expert clinical discretion always complement the finding of the relevant medical
examination.
J. Clin. Med. 2019, 8, xStepwise
FOR PEER evaluation
REVIEW of all of the available information, excluding non-specific
7 ofdata,
20
should be undertaken to confirm diagnosis (Figure 1).

Figure 1. Diagnostic management of sarcoidosis.

7. Biomarkers for Sarcoidosis

Figure 1. Diagnostic management of sarcoidosis.
A biological marker or biomarker refers to a broad subcategory of medical signs that can be
7. Biomarkersobjectively,
accurately, and reproducibly measured [127]. Several biomarkers have been proposed for
for Sarcoidosis
the diagnosis of sarcoidosis and the monitoring of its progression, but none has been accepted wholly
A biological marker or biomarker refers to a broad subcategory of medical signs that can be
in practice [111]. The difficulty in identifying and evaluating biomarkers for sarcoidosis is linked to
accurately, objectively, and reproducibly measured [127]. Several biomarkers have been proposed for
its dubious etiology, non-specific symptoms, and multiple disease phenotypes. Due to this lack of
the diagnosis of sarcoidosis and the monitoring of its progression, but none has been accepted wholly
biomarkers, diagnosis, prognosis, treatment response, and clinical outcomes for this disease are not
in practice [111]. The difficulty in identifying and evaluating biomarkers for sarcoidosis is linked to its
thoroughly predictable.
dubious etiology, non-specific symptoms, and multiple disease phenotypes. Due to this lack of
Various biomarkers, including, serological biomarkers, bronchoalveolar lavage (BAL) biomarkers,
biomarkers, diagnosis, prognosis, treatment response, and clinical outcomes for this disease are not
and exhaled breath biomarkers, have been proposed numerous studies, but all have been shown to
thoroughly predictable.
have limited applicability. Serological biomarkers should be the area of most focus for researchers
moving forward as these are the least invasive and most accessible [128]. Although higher serum
angiotesin converting enzyme (SACE) and BAL lymphocyte ratios are widely discussed, their utility is
limited as these are not specific to sarcoidosis. In Table 3, we discuss all the plausible biomarkers for
the evaluation of sarcoidosis.
J. Clin. Med. 2020, 9, 1081 8 of 21

Table 3. List of potential biomarkers of sarcoidosis.

Diagnostic Prognostic Disease Severity

Biomarkers Indication for Sarcoidosis References
Value Value Assessment
Serological Biomarkers

• Indicates total granuloma load.

SACE + − ++ [129–131]
• Higher in sarcoidosis patients

• Produced by alveolar macrophages

Chitotriosidase − − ++ [132–134]
• Increased level in sarcoidosis

• Produced by macrophages and giant epithelioid cells

Lysozyme − − + [135,136]
• Higher in sarcoidosis patients

• Produced by activated macrophages and monocytes

Neopterin − − + [137–139]
• Elevated level in sarcoidosis

• Higher concentration of calcium in sera of most

Hypercalcemia − − + [140–142]
sarcoidosis patient.

• Marker of T cell activation

Soluble IL2 receptor − + ++ [143–145]
• Higher in sarcoidosis patients

• Elevates the production of TNF-α, IL-18 and IL-10 in lung

SAA cells leading to T cell exhaustion + − + [146–148]
• Higher in sarcoidosis patients

• Higher production of CCL18 led to pulmonary fibrosis

Chemokines − + + [149–151]
• High serum level of CXCL9, CXCL10 in sarcoidosis

• Indicates lymphocytic alveolitis and increased pulmonary

KL 6 − + + [152]
• Elevated level in sarcoidosis
J. Clin. Med. 2020, 9, 1081 9 of 21

Table 3. Cont.

Diagnostic Prognostic Disease Severity

Biomarkers Indication for Sarcoidosis References
Value Value Assessment

• Th1 inflammatory cytokine

IFN-gamma − − − [153,154]
• Sarcoidosis promotes IFN γ secretion

• High TGF-β led to the development of fibrosis and

TGF-β − + + [155,156]
chronic disease.

• Maintenance of granuloma
TNF-α − − − [157,158]
• Higher secretion by macrophages

Biomarkers in BAL
CD4/CD8 ratio in
• Sarcoidosis patients have a higher ratio of CD4/CD8 + − + [159,160]
BAL

Percentage of White • The high percentage of lymphocytes was observed

- − + [161,162]
Blood cells in BAL in patients

Exhaled Breath Biomarkers

• Oxidative stress marker

8-isoprostane + − − [163,164]
• Higher in patients with sarcoidosis

Carbon monoxide • High concentration in sarcoidosis than control − − − [165]

Nitric oxide • Heterogeneity in data − − − [166,167]

SACE: Serum angiotensin converting enzyme; SAA: Serum Amyloid A; IL2: Interleukin 2; CCL18: Chemokine ligand 18; CXCL9: C-X-C Motif; Chemokine Ligand 9; CXCL10: C-X-C Motif
Chemokine Ligand 10; TNF-α: Tumor Necrosis Factor-α; IL-18: Interleukin 18; IL-10: Interleukin 10; KL 6: Kerbs von Lungren 6 antigen; TGF-β: Transforming Growth Factor-β.
J. Clin. Med. 2020, 9, 1081 10 of 21

The application of biomarkers in the diagnosis and prognosis of sarcoidosis is still in its infancy
with relatively few biomarkers appearing to have any real clinical application. However, the advent
of “omics” type approaches (consisting of genomics, proteomics, transcriptomics, metabolomics,
microbiomics, and metallomics) and the increasing number of studies applying these techniques
suggest that we may soon have more valid candidates to choose from. Thus, while biomarkers are not
currently a viable alternative for diagnostic applications, they may soon become effective [168].
In the previous decade, transcriptomics have identified novel gene expression profiles underlying
the pathogenesis of sarcoidosis [169]. All these transcriptomic datasets validate the major role of
IFN-γ-driven STAT1 signaling and type I IFN signaling in sarcoidosis [170]. Micro-RNAs have also
been shown to have some potential as biomarkers for the diagnosis of sarcoidosis. miRNA-29A,
hsa-miR-4306, and hsa-miR-6729-5p have been shown to be associated with sarcoidosis, acting
as non-invasive biomarkers [171,172]. Metabolic changes play a crucial role in the progression
of inflammation. 1 H nuclear magnetic resonance (NMR)-based metabolomic analysis identified
metabolites and metabolic pathways that can discriminate sarcoidosis patients from healthy ones.
Acetoacetate, 3-hydroxybutyrate, carnitine, cystine, and trimethylamine N-oxide levels are significantly
increased in sarcoidosis, with dysregulation of ketone bodies and citric cycle metabolism also being
identified as hallmarks of this disease [173,174].

8. Treatment
In sarcoidosis, a decision on the appropriate intervention precedes the decision of whether or not
to treat the patient. Not every patient needs to be treated. The decision to treat a sarcoidosis patient is
predicated according to the development of specific symptoms and disease progression evidenced
by worsening functional status and imaging abnormalities [175,176]. Patients can be followed-up
over long periods because spontaneous resolution may occur during this time frame. Development
of dangerous clinical conditions and a significant impairment in the quality of life are two major
indications for clinicians to start interventional treatment [177]. Therapeutic strategies should include
mental and emotional well-being, in addition to physical well-being. If treatment is to be initiated,
oral corticosteroids are the first line of treatment. Corticosteroids have proved reliable in providing
symptomatic relief and reversing organ dysfunction, but the risks of using corticosteroids is always a
matter of concern [178].
Treatment is often initiated with 0.5–0.75 mg of prednisolone per kg (body weight) daily for
4 weeks and tapered by 10 mg every 4 weeks, depending on the disease response [179]. It is sometimes
advised that the dose of 0.5-0.75 mg/kg of prednisolone is too high and doses of 20 mg of prednisone
can be used as an alternative. When pulmonary function has improved, therapy can be terminated,
which is usually within 6-12 months. For many patients who have mild clinical manifestations, such
as skin lesions, anterior uveitis, or cough, corticosteroid treatment should be instigated. For those
necessitating systemic treatment, most will recover in a reasonably short time frame but there is a
small group of patients who develop chronic disorders that do not recuperate after 2–5 years. These
chronic patients frequently need long-term treatment, which can necessitate the use of corticosteroids
or additional therapies for more than 5 years.
For patients with intolerable adverse responses to steroids, corticosteroid-sparing regimens
can also be administered. These are considered second line treatments and rely on therapeutics
such as azathioprine [180], methotrexate [181], mycophenolate mofetil [182,183], cyclosporine [184],
cyclophosphamide [185], leflunomide [186], and hydroxychloroquine [187] for symptomatic relief,
but all of these drugs have been shown to be less effective than the steroid interventions (Figure 2).
also be administered. These are considered second line treatments and rely on therapeutics such as
azathioprine [180], methotrexate [181], mycophenolate mofetil [182,183], cyclosporine [184],
cyclophosphamide[185], leflunomide [186], and hydroxychloroquine [187] for symptomatic relief, but
all of these drugs have been shown to be less effective than the steroid interventions (Figure 2).
J. Clin. Med. 2020, 9, 1081 11 of 21

Figure 2. Therapeutic options for first, second, and third-line treatment of sarcoidosis.

Mechanism-based therapeutic treatment is the most advanced and targeted approach for the
treatment of sarcoidosis.
Figure Different
2. Therapeutic optionscytokines play aand
for first, second, pivotal roletreatment
third-line in the immunopathogenesis
of sarcoidosis. of
sarcoidosis. Anti-cytokine monoclonal antibodies are a specific way to modulate cytokine networks,
thus influencing disease progression [188]. These cytokine-directed treatments are manifested as
third line therapies. TNF-α is known to play a significant role in the formation of the granulomas
associated with sarcoidosis [189]. The use of anti-TNF 10 antibodies such as infliximab [190,191] or
adalimumab [192] has shown some therapeutic benefits, although these gains have been relatively low.
Recent studies describing the involvement of Th17 cells and their related cytokines in the pathogenesis
of sarcoidosis, have suggested that IL-23 and IL-1β, inducers of Th17 differentiation, are useful targets
for therapeutic interventions. Treatment with ustekinumab and canakinumab was recently evaluated
with mixed results. Ustekinumab did not show any efficacy in pulmonary sarcoidosis and the results
for canakinumab are still awaited [193] (NCT2888080). In addition, there are still relatively few
guidelines for the clinical intervention of sarcoidosis [194–197] but surveillance for 3–12 months is
typically endorsed to determine the overall course of the disease [198].
Personalized medicine is a novel medical doctrine focused on tailoring therapeutic management
of various diseases [199]. The goal of precision medicine is to address disease prevention, diagnosis,
and treatment while considering individual patient variability. Integration of different omics data
presents comprehensive overviews of pathological molecular pathways that can be targeted for
the development and application of precision medicine [200]. Multi-omics integrative analysis
generates vast amounts of big data from sarcoidosis samples including genomic, transcriptomics,
proteomic, and phenomic studies, all of which have been used to describe novel candidate regions and
genes, altered in sarcoidosis [201]. These new data analysis methods are bridging the gap between
conventional therapies and advanced care and are bound to open new therapeutic paradigms for this
complex disease.

9. Conclusions
Despite extensive research over the past several decades, the etiological agents of sarcoidosis
remain unknown. Numerous potential etiological agents have been identified and the most recent
hypothesis suggests that host-microbe interaction and genetic factors play an important role in the
pathogenesis of this disease when they interact with various environmental factors, which results in the
clinical presentation of this disease. To cure this disease, timely diagnosis is important; therefore, there
is a critical need for clinicians to develop potent diagnostic tools for the identification and prognosis of
sarcoidosis. Recently, new diagnostic strategies for sarcoidosis, including HRCT, FDG-PET scanning,
TBNA, and EBUS technologies, have reinforced its prognosis. More focus should be concentrated on
the development of non-invasive biomarkers. Big data analysis with the integration of ‘-omics’ data