Challenges of Sarcoidosis and Its Management: Review Article

The n e w e ng l a n d j o u r na l of m e dic i n e
Review Article
Dan L. Longo, M.D., Editor
Challenges of Sarcoidosis
and Its Management
Marjolein Drent, M.D., Ph.D., Elliott D. Crouser, M.D.,
and Johan Grunewald, M.D., Ph.D.
S
From the Interstitial Lung Diseases (ILD) arcoidosis is an inflammatory, multisystemic disease of unknown
Center of Excellence, Department of Pul- cause with a wide range of clinical manifestations. The disorder can affect
monology, St. Antonius Hospital, Nieu-
wegein, the Department of Pharmacology virtually any organ in the body — predominantly the lungs, lymphatic sys-
and Toxicology, Faculty of Health and Life tem, skin, or eyes or a combination of these sites — and is characterized by the
Sciences, Maastricht University, Maastricht, formation of noncaseating granulomas. The first description of sarcoidosis is attrib-
and the ILD Care Foundation Research
Team, Ede — all in the Netherlands uted to Jonathan Hutchinson, a surgeon and dermatologist practicing in London
(M.D.); the Division of Pulmonary, Criti- in the late 1800s, who identified patients with unusual skin lesions. The systemic
cal Care, and Sleep Medicine, Ohio State manifestations of the disease were recognized in the decades around the end of the
University, Columbus (E.D.C.); and the
Respiratory Medicine Division, Department 19th century. Despite the efforts of several generations of researchers, our under-
of Medicine Solna, and the Center for Mo- standing of the disease mechanisms and general epidemiology of sarcoidosis re-
lecular Medicine, Karolinska Institutet, and mains limited.1 The clinical presentation of sarcoidosis depends on the intensity
Respiratory Medicine, Theme Inflamma-
tion and Aging, Karolinska University Hos- and duration of the inflammation and the organs involved. It is thought that a dys-
pital — both in Stockholm (J.G.). Address regulated immune response against certain environmental antigens results in sus-
reprint requests to Prof. Drent at ILD Care tained granulomatous inflammation and failure to clear the offending antigens.1,2
Foundation, Heideoordlaan 8, 6711 NR
Ede, the Netherlands, or at m.drent@ The prevalence and presentation of sarcoidosis are variable. The triggering an-
maastrichtuniversity.nl or m.drent@ildcare tigen is likely to vary according to race or ethnic group, geographic location, and
.nl or m.drent@antoniusziekenhuis.nl. individual genetic background.1 The prognosis is also highly variable, ranging
N Engl J Med 2021;385:1018-32. from spontaneous resolution to chronic inflammation complicated by fibrosis or
DOI: 10.1056/NEJMra2101555 associated irreversible organ failure or both. Sarcoidosis adversely affects the lives
Copyright © 2021 Massachusetts Medical Society.
of patients and their families. Disease severity, coexisting conditions, and quality
CME of life are influenced by social status, race or ethnic group, sex, and income.3,4 The
at NEJM.org cause remains elusive, and pathognomonic markers and disease-specific treat-
ments are lacking. Given the unpredictable clinical course and uncertainty about
adequate treatment approaches, the management of sarcoidosis remains challeng-
ing.5,6 A recent report provides an excellent summary of current concepts concern-
ing the epidemiology, pathogenesis, and treatment of sarcoidosis.1 This review
extends the discussion to consider unresolved clinical and research challenges and
related opportunities to improve the care of patients with sarcoidosis.
Epidemiol o gic Fe at ur e s
Sarcoidosis occurs throughout the world, affecting all races and ethnic groups and
both sexes, with a slight predominance among women. It can affect people of all
ages but mostly develops in young and middle-aged adults. The incidence has been
reported to peak at 30 to 50 years of age in men and at 50 to 60 years of age in
women.7 Some data suggest that the age at onset is increasing. A family history of
the disease increases the risk; for persons with one affected first-degree relative, the
risk is increased by a factor of 3.7.7 The true prevalence remains unknown because
1018 n engl j med 385;11 nejm.org September 9, 2021
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Sarcoidosis
Table 1. Selected Adverse and Favorable Prognostic Factors in Sarcoidosis.*
Variable Adverse Prognostic Factors† Favorable Prognostic Factors

Demographic characteristics Age ≥40 yr at onset 10
Age <40 yr at onset10
Black race11
Black race and female sex
Lower income4,11
Pulmonary involvement12,13 Scadding stage III (absence of lymphadenopathy) or Asymptomatic Scadding stage I or II (presence
stage IV (signs of fibrosis) on chest radiography‡ of lymphadenopathy) on chest radiography‡
Severe dyspnea or hypoxemia with minimal exertion
at presentation13
Clinically significant lung functional impairment
Pulmonary hypertension13
Bronchoalveolar lavage fluid Neutrophilia at presentation14 Lymphocytosis without increased eosinophils
Elevated metalloproteinases (MMP12) or neutrophils or both15
Increased CD4:CD8 ratio15
Extrapulmonary involvement Lupus pernio: nasal mucosal involvement10 Acute inflammatory manifestations (e.g.,
Vitiligo Löfgren’s syndrome: acute onset with fever,
Chronic uveitis10 erythema nodosum, bilateral ankle arthritis,
Cardiac involvement and bilateral hilar lymphadenopathy)1
Hepatomegaly Isolated cranial-nerve palsy
Splenomegaly
Neurologic involvement
Osseous involvement10
Hypercalcemia10
Nephrolithiasis or nephrocalcinosis10
Small-fiber neuropathy–associated symptoms16,17
Requirement for treatment Risk of disease progression and organ failure or death12 No risk of disease progression or organ failure
Associated genetic variants§ HLA-DRB1*14, HLA-DRB1*15+ 1
HLA-DRB1*03+, HLA-DQB1*0201
Presence of a TNF-α rs1800629 G/A variant allele¶ Absence of a TNF-α variant allele
Presence of a BTNL2 rs2076530 G/A variant allele18¶ Absence of a BTNL2 variant allele
Presence of an ANXA11 rs1049550 C/T variant allele Absence of an ANXA11 variant allele
* See References Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org, for additional references per-
taining to this table.
† An adverse prognosis indicates a severe course, the need for prolonged treatment, the risk of organ damage, and in some cases, the risk of
death. The genetic risk factors presented here may not be applicable to all populations.
‡ According to the Scadding radiographic staging system for pulmonary sarcoidosis, stage 0 is characterized by normal chest radiographic
findings, stage I by bilateral hilar lymphadenopathy, stage II by bilateral hilar lymphadenopathy and parenchymal abnormalities, stage III by
parenchymal abnormalities without bilateral hilar lymphadenopathy, and stage IV by advanced lung fibrosis.
§ HLA variants vary among patients of different ethnic origins. ANXA11 denotes annexin A11, BTNL2 butyrophilin-like protein 2, and TNF-α
tumor necrosis factor alpha.
¶ The presence of this variant allele may depend on associations with HLA-DRB1* alleles.
the epidemiologic assessment of sarcoidosis and En v ironmen ta l a nd Gene t ic

its manifestations is hampered by the lack of a Fe at ur e s
consistent case definition; by a lack of diagnos-
tic sensitivity; by variations in diagnostic meth- The development of sarcoidosis requires both a
ods, in access of patients to health care, and in genetic predisposition and environmental and
the regional distribution of subphenotypes; and sometimes occupational exposure to unknown
by seasonal variations, among other factors.8,9 substances or microbial antigens. It is generally
However, the available evidence indicates that accepted that a dysregulated immune response
the prevalence and incidence of sarcoidosis and against one or more disease-promoting antigens
associated mortality vary according to factors results in an inflammatory process to eliminate
including race or ethnic group, the intensity and the offending antigen.1 Multiple occupations and
duration of disease-associated environmental ex- environmental exposures are associated with sar-
posure, individual genetic background, and geo- coidosis, including exposure to moldy environ-
graphic location (Table 1). ments, occupational exposure to insecticides,
n engl j med 385;11 nejm.org September 9, 2021 1019

agricultural employment, metalworking, fire- Figure 1 (facing page). Immunologic Cascade Causing Granuloma Formation in
fighting, exposure to inorganic dust, exposure to Sarcoidosis, with Resolution or Persistence in Genetically Predisposed Persons.
silica dust, and the handling of building supplies Panel A shows the immunologic cascade during granuloma formation. The
(as indicated by cases of sarcoidosis in rescue early phase of an innate immune response is the result of genetic, epigenetic,
workers at the World Trade Center).19 The role of and environmental factors interacting with environmental or occupational
triggers (e.g., exposure to antigens such as microorganisms) or other extrin-
genetic factors in sarcoidosis is supported by sic agents in the context of an “initial insult” that are capable of triggering
familial clustering of cases and by the variation membrane-bound pattern-recognition receptors (PRRs), such as toll-like
in the manifestations and course of disease receptors (TLRs).21 Persons with a specific genetic background (e.g., certain
across racial and ethnic groups. The importance HLA alleles) have a predisposition to a dysfunctional immune response,
with the formation of granulomas. A second insult (which may take years
of interactions between the environment and
to occur) might be required to boost and sustain the immune response.
genetic factors is underscored by a study identify- Each exposure is followed by stimulation of transcription factors, resulting
ing certain gene variants on chromosome 6 that in the production of cytokines and the expression of chemokine receptors
substantially increased the risk of sarcoidosis in and chemokines. This process will also attract immune cells of an adaptive
persons exposed to pesticides, as compared with immune response, such as CD4+ and CD8+ T cells, to the site of insult.
The immune response can eventually eliminate the inciting antigen, after
unexposed persons.18 Furthermore, the combina- which the response shuts down. Alternatively, if the antigen persists, for-
tion of certain gene variants and smoking sub- mation of nonnecrotizing epithelioid-cell granulomas ensues.1
stantially increases the risk of disease.20 Genetic In a second phase, shown in Panel B, interleukin-13 promotes the AM2 (alve-
factors identified in genomewide association olar macrophage 2) phenotype, monocytes differentiate into epithelioid cells
studies affect not only the risk that the disease and antigen-presenting cells, and mammalian target of rapamycin complex
(mTORC1) is activated, further promoting and sustaining granuloma forma-
will develop but also the course of the disease tion.22,23 Cytokines, especially interferon-γ, will activate the Janus kinase (JAK)
and the organs involved.1 However, gene asso- and signal transducer and activator of transcription (JAK-STAT) pathway,
ciation studies have limitations, including the which could be blocked therapeutically.1 Through so-called T-cell plasticity,
identification of genes with no apparent biologic helper T cells can, under the influence of interleukin-12, interleukin-18, and
interferon-γ, differentiate into classical type 1 helper T (Th1) cells, produc-
relevance to sarcoidosis.
ing interferon-γ, tumor necrosis factor α (TNF-α), and interleukin-2 and pro-
viding protection against microorganisms.1 Adding transforming growth fac-
tor beta (TGF-β) and interleukin-6 to helper T cells will stimulate expression
Pathoph ysiol o gic a l
of type 17 helper T (Th17) cells and production of various interleukins in
Ch a r ac ter is t ic s the pulmonary environment. Whereas interleukin-23 initiates a more pro
inflammatory process with the production of granulocyte–macrophage colony-
Pathogenesis
stimulating factor (GM-CSF), the absence of interleukin-23 can induce Th17
As mentioned previously, the histologic hallmark cells to take on a more regulatory role, producing interleukin-10. In the lungs,
of sarcoidosis — granulomatous inflammation however, the Th17.1 phenotype production of interferon-γ appears to pre-
— is thought to be a dysregulated antigenic re- dominate.24
sponse to unknown environmental exposures in Panel C shows the processes through which granulomas either persist, re-
sulting in chronic disease and fibrosis, or resolve. Specific antigens are pre-
a genetically susceptible person. Loci that house sented in the form of peptides by HLA molecules on antigen-presenting cells.
genes involved in antigen presentation (e.g., loci T cells expressing a T-cell receptor for antigen (TCR) that recognizes the
in the HLA class II region and the butyrophilin- HLA–peptide complex will be further stimulated, activating other immune
like 2 gene [BTNL2]) are linked to the develop- effector cells. HLA-DRB1*03–positive (DR3-positive) persons have large
T-cell populations expressing alpha-chain variable 2.3 (AV2.3) in the lungs,
ment of sarcoidosis and to certain disease pheno- suggesting recognition of specific antigens there. Granulomas consist of a
types (Table 1). Subclinical inflammation begins core of activated and highly differentiated epithelioid cells, structurally well
with activation of membrane-bound pattern- formed and typically nonnecrotizing. They are situated along lymphatic
recognition receptors (e.g., toll-like receptors). routes and characteristically contain intracellular bodies (Schaumann’s
bodies) and multinucleated giant cells.24 Cytokines interferon-γ and TNF-α
When stimulated, macrophages and other innate
in particular promote the formation of granulomas that are surrounded by
immune cells promote transcription factors, re- a ring of lymphocytes, primarily CD4+ T cells, but also some CD8+ T cells,
sulting in the production of cytokines (Fig. 1).1,21‑27 as well as B cells. The complex fibrotic process includes the release of cyto-
“Classically” activated macrophages are re- kines such as TNF-α, interferon-γ, or both; a transfer of monocytes as pro-
garded as drivers of the inflammatory process moted by interleukin-13; and the release of other fibrosis-stimulating cyto-
kines such as TGF-β and interleukin-10.25 Fibrocytes, which circulate in the
(proinflammatory M1 type) associated with blood, can differentiate into fibroblasts and release collagen and other sub-
granuloma formation. Cytokines can also pro- stances that promote the development of fibrosis.26 FoxP3-expressing regu-
mote CD4+ helper T cells and sometimes their latory T (Treg) cells could, on activation, aid in the resolution of granulomas,
differentiation into type 17 helper T (Th17) but they are dysfunctional.22 The role of Th17 cells and subtypes in the reso-
lution and maintenance of granulomatous inflammation is probably tissue-
cells.1 Professional antigen-presenting cells (e.g., specific and warrants further studies.1 ANXA11 denotes annexin A11, and
dendritic cells) are also activated to generate and BTNL2 butyrophilin-like 2.
display antigen peptides, which are recognized

Sarcoidosis
A Exposure in Genetically Predisposed Persons
Initial insult Second insult Persistent antigen presence, antigen

(environmental or (environmental or presentation, and increased immune response
occupational exposure) occupational exposure)
Antigen or Proinflammatory
extrinsic agent and Th1-skewing cytokines
Interleukin-1, 6, 8, 12, and 18, CD4 and CD8
interferon-γ, and TNF-α
T cells Granuloma formed
T cell
(antigen persistent)
Antigen-
presenting
cell May be years Granuloma not
between formed or
insults dissolved
Chemokines and
(antigen eliminated)
Triggering of PRRs chemokine receptors
(CXCR3, CCR5, CCR6) Monocyte Neutrophil
Affected genes (TLR2, TLR4)
(e.g., HLA class II, B cell
BTNL2, ANXA11, CCR2) Transcription factors activated
B Influence of an M1 or M2 Imbalance
Granuloma formation promoted Granuloma formed and symptoms appear

(proinflammatory cytokines and chemokines)
JAK-STAT Th1
Proinflammatory cytokines pathway activated cell
Interleukin-12
Interleukin-6, 12, 13, 17, and 18, and 18 and Interleukin-6
Antigen TNF-α, and interferon-γ interferon-γ and TGF-β
Interferon-γ
AM1 Th17.1
monocyte cell Interferon-γ
Antigen-
presenting Monocyte Antigen
cell
Interleukin-13 T cell
Epithelioid
cell
AM2
Proinflammatory chemokines monocyte Antigen-
CCL3, CCL5, and RANTES presenting
cell B cell
mTORC1 activated
C Persistent Granulomas Associated with Chronic Disease, Fibrosis, or Granuloma Resolution
Antigen presentation Granuloma formed and profibrotic elements activated

(more immune cells activated)
Treg Activated
cell Treg cell
CD4 and CD8 FoxP3+
Macrophage
Antigen T cells
Granuloma
Peptide Interleukin-10 dissolved
TCR Interferon-γ
Giant cell
Antigen- JAK-STAT
presenting T cell pathway activated
cell Antigen T cell
Interleukin-10 and 13, TNF-α, Fibrocyte
TNF-α and TGF-β, and interferon-γ
interferon-γ Interleukin-13
Fibroblast
Neutrophil
AM1
AM2 Fibrosis
B cell Collagen

by T cells that use their antigen receptor. These Figure 2 (facing page). Clinical and Diagnostic Features That Are Helpful
interactions result in a specific adaptive immune in the Diagnosis and Follow-up of Sarcoidosis.
response with different qualities depending on, Panel A shows skin lesions associated with sarcoidosis, including burns on
for example, the surrounding milieu and directed the hand of a patient who did not feel the difference between hot and cold
against the offending antigen.28 water because of small-fiber neuropathy; macular edema, a rather common
eye manifestation in sarcoidosis; and multinucleated alveolar macrophages
(AMs, stained with May–Grünwald Giemsa), which can be found in broncho
Alveolar Macrophages
alveolar lavage fluid (BALF) from patients with sarcoidosis.15
Granulomas often resolve spontaneously, but in High-resolution computed tomography (HRCT) is superior to chest radiog-
some patients they persist and function as a ni- raphy and is more sensitive in assessing the extent of the disease. Panel B
dus for the development of fibrosis, a process shows a chest radiograph of bilateral hilar lymph nodes (upper left image,
that probably depends on the nature of the of- arrows), which are better seen on coronal CT (upper right image). In the
fending antigen.24 Interleukin-13 stimulates polar- second pair of images, the left image shows a CT scan of micronodules in
the peribronchovascular interstitium (arrows) and in the subpleural inter-
ization toward M2-type activated macrophages stitium (arrowheads) and the right image shows micronodules in the inter-
(which are antiinflammatory and proangiogenic lobular septa (arrows), which suggest a perilymphatic distribution. The bot-
and promote type 2 helper T [Th2] cell function) tom image shows end-stage fibrosis with extensive deformation of the lungs,
that are reported to influence early granuloma axial traction bronchiectasis, and honeycombing. Some CT features may
formation.29 In addition, M2 can promote fibro- discriminate between active lung inflammation and fibrosis. Typical inflam-
matory findings on HRCT include a bilateral distribution of micronodules,
sis (e.g., by recruiting and differentiating fibro- perilymphatic and bronchocentric distribution, perihilar ground-glass opac-
cytes and through differentiation into fibrocyte- ities, and varying degrees of fibrosis.56,57
like cells expressing collagen [fibroblasts]).30 The Positron-emission tomography (PET) and CT with 18F-fluorodeoxyglucose
neutrophilic component of the inflammation, (FDG PET-CT) is a sensitive method for assessing inflammatory activity
including mediators such as collagenase, oxidant and the extent of disease in sarcoidosis. In Panel C, FDG PET-CT reveals
radicals, and proteases, can also contribute to extensive hypermetabolic lymphadenopathy (cervical, supraclavicular, axil-
lary, mediastinal, abdominal, and inguinal), as well as high activity in the
alveolar-wall injury in sarcoidosis and to the lung parenchyma, spleen, and bone marrow; heterogeneous activity in the
evolution toward pulmonary fibrosis.14,15,31,32 Tis- parotids is more pronounced on the left. FDG PET-CT is especially useful
sue-resident macrophages in the liver (Kupffer in patients with unexplained symptoms that have no connection with already
cells) or microglia in the brain originate from known organ involvement, in patients with persistent symptoms without
progenitor cells. Although not as effective as serologic signs of inflammatory activity, and in patients with radiologic signs
of fibrosis in whom the presence of inflammation is uncertain, as well as for
dendritic cells, these macrophages can also func- the detection of a suitable location for biopsy and for the detection of active
tion as antigen-presenting cells. After activation, cardiac sarcoidosis.58 Panel D shows an FDG PET-CT scan of the heart, with
they begin to differentiate into histiocytes and epi- focal areas of inflammatory activity in the left ventricle (orange arrows), inter-
thelioid cells, forming the core of the granuloma.33 mediate wall (white arrows), and right ventricle wall (gray arrows). Locali
zation is similar on magnetic resonance imaging (MRI); an MRI scan ob-
tained after contrast administration shows late gadolinium enhancement
T Cells
with increased signal intensity or contrast enhancement in the side wall of
In sarcoidosis, the accumulation of activated the left ventricle (orange arrows), partition wall (white arrows), and right
helper T cells in the lungs, which promotes the ventricle wall (the left-most arrow).
formation of nonnecrotizing epithelioid-cell gran- In Panel E, CT and MRI scans obtained after contrast administration show
ulomas, suggests that specific antigens trigger a left parietal occipital enhancing lesion (orange arrows); the image on the
an immune reaction. Sarcoidosis has been char- right shows myelum involvement (between the two arrows) on gadolinium-
enhanced MRI, which is the imaging study of choice for the diagnosis of
acterized as an archetypal type 1 helper T (Th1) neurosarcoidosis.
cell–driven disease, with helper T cells in bron- Panel F shows bone involvement. Panel G (hematoxylin and eosin stain)
choalveolar lavage fluid (BALF) expressing high shows histologic images of granulomas; a biopsy is indicated when possi-
levels of interferon-γ, interleukin-2, and tumor ble for detection of granulomas, but it is not always possible to obtain rep-
necrosis factor α (TNF-α)34; with high levels of resentative biopsy material.52 GC denotes glucocorticoid.
the Th1-skewing cytokines interleukin-12 and
interleukin-18 in BALF; and with increased ex-
pression of Th1-associated chemokine recep- such as HLA-DR, but also by the release of spe-
tors CXCR3 and CCR5.35 Activation of alveolar cific mediators (interleukin-2 and interferon-γ).
T lymphocytes is a characteristic feature of sar- The exaggerated Th1/Th17-oriented immune re-
coidosis, as reflected by increased expression of sponse in sarcoidosis includes up-regulation of
typical activation markers on the cell surface, Th1-specific transcription factor (T-box tran-

Sarcoidosis
A Clinical Features B Diagnostic Features

Granuloma Annulare Subcutaneous Granuloma Bilateral Hilar Lymph Nodes
on the Face on the Lips Lupus Pernio Radiograph CT
Striae Due to
GC Treatment Vitiligo Burns on the Hand Micronodular Pattern
CT CT
Erythema Nodosum,
Lower Legs Macular Edema Multinucleated AMs
End-Stage Fibrosis
CT
C FDG PET-CT D Cardiac Involvement E Neurosarcoidosis

FDG PET-CT Left Parietal Occipital Enhancing Lesion Myelum Involvement
CT MRI MRI
MRI
F Bone Involvement G Biopsy Specimens Showing Granulomas

of the Skull
CT Bone Quadriceps Femoris Artery Sural Nerve
Muscle
Fascicle
Granuloma Granuloma
Granuloma
scription factor 21 [TBX21]), which in turn con- subtypes. In a milieu with elevated levels of
trols the Janus kinase and signal transducer and macrophage-derived interleukin-1 and interleu-
activator of transcription (STAT) pathways and kin-6, CD4+ T cells can differentiate into Th17
the Th1 hallmark cytokine, interferon-γ. Accord- and Th17.1 cells, with high production of inter-
ingly, STAT-dependent transcripts are abundant in leukin-17 and interferon-γ, respectively.23 Ram-
the transcriptome of blood cells, lung tissues, and stein et al. described a marked increase of Th17.1
lymph nodes in patients with sarcoidosis.36,37 cells in sarcoidosis, and they proposed that
Through T-cell plasticity, CD4+ T cells can Th17.1 cells might be the predominant produc-
differentiate into other (related) functional T-cell ers of interferon-γ in pulmonary sarcoidosis.16

Another part of the immune response is interfer- mune conditions. These results provided new
ence with the ability of memory T lymphocytes evidence of autoimmune mechanisms and an
to recall antigens. In sarcoidosis, however, damp- important role of humoral immune responses in
ening of the immune response by regulatory sarcoidosis.42 Furthermore, sarcoidosis appears
T cells appears to be dysfunctional and is accom- to be associated with activation of the metabolic
panied by an exaggerated adaptive immune re- checkpoint kinase mammalian target of rapamy-
sponse.28,37 Thus, according to current concepts, cin complex 1 (mTORC1), which can be involved
the disturbed adaptive immune response in sar- in the granulomatous process by activating mac-
coidosis contributes to the pathogenesis of the rophages and their differentiation into epithelioid
disorder.1 cells (which tend to aggregate) and multinuclear
giant cells. A disturbed autophagy process that
T-Cell Antigens normally eliminates antigens will further stimu-
In many patients with sarcoidosis, CD4+ T cells late granuloma formation.23 Thus, growing knowl-
accumulating in the lung preferentially express edge about newer pathophysiological pathways,
certain T-cell receptor variable gene segments, such as mTORC1 and dysfunctional autophagy
suggesting recognition of specific antigens.34 A and activation of the nucleotide-binding oligomer-
number of potential autoantigens were identified ization domain–like receptor protein 3 (NLRP3)
in HLA molecules of BALF cells from HLA-DR3– inflammasome, may guide the development of
positive patients with sarcoidosis (e.g., peptides new therapeutic targets.43
derived from ATP synthase, lysyl–transfer RNA
synthetase, and vimentin).38 Hypothetically, these Cl inic a l Pr e sen tat ion, C our se ,
T cells are recruited to the lungs because they a nd Pro gnosis
recognize disease-specific antigenic peptides pre-
sented by the HLA-DRB1*03+ molecules ex- The presentation of patients with sarcoidosis is
pressed on the surface of local antigen-present- highly variable, with many clinical phenotypes.
ing cells. Furthermore, T-cell stimulation tests Although virtually any organ can be affected by
have suggested a role for vimentin, a constituent this chameleon-like, multisystemic disease, the
of the cytoskeleton that is secreted during cellular lungs are usually involved, with symptoms such
activation and that can function as an autoanti- as cough, shortness of breath, chest pain, and
gen in rheumatoid arthritis.39 Positive evolution- most commonly, pronounced fatigue.1,8 Clinical
ary selection driven by infections may also play symptoms vary widely, depending on which
a role, as suggested by a study showing that HLA organs are affected.6 Apart from organ-related
genotypes conferring a predisposition to sarcoid- symptoms, patients with sarcoidosis, like patients
osis have enhanced binding to tuberculosis anti- with chronic diseases in general, often have a
gens and provide protection against tuberculo- wide spectrum of systemic, nonspecific symp-
sis.40 Similarly, Cutibacterium acnes has been proposed toms, which are not related to a single organ
as an etiologic agent, given the increased fre- and cannot be explained by the granulomas but
quency of genetic material in sarcoidosis granu- are likely to be caused by the systemic release of
lomas as compared with control granulomas, as inflammatory mediators (e.g., TNF-α) and are
well as a similar exaggerated immune response difficult to verify. Nonspecific symptoms of sar-
to cutibacterium in sarcoidosis T cells as com- coidosis such as fatigue, exercise limitations,
pared with normal T cells.41 cognitive impairment, and symptoms associated
with small-fiber neuropathy have a great effect
Pathways to Be Explored on well-being and quality of life.3,17,44-47
It was assumed that B cells, as well as Th2- and The clinical manifestations of the disease can
Th17-like cells — the most effective cell type in generally be classified according to activity or
supporting B-cell activity, particularly in auto- severity (e.g., organ dysfunction) or both. Active
antibody production, including specific vimentin sarcoidosis does not necessarily indicate a pro-
recognition — may be involved in the develop- gressive course, a fatal prognosis, or the need
ment of sarcoidosis and several other autoim- for treatment. Moreover, the absence of evidence

Sarcoidosis
Clinical presentation
Highly suggestive of sarcoidosis Suggestive of sarcoidosis Not suggestive of sarcoidosis

• Löfgren’s syndrome
• Lupus pernio
• Heerfordt’s syndrome
• Bilateral hilar adenopathy,
no symptoms Perform biopsy or BALF cytology
compatible with sarcoidosis, if no
biopsy is available
Granulomatous No granulomatous
inflammation inflammation
Alternative causes
No diagnosis
of granulomatous
inflammation?
Follow up with the patient

No Yes
after 6 mo, and repeat if
clinical picture has progressed
Sarcoidosis Alternative
highly likely diagnosis
• Perform functional assessment of major

organs, if involved
• Refer patient to an ophthalmologist
• Assess exercise capacity
• Assess fatigue, SFN-associated symptoms,
and other QoL-related issues due to sarcoidosis
• Establish an individualized treatment plan
(by a multidisciplinary team with sarcoidosis expertise)
in shared decision making with the patient
• Follow up
Figure 3. Proposed Algorithm for Diagnosing Sarcoidosis.

A simple algorithm for the diagnosis of sarcoidosis is not feasible, in view of the many faces of sarcoidosis. The pro-
posed algorithm is based on expert opinion1 and the evidence-based diagnostic pathway provided by the American
Thoracic Society.52 The diagnosis usually depends on a combination of compatible clinical findings, histologic evi-
dence of nonnecrotizing granulomas (e.g., in transbronchial biopsy samples or ultrasonography-guided transbronchial
needle aspiration of mediastinal lymph nodes), and the ruling out of alternative causes of granulomas that result in
a similar histologic or clinical pattern.1,52 BALF with an increased ratio of CD4+ T cells to CD8+ T cells supports the
diagnosis. However, there is no single cell type in BALF that appears to be predictive of sarcoidosis,15 although cer-
tain T cells have been found to be highly specific for Löfgren’s syndrome.60 Nevertheless, BALF analysis can be very
helpful in the differential diagnosis. An elevated total cell count and a predominance of lymphocytes, together with
nearly normal percentages of eosinophils and polymorphonuclear neutrophils and the absence of plasma cells, dis-
tinguish sarcoidosis from the most common interstitial lung diseases (extrinsic allergic alveolitis, nonspecific inter-
stitial pneumonia, and idiopathic pulmonary fibrosis).15 Assessment of organ involvement is very important.1,46,52
FDG PET-CT is a sensitive method for assessing inflammatory activity and the extent of disease in sarcoidosis. FDG
PET-CT is especially useful in the case of unexplained symptoms without any connection to known organ involvement.58
Attention should also be paid to nonspecific organ-related symptoms (e.g., fatigue, everyday cognitive failure, and
symptoms associated with small-fiber neuropathy [SFN]), since they can substantially influence quality of life (QoL).3,46

of disease activity does not rule out subclinical nodular pattern) are highly specific for sarcoid-
disease activity. Emerging evidence links the osis55,56 (Fig. 2). Biopsy specimens obtained from
genetic risk of sarcoidosis (genotype) to the the lungs or mediastinal lymph nodes provide the
clinical manifestation and outcome (phenotype). greatest diagnostic yield.25,26 Surgical approaches
Patients with Löfgren’s syndrome have an acute (e.g., video-assisted thoracoscopic surgery or
clinical presentation of systemic sarcoidosis de- mediastinoscopy) reliably provide diagnostic tis-
fined by the triad of erythema nodosum, bilat- sue but are invasive, inconvenient, and more
eral hilar adenopathy, and polyarthralgia or poly- costly than bronchoscopic procedures. A system-
arthritis, often with fever; they usually have a atic analysis of the literature showed that endo-
very good prognosis, especially those who are bronchial ultrasound-guided transbronchial needle
HLA-DRB1*03–positive.1 More than 50% of pa- aspiration (TBNA) or bronchoscopy with TBNA
tients with non–Löfgren’s syndrome sarcoidosis was safe and highly effective, as well as more
will have a remission, whereas in approximately convenient and less expensive than mediasti-
one third of patients, the disease takes a chron- noscopy.52
ic course. The presence of cardiac, neurologic, Cardiac sarcoidosis is the second leading
renal, and progressive fibrotic pulmonary involve- cause of death among affected patients, after
ment with respiratory failure is associated with pulmonary sarcoidosis. Hence, current practice
increased morbidity and mortality and often guidelines recommend routine screening for
dictates the need for treatment.12,48,49 Certain cardiac sarcoidosis in patients with newly diag-
patient characteristics and genetic variants are nosed sarcoidosis, beginning with a history tak-
prognostic (Table 1). Less than 10% of patients ing, physical examination, and 12-lead electro-
die from sarcoidosis; most fatal cases are due to cardiogram. Patients presenting with high-risk
advanced lung disease, followed by cardiac com- symptoms, electrocardiographic changes (e.g.,
plications.1,50 The net effect is a reported increase high-degree heart block27), or both (Table S1 in
in the risk of death by a factor of 0.9 to 2.4.11 the Supplementary Appendix, available with the
Although most patients with sarcoidosis are full text of this article at NEJM.org) should un-
asymptomatic or have acute symptoms with dergo either cardiac magnetic resonance imag-
spontaneous resolution, chronic disease develops ing (MRI) or cardiac 18F-fluorodeoxyglucose
in approximately one third of patients, waxing positron-emission tomography and CT (FDG
and waning or relentlessly progressing (if un- PET-CT) to confirm cardiac involvement on the
treated) over an extended period.51 Table 1 lists basis of characteristic radiographic manifesta-
some possible adverse prognostic factors and tions (Fig. 2). Imaging is sufficient to establish
some possible favorable prognostic factors. a diagnosis of cardiac sarcoidosis in most cases,
obviating the need for myocardial biopsy.59
Awareness of other nonpulmonary manifesta-
Di agnos t ic Ch a l l enge s
tions of sarcoidosis may expedite management
The clinical diversity of sarcoidosis, as well as its decisions.46 Many features of sarcoidosis may aid
resemblance to other, more common disorders, in establishing its diagnosis and should be con-
often leads to diagnostic uncertainty and treat- sidered in the context of treatment (Figs. 2 and 3).
ment delays. Ultimately, the diagnosis of sar- Clinical manifestations that are highly predictive
coidosis is based on three major criteria: com- of sarcoidosis and preclude the need for further
patible clinical characteristics, identification of diagnostic testing include Löfgren’s syndrome
nonnecrotizing granulomas in one or more tis- and lupus pernio (Fig. 2). In contrast, neurosar-
sue samples, and the ruling out of other causes coidosis is often a diagnostic puzzle, most com-
of granulomatous disease.52-54 Patients most commonly manifested as cranial-nerve deficits, and
monly present with subacute or chronic respira- delays in diagnosis and treatment can lead to
tory symptoms, and a diagnosis of sarcoidosis is permanent disability. The diagnostic workup for
considered on the basis of typical features on a neurosarcoidosis includes MRI of the head, cere-
chest radiograph or computed tomographic (CT) brospinal fluid analysis, and detection of sar-
scan. Certain CT findings (e.g., bilateral hilar coidosis outside the nervous system.
lymphadenopathy with a perilymphatic, micro Biomarkers should be viewed as evidence of

Sarcoidosis
active inflammation, not as pathognomonic late with prolonged use.49,69 Moreover, no dis-
tests.61 The serum angiotensin-converting en- cernible benefits in disease outcomes are noted
zyme level is elevated in 50 to 60% of patients with higher doses versus lower doses, particularly
with sarcoidosis. However, this biomarker lacks for maintenance therapy.48,49 Thus, for patients
diagnostic specificity, so its use is limited to requiring long-term suppression of inflammation
evaluating the therapeutic response.61,62 Other to prevent irreversible organ damage or intoler-
biomarkers — soluble interleukin-2 receptor, able symptoms, early institution of glucocorti-
C-reactive protein, serum amyloid A, and chito- coid-sparing antisarcoidosis agents is generally
triosidase — are generally useful for assessing recommended, either alone as first-line treat-
disease activity, but FDG PET-CT is most effec- ment or with a rapid reduction in glucocorticoid
tive for detecting tissue-specific inflammatory doses (Fig. 4).13,49 Commonly used glucocorticoid-
activity and identifying sites for diagnostic biop- sparing agents for second-line treatment include
sies (Fig. 2).58,61,63 Table S1 lists recommended methotrexate (the agent studied and prescribed
approaches to screening and evaluation for vari- most often), azathioprine, leflunomide, and my-
ous manifestations of sarcoidosis and sarcoid- cophenolate. An alternative in this category is
osis-associated symptoms, as well as goals of the antimalarial agent hydroxychloroquine, which
care and management strategies, in more detail. has proved particularly useful for cutaneous
disease, hypercalcemia, and some cases of neuro-
sarcoidosis.48
M a nagemen t
If nonglucocorticoid antisarcoidosis agents,
Management of sarcoidosis is a major clinical administered alone or in combination with glu-
challenge because of the highly variable disease cocorticoids, are toxic or ineffective or if the
manifestations. The decision of whether (and, if disease is severe and progressive, third-line treat-
so, when) to treat an individual patient who has ment with biologic agents or advanced immuno-
sarcoidosis depends on two major factors: the modulating agents may be considered.12,48,49
risk of organ failure or death and the extent Infliximab and adalimumab (both TNF-α inhibi-
to which the patient’s quality of life is im- tors) are effective options (Fig. 4).64 Although
paired.3,12,46,48,49 The decision is complex and cannot yet extensively studied in sarcoidosis, bio-
not be standardized.3,48 In most patients with similar anti–TNF-α agents also seem promis-
sarcoidosis, the disease resolves spontaneously ing.12 Third-line alternatives, although they are
and does not require systemic therapy. However, associated with a risk of specific toxic effects
for patients with severe disease, timely treat- themselves, mitigate the risks associated with
ment can mitigate disease manifestations and glucocorticoids but present other problems and
prevent long-term complications.48 Current treat- risks, including greater cost, the need to moni-
ment standards are based on low-quality evi- tor patients for the toxic effects of the drugs,
dence,64 but experts agree that therapeutic goals and the inconvenience of intramuscular or intra-
should focus on suppression of inflammation- venous administration, as well as lack of famil-
induced organ dysfunction, assessed on the ba- iarity with these agents on the part of many
sis of objective metrics (e.g., lung function), and physicians.49 Since immunomodulating drugs
on the avoidance of toxic effects of drugs.1,12,48,49 compromise antimicrobial defenses, vaccination
However, these two measures of disease mani- and other measures for preventing infection are
festations can be misleading, since many pa- crucial in patients with sarcoidosis who are
tients continue to feel unwell despite objective treated with these agents.70
resolution. The side-effect profile associated with treat-
A consensus statement from sarcoidosis ex- ments for sarcoidosis varies greatly from one
perts endorses glucocorticoids as the primary patient to the next, as does the efficacy of treat-
treatment for sarcoidosis, on the basis of their ments, so a simple treatment algorithm that
efficacy and ease of use (low cost and oral ad- works for all patients is not feasible. The dura-
ministration) (Fig. 4).64 Unfortunately, glucocor- tion of treatment depends on the individual
ticoids are associated with a dose-dependent risk phenotype. A small subgroup of patients with
of serious adverse effects, which tend to accumu- sarcoidosis requires long-term treatment to pre-

Inform the patient well and share care and decision making
Assess the need for sarcoidosis treatment Assess for the following conditions
repeatedly and define the target organs and symptoms and define treatment options
Clinical
phenotypes Conditions
• Fatigue
Asymptomatic; Symptomatic Symptomatic Severe danger:
no risk of or impaired QoL or impaired QoL risk of • Sleep apnea or OSAS
organ damage or both; no risk or both; risk irreversible • Depressive symptoms
or disease of organ damage of organ damage organ damage • Pain
progression or functional or functional or death • SFN-associated symptoms
impairment impairment • Cognitive failure
• Progressive pulmonary fibrosis
• Hypoxemia
• Life-threatening heart rhythm
disturbances
• Sarcoidosis-associated
pulmonary hypertension
• End-stage organ damage
Treatment
options
Observation Local treatment First-line Second-line Third-line New therapies

No treatment • Lung: inhalation treatment treatment treatment that are under
indicated; * GCs * * * investigation
GCs; consider GCs and SSAS: GCs and SSAS;
encourage • Skin: cream, HCQ in severe MTX, AZA, add-on TNF-α Rituximab or
exercise and a ointment skin lesions or MMF, or LEF; inhibitor newer agents such
healthy lifestyle • Eye: drops, ointment hypercalcemia consider add-on as JAK2 inhibitors,
• LS: consider NSAIDs HCQ tocilizumab, RCI,
VIP, antifibrotics (in
* Denotes unacceptable side
case of refractory
effects or insufficient response
fibrotic lung disease),
and nicotine
Goals of care:
Disease control, Disease control, Disease control, Disease control, transdermal patches
prevent or
minimize organ no unacceptable no unacceptable no unacceptable no unacceptable
damage and side effects, side effects, side effects, side effects,
tapering of tapering of GCs complete tapering of GCs,
improve QoL
agents withdrawal of continuation of
GCs and induction third-line
of SSAS agents treatment
Consider personalized treatment
Treatment
options
Organ Supportive care Pharmacologic

transplantation agents not directed
• Exercise, healthy lifestyle
options at granulomas
• Rehabilitation
• Lungs • Psychological counseling • Antioxidants
• Heart • Patient support groups • Neurostimulants
• Liver • Cognitive behavioral therapy • Antidepressants
• Mindfulness-based therapy • Analgesics
• CPAP and BiPAP • Anticonvulsants
• Supplemental oxygen • IVIG
• ICD or pacemaker • SAPH treatment

Sarcoidosis
Figure 4 (facing page). Proposed Treatment Algorithm vent progressive organ damage. Factors not di-
for Sarcoidosis. rectly related to inflammation or treatment side
The lack of approved drugs tested in randomized, con- effects often compromise the well-being of pa-
trolled trials hampers the development of standardized tients with sarcoidosis. For instance, many such
treatment protocols for sarcoidosis.1,65 The care of pa- patients report severe, life-altering fatigue and
tients with sarcoidosis should be modified on the basis
of the organs involved, the associated symptoms, and
an inability to concentrate,46 affecting their pro-
the risk of irreversible organ damage or death. Some ductivity at work71 and overall quality of life.3,5
symptoms associated with sarcoidosis respond to ther- Patients with sarcoidosis are often decondi-
apies that do not directly suppress sarcoidosis granulo- tioned and may benefit from structured, regular
mas.5 A stepwise approach to therapy is generally recom- exercise to reduce fatigue and improve their
mended. Systemic sarcoidosis with burdensome symptoms
usually responds to first-line treatment with glucocorti-
quality of life.5,68,72 Sarcoidosis-associated pul-
coids (GCs), but one needs to weigh the risk of toxic ef- monary hypertension, chronic neuropathic pain,
fects that are associated with long-term use against the or dysautonomia often responds poorly to im-
risk of relapse.49 The ideal dosing and duration of ther munosuppressive therapy and may benefit from
apy are unknown and are likely to vary on an individual
alternative treatments (e.g., antidepressant agents
basis. A starting dose of 20 to 40 mg of prednisone or
the equivalent per day, with a maximum of 0.5 mg per or dietary measures) to mitigate symptoms.44,73
kilogram of body weight, is generally recommended, Transplantation for sarcoidosis is performed
although patients with severe disease manifestations infrequently (in 3 to 5% of patients) but is effec-
may initially be given much higher doses for a short tive, as reflected by a post-transplantation pa-
period. Lower induction doses of GCs may be reason-
able in less severe cases. GCs are not desirable for the
tient survival rate (approximately 70% at 5 years)
management of chronic disease, since there is a dose- that is similar to the rate for patients with other
dependent risk of complications, including serious car- indications for lung transplantation (50 to 60%
diovascular complications.66 Thus, tapering to the lowest at 5 years).74 The main factors associated with
effective dose (or tapering to withdrawal of GCs) is an worse survival are older age and extensive preop-
ultimate treatment goal, and GC-sparing agents should
be considered. In GC-refractory cases, second-line treat- erative lung fibrosis. Treatment guidelines for
ment with GC-sparing drugs, referred to as steroid-sparing sarcoidosis are evolving, and health care provid-
antisarcoidosis (SSAS) agents, is a reasonable alterna- ers are advised to consider a personalized ap-
tive. Methotrexate (MTX) is commonly prescribed, with proach based on individual variations in disease
a starting dose of 10 to 15 mg weekly, adjusted up to
manifestations (Tables S1 and S2).
20 mg or higher if necessary and if the side-effect pro-
file is acceptable. It is advised to combine MTX with folic
acid.67 Subcutaneous MTX is recommended in the event
F u t ur e Dir ec t ions
of gastrointestinal side effects.49 Monoclonal antibodies
targeting TNF-α, particularly infliximab and adalimumab, There is now a great need to identify (through
are recommended as third-line treatment. Concomitant
use of adjunctive immunosuppressants such as MTX
proteomics, genetics, and epigenetics) additional
reduces the risk of neutralizing antibodies and increases key genetic components of sarcoidosis to reveal
drug efficacy. In addition to pharmacologic treatment, new factors that drive or resolve granuloma for-
it is often beneficial, in terms of improving QoL, to offer mation. New methods allowing in situ sequenc-
counseling and encourage lifestyle changes, such as
ing can localize immune transcripts within
physical training for patients with fatigue or decondition-
ing.68 Dietary modifications may also be beneficial, as granulomas, in order to elucidate their role in
suggested by studies indicating that antioxidants may progressing or nonprogressing granulomas that
mitigate chronic cough and reduce reliance on GCs.31,32 correlate with disease development.1,65 Applying
AZA denotes azathioprine, BiPAP bilevel positive airway new techniques such as whole-exome sequenc-
pressure, CPAP continuous positive airway pressure,
HCQ hydroxychloroquine, ICD implantable cardioverter–
ing in patient cohorts that are carefully pheno-
defibrillator, IVIG intravenous immune globulin, LEF typed will improve the characterization of in-
leflunomide, LS Löfgren’s syndrome, MMF mycopheno flammatory pathways, identify disease markers,
late mofetil, NSAIDs nonsteroidal antiinflammatory reveal new therapeutic targets, and encourage
drugs, OSAS obstructive sleep apnea syndrome, RCI the investigation of new therapies (Fig. 4).75,76
repository corticotropin injection, SAPH sarcoidosis-
associated pulmonary hypertension, and VIP vasoactive
This initiative will have an important effect on
intestinal peptide. clinical management. The ongoing search for
specific sarcoidosis antigens, as suggested by

features of the immune response, may reveal for antiinflammatory action.31 The benefits of
markers of importance for pathogenesis. New flavonoids and other antioxidant supplements
concepts suggest that sarcoidosis — or sub- may be related to the restoration of normal anti-
groups or variants of sarcoidosis — is an auto- oxidant levels in patients with sarcoidosis.31,77
immune disease with immune reactions against Advancing our understanding of the patho-
self-proteins.2 We expect to learn more about physiology of sarcoidosis and improving clinical
functions of T lymphocytes, their various stages care for patients will require physicians with
of differentiation, their activation through inter- multidisciplinary skills who are dedicated to the
action with cells of the innate immune system, treatment of patients with sarcoidosis, focus on
and their influence on the disease outcome. somatic as well as psychosocial aspects of the
A major challenge for clinicians is to rethink disease, and actively engage with patients to
and reconfigure therapeutic approaches to the improve adherence to treatment, optimize its
disease. Treating patients with immunosuppres- benefits, and reduce the risk of side effects.5,6
sive drugs such as glucocorticoids, glucocorticoid- Patients with sarcoidosis will benefit from the
sparing antisarcoidosis agents, and anti–TNF-α care provided by a treating physician who under-
agents is well accepted.1,65 However, we need to stands what the disease is all about and seri-
optimize the use of pharmacotherapeutic inter- ously considers each patient’s symptoms.46 En-
ventions targeting phenotype-specific mecha- hanced awareness of the special needs of patients
nisms in order to individualize treatment while with sarcoidosis — for instance, through patient
improving the quality of life.13 A pivotal aspect advocacy groups — and specialized training of
is to regularly consider how to reduce the side health care providers are necessary to provide
effects of glucocorticoids. Besides reducing glu- adequate and standardized care globally for pa-
cocorticoid doses by combining them with im- tients with sarcoidosis.3,5,46
munosuppressive drugs, new strategies for opti- Disclosure forms provided by the authors are available with
mizing treatment need to be explored, including the full text of this article at NEJM.org.
We thank Marjon Elfferich, M.Sc., for critically reviewing an
lifestyle changes, physical therapy, and dietary earlier version of the manuscript and for her help in preparing
guidance.31,68 For instance, a flavonoid-rich diet drafts of the figures, Prof. Johny Verschakelen for providing CT
in conjunction with glucocorticoids has been images along with clinical data and interpretation, Drs. Ruth
Keijsers and Renske Vorselaars for providing the FDG PET-CT
reported to increase the efficacy of glucocorti- images, and Dr. Elske Hoitsma for providing the image of the
coid therapy, thereby reducing the dose required sural nerve biopsy.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Dan L. Longo, M.D., Editor

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Table 1. Selected Adverse and Favorable Prognostic Factors in Sarcoidosis.*

Variable Adverse Prognostic Factors† Favorable Prognostic Factors

the epidemiologic assessment of sarcoidosis and En v ironmen ta l a nd Gene t ic

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A Exposure in Genetically Predisposed Persons

Initial insult Second insult Persistent antigen presence, antigen

Granuloma formation promoted Granuloma formed and symptoms appear

C Persistent Granulomas Associated with Chronic Disease, Fibrosis, or Granuloma Resolution

Antigen presentation Granuloma formed and profibrotic elements activated

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A Clinical Features B Diagnostic Features

C FDG PET-CT D Cardiac Involvement E Neurosarcoidosis

F Bone Involvement G Biopsy Specimens Showing Granulomas

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Highly suggestive of sarcoidosis Suggestive of sarcoidosis Not suggestive of sarcoidosis

Follow up with the patient

• Perform functional assessment of major

Figure 3. Proposed Algorithm for Diagnosing Sarcoidosis.

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Observation Local treatment First-line Second-line Third-line New therapies

Consider personalized treatment

Organ Supportive care Pharmacologic

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