Neves et al.

Advances in Rheumatology (2024) 64:57 Advances in Rheumatology

https://doi.org/10.1186/s42358-024-00381-z

REVIEW Open Access

Sarcoidosis: a general overview

Fabricio Souza Neves1* , Ivanio Alves Pereira2, Flavio Sztajnbok3 and Nilton Salles Rosa Neto4,5

Abstract
Sarcoidosis is a systemic inflammatory disease of unknown origin, which consists of the formation of multiple
sterile noncaseating granulomas. Inhaled antigens are believed to initiate disease in prone individuals, considering
that almost all patients present pulmonary or mediastinal lymph node disease. Extrapulmonary manifestations are
common and diverse: practically any organ system can be affected, and treatment can range from simple watchful
waiting to intense immunosuppression. In this article, we review current concepts about sarcoidosis in an overview,
focusing on recognition and treatment of its major clinical phenotypes.
Keywords Sarcoidosis, Rare diseases, Review, Noncaseating granuloma

Background higher in people of African descent living in the United

Sarcoidosis is a systemic inflammatory disease of States [1, 2].
unknown origin. It is more common in Western coun-
tries and typically occurs in adults. It affects the lungs Pathogenesis and pathology
and mediastinal lymph nodes in almost all cases, but it Like many other idiopathic inflammatory diseases, sar-
can also involve the heart, skin, kidneys, eyes, peripheral coidosis is believed to occur in individuals with certain
and central nervous system, and joints. Biopsy of affected genetic predispositions after exposure to environmental
sites remains the cornerstone of the diagnosis, given that triggers. However, both factors are essentially unknown
its main characteristic is the pathologic pattern based on [1]. Sarcoidosis is associated with some human leukocyte
noncaseating granulomas [1]. Although many cases may antigens (HLA) class II alleles, but not with a specific
be self-limiting, some patients require immunosuppres- genetic variant [2, 3]. In granulomatous lesions of sar-
sive therapy to prevent end-organ damage or even death coidosis, different microbial DNA was found, but viable
due to failure of vital organs, particularly heart and lungs. microorganisms were never observed [4]. Also exposure
The incidence and severity of the disease appears to be to inorganic dusts [5] and immunoreactivity against these
compounds [6] are associated with sarcoidosis. There-
fore, sarcoidosis is neither a genetic nor an infectious dis-
*Correspondence: ease; it is probably a disease that arises in individuals who
Fabricio Souza Neves develop an inappropriate immune response when chal-
fabricio.souza.neves@ufsc.br lenged by certain infectious or inorganic antigens. This
1
Internal Medicine Department, Rheumatology Division, Health Sciences
Center, Universidade Federal de Santa Catarina (UFSC), Florianópolis, inappropriate immune response is based on the Th1 and
Brazil Th17 pathways and induces the granulomatous inflam-
2
Medicine School, Rheumatology Division, Universidade do Sul de Santa matory process typical of sarcoidosis, in which tumour
Catarina (UNISUL), Palhoça, Brazil
3
Department of Pediatrics, Universidade Federal do Rio de Janeiro, Rio de necrosis fator alpha (TNFa) produced by activated mac-
Janeiro, Brazil rophages has a fundamental role (Table 1) [7].
4
Centro de Doenças Raras e da Imunidade, Hospital Nove de Julho, São An interesting hypothesis is that the granulomatous
Paulo, Brazil
5
Universidade Santo Amaro, São Paulo, Brazil response persists as long as there is insufficient clearance

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Neves et al. Advances in Rheumatology (2024) 64:57 Page 2 of 7

Table 1 HLA alleles linked to sarcoidosis risk, sources of antigens Table 2 Chest radiography staging for pulmonary
found in sarcoid lesions and characteristics of immune response sarcoidosis (adapted from Scadding, 1961) [12]
of sarcoidosis (adapted from Greaves et al, 2020) [7] Stage Radiographic findings
HLA alleles DRB1*12:01, *11:01, *03:01 0 Normal
DQA1*06:02 I Only hilar lymphadenopathy
DQB1*05:03, *06:04
II Hilar lymphadenopathy and parenchymal abnormality
Source of antigens Mycobacterium tuberculosis; Cutibacteri-
III Only parenchymal abnormality
um acne ; Borrelia burgdorferi; Aspergillus
IV Pulmonary fibrosis with volume loss
fumigatus
Silica; berilium
Immune response Th1: IFNg and IL-2 General clinical features and approach to diagnosis
Th17: IL-17 and IL-23
Macrophages and epithelioid cells: TNFa
Almost any organ can be affected by sarcoidosis. Skin
(14–16%), eyes (8–20%), liver (11–18%), spleen (7–20%),
heart (2–11%), joints (8–9%), nervous system (2–7%),
of the causative antigen, and throughout this period it parotid glands (4%) and kidneys (2%) are common sites
causes different symptoms to the patient (it could explain of sarcoid disease. However, lungs and mediastinal
the habitual self-limited course of the disease). In this lymph nodes are by far most affected (> 90% of patients)
hypothesis, the entry of the causative antigens is possi- [10, 11]. Thus, respiratory symptoms and abnormali-
bly via inhalation, an idea that can be deduced from the ties on chest radiography (CXR) or computed tomogra-
fact that almost all cases of sarcoidosis begin with pul- phy (CT) are the most frequent initial clinical picture. If
monary involvement and mediastinal lymphadenopathy. sarcoidosis is suspected in any organ system, respiratory
Biopsies of organs affected by sarcoidosis reveal multiple symptoms must be inquired, and CXR and CT obtained.
granulomas, which consist of clusters of multinucleated Chest radiography in sarcoidosis is still classified accord-
giant cells and epithelioid cells, organized in a round ing to the staging system proposed by Scadding in 1961,
shape, surrounded by lymphocytes. Staining for infec- with prognostic implications (Table 2) [12]. Thoracic CT
tious agents (at least mycobacteria and fungi) must be has greater sensitivity and interobserver reliability than
negative. In the center of these granulomas there is gen- CXR and increases the accuracy of diagnosing sarcoid-
erally no necrosis [8]. For this reason, they are usually osis [13]. Typical findings in pulmonary parenchyma
described as noncaseating granulomas, as opposed to are micronodules with perilymphatic distribution in
the granuloma typical of infectious diseases, which often the upper and middle zones (active sites of granuloma-
reveals extensive necrotic areas in its center, presenting a tous inflammation), ground-glass opacities, interlobu-
macroscopic “cheese-like” (caseating) appearance. How- lar septal thickening and finally fibrotic alterations with
ever, mature granulomas in sarcoidosis also may present septal bands, bullae, honeycombing, traction bronchi-
central areas of fibrinoid necrosis, and there are reports ectasis, and loss of lung volume. Respiratory symptoms
of extensive necrosis in sarcoid granulomas described as can occur in any stage of the disease but are not univer-
“caseating” in some areas. Thus the finding of necrosis or sal. Cough (productive or non-productive) is the most
even some “caseum” at biopsy is not sufficient to rule out common symptom (up to 50% of patients). Dyspnea may
the diagnosis of sarcoidosis [9]. occur in later stages of disease and wheezing may appear
due to airway reactivity to inflammation. Chest pain
Epidemiology and hemoptysis are less common. Hence, almost half
Sarcoidosis is a worldwide disease, but the frequency of of patients can be asymptomatic, reinforcing the role of
diagnosis is unevenly distributed. The annual incidence chest imaging.
is highest in Northern Europe (15 cases / 100,000 inhab- Regardless of the presence or absence of respiratory
itants) and North America (10/100,000), while it is rare symptoms, almost half of patients with sarcoidosis have
in Eastern Asia and in the Southern Hemisphere (less extrapulmonary findings. Two clinical syndromes have
than 1/100,000). The reasons for this distribution are high specificity for sarcoidosis and its recognition is use-
unknown. In the United States, the incidence in the Afri- ful for diagnosis. Löfgren syndrome, which is defined by
can American population (18/100,000) is approximately acute onset of erythema nodosum and ankle arthritis
twice that in the white American population (8/100,000), with hilar adenopathy at CXR, occurs in up to 10% of
and this is approximately twice that in the American patients [14]. Heerfordt syndrome is a rare presentation
Latino population (4/100,000) and Asian-American consisting of acute bilateral parotid gland enlargement,
(3/100,000). Again, the reasons for these differences are anterior uveitis, and facial nerve palsy [15]. In these two
unknown [1, 9]. Sarcoidosis incidence is approximately clinical scenarios, the diagnosis of sarcoidosis can be
the same in men and women and the average age at the defined without assessing mediastinal lymph nodes for
diagnosis is around 50 years [1]. biopsy. Caution must be taken, however, in locations with
Neves et al. Advances in Rheumatology (2024) 64:57 Page 3 of 7

high prevalence of tuberculosis, which also can cause CXR, can be initially monitored without treatment,
mediastinal lymph node enlargement and erythema because most asymptomatic patients with sarcoidosis
nodosum mimicking the Löfgren syndrome (tuberculin falling in these categories will progress to spontaneous
skin test and interferon gamma release assay are useful to remission. A reasonable approach is to assess symptoms,
assess the possibility of tuberculosis in these cases). For radiographic progression and pulmonary function tests
all other clinical presentations, a biopsy of an affected tis- results (ideally including carbon monoxide diffusion)
sue revealing typical sarcoid granuloma should be done. every 3 to 6 months.
A particular situation occurs in cases where sarcoidosis For symptomatic patients, for those with severe disease
is suspected in a clinically asymptomatic patient, where (CXR stage IV) and for those with progressive disease
a CXR was ordered for another reason (trauma, periodic under follow-up, treatment should be offered.
examination, etc.) and enlarged mediastinal lymph nodes First-line treatment is based on oral glucocorticoids
were found. In these cases, expectant observation may be (prednisone 20–40 mg/day). In a periodic follow-up of
an appropriate approach, considering that a significant 3 to 6 months, improvement in the disease would allow
amount of sarcoidosis cases progress to spontaneous the clinician to taper the dose until withdrawal or reach-
remission. However, if this is the case, monitoring the ing the lowest dose that provides satisfactory relief of
patient with imaging tests must be rigorous due to the symptoms and control of the disease. A second line (usu-
possibility of lymphoma as a differential diagnosis. The ally methotrexate) and a third line (usually mycopheno-
appearance of symptoms or further increase in lymph late) non-biologic agents can be used if glucocorticoids
node size would indicate the inevitability of lymph node monotherapy was not effective. Hydroxychloroquine can
biopsy. be added in combination with other non-biologic agents.
Unless there is an easily accessible affected organ (e.g., Failure of non-biologic treatment should lead to the pre-
skin, parotid gland), mediastinal lymph nodes or lung scription of anti-TNF treatment (there is greater evidence
parenchyma are usually chosen for biopsy, which can be on infliximab at a dosage of 5 mg/kg, with the usual load-
performed through endobronchial ultrasound-guided ing dose at 0, 2 and 6 weeks) [21]. Efzotimimod, a Fc
transbronchial needle aspiration [16]. During this pro- fusion protein that binds to neuropilin-2 (NRP-2) highly
cedure, a bronchoalveolar lavage is usually performed expressed in sarcoid granulomas, has been evaluated in
for the differential diagnosis of infectious granulomatous refractory pulmonary sarcoidosis with promising results
disease (the exclusion of these diseases is an essential [22].
part of the diagnostic workup for sarcoidosis). The typi-
cal finding of sarcoidosis is a sterile lavage revealing lym- Sarcoid arthropathy
phocytosis with elevated CD4/CD8 ratio > 3.5 and T cells Löfgren syndrome is the most common presentation
expressing the Vα2.3 receptor > 10.5% [17, 18]. Other of acute sarcoid arthropathy. More than half of patients
approaches to the lymph nodes or pulmonary paren- will progress to spontaneous remission (erythema nodo-
chyma (mediastinoscopy or thoracoscopic biopsy) may sum for up to six months, but joint pain may persist up
be the choice according to the clinical presentation of the to 2 years) especially those who are positive for HLA-
disease. If an affected site is not easily identified, 18-flu- DRB1*03 [23, 24]. Arthritis is usually oligoarticular and
orodeoxyglucose-positron emission tomography (PET- commonly affects the knees, ankles, elbows, wrists, and
CT) may be helpful in detecting lesions that are likely to small joints of the hands and feet [25]. Due to the self-
be biopsied [19]. limiting nature of this condition, treatment is symp-
Serum biomarkers (serum angiotensin converting tomatic and can be based in the use of nonsteroidal
enzyme, soluble interleukin-2 receptor (sIL-2R)) have antiinflammatory agents with or without low-dose pred-
limited diagnostic accuracy and they are not substitutes nisone (≤ 10 mg/day). Less than a third of patients will
for biopsy [20]; Erythrocyte sedimentation rate and evolve to persistent disease and require treatment similar
C-reactive protein, as markers of systemic inflammation, to that of chronic sarcoid arthropathy [14].
are usually elevated in active sarcoidosis. Patients may Chronic sarcoid arthropathy is uncommon and can
complain of nonspecific symptoms of inflammation, such present as a polyarthritis in a rheumatoid-like pat-
as fever and fatigue. tern (proximal interphalangeal, metacarpophalangeal,
hands, wrists, knees, and ankles). Jaccoud deformities
Clinical phenotypes of sarcoidosis and treatment and bone erosion may occur in the course of disease. In
Pulmonary and mediastinal lymph node sarcoidosis rare cases, Synovial biopsies reveal typical noncaseating
Pulmonary and lymph node sarcoidosis is the most granulomas, but they are rarely necessary for the diagno-
common sarcoidosis phenotype and serves as a basic sis, which is generally made by combining the recogni-
reference for the treatment of sarcoidosis in general. tion of typical chronic polyarthritis in a patient with an
Asymptomatic patients with stage I, or even II or III already confirmed diagnosis of pulmonary and lymph
Neves et al. Advances in Rheumatology (2024) 64:57 Page 4 of 7

node sarcoidosis, and the exclusion of the possibility of used. Periocular and intravitreal injections of gluco-
rheumatoid arthritis. In situations of diagnostic doubt corticoids or long-acting glucocorticoids implants can
that require synovial biopsy, arthroscopy-guided biopsies be added to the therapy before progression of systemic
should be preferred, as blind punctures have lower diag- immunosuppression. Symptomatic therapy to minimize
nostic yield. ocular dryness in keratoconjunctivitis sicca should be
Patients with chronic sarcoid arthropathy should used whenever necessary [31].
receive hydroxichloroquine in combination with low-
dose glucocortidoids. Failure of this treatment should Cutaneous sarcoidosis
lead to the association of methotrexate as a second-line Skin lesions occur in approximately one-quarter of
agent and leflunomide as a third-line agent. Failure to patients with sarcoidosis. The skin lesions of sarcoidosis
non-biologic treatment should prompt the prescription are easily accessible for biopsy, facilitating the diagnostic
of anti-TNF agents. There is evidence on the use of inf- work in a suspected case, eventually eliminating the need
liximab, at a dosage of 5 mg/kg every four to eight weeks for a mediastinal lymph node biopsy. However, the most
[26]. common skin lesion appearing in sarcoidosis, erythema
nodosum, is nonspecific for the diagnosis of sarcoid-
Ocular sarcoidosis osis. Its pathology reveals only septal paniculitis (with-
The eyes and surrounding structures may be affected out granulomas), as occurs in many other diseases that
in about a quarter of patients with sarcoidosis. Uveitis, manifest erythema nodosum. The typical noncaseating
keratoconjunctivitis sicca and ocular adnexal granulo- granulomas are only seen in the so-called specific sarcoid
mas are the most common presentations [27]. Screening cutaneous lesions: papular sarcoidosis (non-scaly papules
for ocular sarcoidosis by an ophthalmologist is recom- occuring on the face, mainly on the eyelids and nasolabial
mended at the time of the diagnosis (baseline), and oph- folds); plaque sarcoidosis (more common on the trunk,
thalmologic examination should be performed whenever especially the shoulders and back); nodular sarcoidosis
ocular symptoms appear during follow-up [28]. (a collection of granulomas grouped in dermis or subcu-
Sarcoid uveitis can be anterior, intermediate, or poste- taneous fat tissue) and the lupus pernio (infiltrative ery-
rior. It is usually bilateral and has a good prognosis [29]. thematous plaques distributed on the central face and
Anterior uveitis typically causes pain and redness in the surroundings) [32]. Many variations, subtypes and com-
limbus (boundary between the cornea and sclera); poste- binations of these major cutaneous specific lesions may
rior or intermediate uveitis is usually painless, more often occur in sarcoidosis, and treatment may vary according
associated only with the patient perception of visual to the predominant skin feature and its severity. Lupus
floaters. Slit-lamp examination can reveal intraocular pernio is usually resistant to traditional sarcoidosis treat-
signs suggestive of sarcoid uveitis, which can define the ment and may require anti-TNF therapy more frequently
diagnosis in a patient with previously established diagno- than other lesions [25, 33].
sis of pulmonary or lymph node sarcoidosis [30]. Optical
coherence tomography of the macular region to exclude Cardiac sarcoidosis
macular edema, or fluorescein angiography to rule out Sarcoidosis affects the heart in up to 30% of patients, but
papillitis and/or vasculitis or ischemia of the retina can the prevalence may be higher, such as 50%, as shown in
be done. In rare cases, anterior chamber biopsy or con- Japanese post-mortem studies [34]. Considering the risk
junctival biopsy may be needed to investigate a doubtful of death, it is important to screen for cardiac involvement
case. Anterior uveitis can be treated with topical gluco- in all patients with sarcoidosis. Patients may experience
corticoids. However, refractory cases, intermediate and palpitations, syncope, chest pain or even sudden death.
posterior uveitis need first-line treatment with high- Atrioventricular blocks and ventricular arrhythmias are
dose systemic glucocorticoids (prednisone 40–60 mg/ more frequent, but ventricular tachycardia and supra-
day). Sarcoidosis also may affect extraocular orbital tis- ventricular arrhythmia also occur. Heart failure with
sues, including the lacrimal glands (leading to kerato- reduced ejection fraction due to dilated cardiomyopathy
conjunctivitis sicca), the conjunctiva and extraocular and heart failure with preserved ejection fraction due to
muscles, where it can present as an orbital soft tissue restrictive cardiomyopathy are observed. Echocardiog-
mass. These lesions are also usually treated with systemic raphy can show abnormalities in longitudinal strain pat-
glucocorticoids. terns detecting subclinical myocardial dysfunction, or
Failure to this treatment should lead to the prescrip- regional wall movements that do not correspond to the
tion of second-line therapy with methotrexate or aza- territory of coronary arteries [35, 36].
thioprine. A second failure should lead to the use of a Endomyocardial biopsy shows granulomatous inflam-
calcineurin inhibitor (cyclosporine or tacrolimus) or mation of the myocardium on histopathology, but
mycophenolate. After that, anti-TNF agents should be the procedure is associated with considerable risk of
Neves et al. Advances in Rheumatology (2024) 64:57 Page 5 of 7

complications and has low sensitivity due to the irregu- Renal sarcoidosis
lar distribution of granulomas in cardiac tissues. There- The kidneys may be indirectly affected in sarcoidosis due
fore, the diagnosis of cardiac involvement relies heavily to hypercalcemia. Almost 10% of sarcoidosis patients
on cardiac imaging studies. Both gadolinium-enhanced present with high serum calcium concentration due to
cardiovascular magnetic resonance (MRI) and 18 F-fluo- extrarenal production of calcitriol by activated macro-
rodeoxyglucose PET-CT are useful for diagnosing cardiac phages, leading to hypercalciuria that can induce neph-
sarcoidosis [34, 37]. The characteristic MRI pattern is rocalcinosis and urolithiasis. Chronic renal failure may
multifocal areas of subepicardial and mid-myocardial late develop in untreated, complicated cases [40]. In addition
gadolinium enhancement, which is an indicator of fibro- to controlling sarcoidosis, treatment includes increasing
sis. Late gadolinium enhancement is typically seen in the the solubility of urinary calcium phosphate or calcium
basal segments of the septum and lateral wall, although oxalate. Kidneys can also be directly damaged by sar-
more extensive involvement can be seen, including the coidosis from tubulointerstitial sarcoid chronic nephritis.
right ventricle [25]. Biopsies of this condition reveal the typical noncaseating
Treatment of cardiac sarcoidosis begins with pred- granulomas between normal renal glomeruli, but it rarely
nisone 40–60 mg/day, but methotrexate can be added. leads to renal failure, thus aggressive immunosuppressant
The use of anti-TNF drugs such as infliximab and adali- treatment usually is not required [41].
mumab is a good option in severe cases or patients who
have failed treatment. For patients with severe atrioven- Gastrointestinal and abdominal sarcoidosis
tricular blocks, pacemakers are used along with implant- Sarcoidosis can affect any part of the gastrointestinal
able cardioverter defibrillators for patients with low tube, liver, pancreas, spleen, and peritoneum, although it
ejection fraction. is considered as a rare phenotype of the disease. Defini-
tive diagnosis of sarcoidosis in this context can be diffi-
Neurological sarcoidosis cult, because intestinal non-caseating granulomas can
The nervous system is affected in 5–10% of sarcoidosis have more frequent etiologies, as Crohn’s disease. In
patients. Any part of the central or peripheral nervous addition to gastrointestinal biopsy, it is recommended to
system can be involved, but cranial peripheral neuropa- check the occurrence of sarcoidosis in another organic
thy is particularly common (almost half of neurosar- system, increasing the probability of diagnosis [42].
coidosis patients have some form of cranial peripheral Symptoms associated with intra-abdominal sarcoidosis
neuropathy, mostly facial nerve palsy). Meningeal, cere- depend on the affected site and may range from visible
bral, hypothalamic/hypophyseal, spinal cord and radicu- lesions (oral cavity), dysphagia (esophagus), occult bleed-
lar dysfunctions may occur due to perivascular formation ing and diarrhea (stomach and intestine), abdominal
of sarcoid granulomas. Peripheral axonal, demyelinating, pain, among others. All intra-abdominal forms of sar-
and small fiber neuropathies have also been described. coidosis are considered rare, except for the occurrence of
Diagnosis is based on clinical, imaging, neurophysio- intrahepatic granulomas, which is present in almost half
logical examinations and analysis of cerebrospinal fluid, of patients with sarcoidosis undergoing liver biopsy and is
according to each case. Neurological biopsy is generally generally asymptomatic. There is no consensus regarding
unnecessary when sarcoidosis occurs in another, more the indication for treatment. Treatment (glucocorticoids
easily accessible organ system. When involvement of as first line therapy) is normally done in symptomatic
other organic systems is not clinically evident, 18 F-flu- cases or when there is a significant increase in the serum
orodeoxyglucose PET-CT may be useful in searching for concentration of hepatic or canalicular enzymes, particu-
potential biopsy sites. larly to those cases with intrahepatic biliary strictures
Treatment of neurological sarcoidosis is also based, due to sarcoid granulomas [43].
primarily, on glucocorticoids. Very high dosages (intra-
venous methylprednisolone 20 mg/kg/day for 3 days) Pediatric sarcoidosis
can be used for life-threatening or rapidly progressive The sarcoidosis described in this article (a disease of mul-
neurological disease. Second-line therapy also consists of tifactorial etiology) may affect the pediatric population,
non-biological immunosuppressive therapy (mycopheno- although rarely. When this happens, the disease usu-
late, azathioprine, methotrexate, cyclophosphamide, and ally occurs in adolescents and older children similarly to
leflunomide have been used). Third-line therapy com- adult cases (frequent involvement of the lungs and medi-
prises biologic therapy. Again, there is more evidence astinal lymph nodes associated to several other systemic
with anti-TNF agents (mostly infliximab). Radiation ther- manifestations) and is called pediatric-onset adult-type
apy may also be considered for refractory lesions [38, 39]. sarcoidosis [44]. In younger children, systemic granulo-
matous inflammatory disease is most frequently caused
by one of numerous possible gain-of-function variants of
Neves et al. Advances in Rheumatology (2024) 64:57 Page 6 of 7

References
NOD2 (nucleotide-binding oligomerization domain-con- 1. Rossides M, Darlington P, Kullberg S, Arkema EV. Sarcoidosis: Epidemiology
taining protein 2) and generally presents without lung or and clinical insights. J Intern Med. 2023;293:668–80. https://doi.org/10.1111/
lymph node involvement. Arthritis is the most common joim.13629.
2. Levin MA, Adrianto I, Datta I, et al. Association of HLA-DRB1 with Sarcoidosis
manifestation, sometimes with the triad of polyarthri- susceptibility and progression in African americans. Am J Respir Cell Mol Biol.
tis, erythematous rash and uveitis, mimicking systemic 2015;53:206–16. https://doi.org/10.1165/rcmb.2014-0227OC.
juvenile arthritis. This condition is called Blau syndrome/ 3. Sikorova K, Osoegawa K, Kocourkova L, et al. Association between sarcoidosis
and HLA polymorphisms in a Czech population from Central Europe: focus
Early Onset Sarcoidosis and can be recognized by typi- on a relationship with clinical outcome and treatment. Front Med. 2023.
cal family history (autosomal dominant inheritance) https://doi.org/10.3389/fmed.2023.1094843.
or appear sporadically with a de novo variant. Despite 4. Inaoka PT, Shono N, Kamada M, Espinoza JL. Host-microbe interactions in
the pathogenesis and clinical course of sarcoidosis. J Biomed Sci. 2019;26:45.
the name and the typical non-caseating granulomas on https://doi.org/10.1186/s12929-019-0537-6.
biopsy, it should be considered an entity distinct from 5. Graff P, Larsson J, Bryngelsson IL, Wiebert P, Wihlborg P. Sarcoidosis and silica
adult-type sarcoidosis. Pathogenic NOD2 variants have dust exposure among men in Sweden: a case-control study. BMJ Open.
2020;10(9):e038926. https://doi.org/10.1136/bmjopen-2020-038926.
not been observed in adult-type sarcoidosis and clinical 6. Beijer E, Meek B, Bossuyt X, et al. Immunoreactivity to metal and silica associ-
presentation of both diseases are quite different. There is ates with sarcoidosis in Dutch patients. Respir Res. 2020;21:141. https://doi.
similarity in treatment (mainly based on glucocorticoids, org/10.1186/s12931-020-01409-w.
7. Greaves AS, Atif SM, Fontenot AP. eCollection. Adaptive Immunity in Pulmo-
non-biologic immunosuppressant agents and anti-TNF nary Sarcoidosis and Chronic Beryllium Disease. Front Immunol 2020:11:474.
biologic therapy), but evolution in adult-type sarcoidosis https://doi.org/10.3389/fimmu.2020.00474. 2020.
is for remission in nearly half of cases, while Blau syn- 8. Cooper D, Suau S, Sarcoidosis. Immunol Allergy Clin N Am. 2023;583–91.
https://doi.org/10.1016/j.iac.2022.10.011.
drome/early onset sarcoidosis is, with currently available 9. Binesh F, Halvani H, Navabii H. BMJ Case Rep. 2012. https://doi.org/10.1136/
treatments, an inevitably permanent disease that usually bcr.05.2011.4278. bcr0520114278.
requires lifelong immunosuppressive therapy [45]. 10. Te HS, Perlman DM, Shenoy C, et al. Clinical characteristics and organ
system involvement in sarcoidosis: comparison of the University of Min-
nesota Cohort with other cohorts. BMC Pulm Med. 2020;20:155. https://doi.
Conclusion org/10.1186/s12890-020-01191-x.
A rheumatologist can obviously treat and help people 11. Shupp JC, Freitag-Wolf S, Bargagli E et al. Phenotypes of organ
involvement in sarcoidosis. Eur Resp J 2018 51: 1700991. https://doi.
with sarcoid arthropathy, but not only this. It is even org/10.1183/13993003.00991-2017.
more common for a rheumatologist to be asked in a sus- 12. Scadding JG. Prognosis of intrathoracic sarcoidosis in England. A review of
pected case of sarcoidosis to act as a clinician experi- 136 cases after five years’ observation. Br Med J. 1961;2:1165–72. https://doi.
org/10.1136/bmj.2.5261.1165.
enced in the investigation and treatment of rare systemic 13. Levy A, Hamzeh N, Maier LA, F1000Res. Is it time to scrap Scadding and adopt
inflammatory disorders in general, not focusing on a sin- computed tomography for initial evaluation of sarcoidosis?. 2018; 7: F1000
gle organ system. For this reason, rheumatologists must Faculty Rev-600. https://doi.org/10.12688/f1000research.11068.1.
14. Maña J, Gómez-Vaquero C, Montero A, et al. Löfgren’s syndrome revisited: a
be aware of the several phenotypes of sarcoidosis, includ- study of 186 patients. Am J Med. 1999;107:240–2455. https://doi.org/10.1016/
ing the distinct Blau syndrome/early onset sarcoidosis of s0002-9343(99)00223-5.
young children, collaborating with the focal specialists 15. Denny MC, Fotino AD. The Heerfordt-Waldenström syndrome as an initial
presentation of sarcoidosis. Proc (Bayl Univ Med Cent). 2013;26:390. https://
appropriate to each case. doi.org/10.1080/08998280.2013.11929014.
16. Crombag LMM, Moij-Kalverda K, Szlubowski A, et al. EBUS versus EUS-B for
Author contributions diagnosing sarcoidosis: the International Sarcoidosis Assessment (ISA) ran-
All authors contribute equally for this work. domized clinical trial. Respirology. 2022;27:152–60. https://doi.org/10.1111/
resp.14182.
Funding 17. Darlinton P, Kullberg S, Eklund A, et al. Lung CD4 + Vα2.3 + T-cells in sarcoid-
There was not any funding for this work. osis cohorts with Löfgren’s syndrome. Respir Res. 2020;21:61. https://doi.
org/10.1186/s12931-020-1327-0.
Data availability 18. Shen Y, Pang C, Wu Y et al. Diagnostic performance of Bronchoalveolar
Not applicable. Lavage Fluid CD4/CD8 ratio for sarcoidosis: a Meta-analysis. EBioMedicine
2016:8:302–8. https://doi.org/10.1016/j.ebiom.2016.04.024.
Declarations 19. Costabel U, Bonella F, Ohshimo S, Guzman J. Diagnostic modalities in sarcoid-
osis: BAL, EBUS, and PET. Semin Respir Crit Care Med. 2010;31:404. https://doi.
Ethics approval and consent to participate org/10.1055/s-0030-1262207.
Not applicable. 20. Ramos-Casals M, Retamozo S, Sisó-Almiral A, et al. Clinically-useful serum bio-
markers for diagnosis and prognosis of sarcoidosis. Expert Rev Clin Immunol.
Consent for publication 2019;15:391–405. https://doi.org/10.1080/1744666X.2019.1568240.
Not applicable. 21. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommen-
dations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev.
Competing interests 2020;29:190146. https://doi.org/10.1183/16000617.0146-2019.
The authors declare that they have no competing interests. 22. Baughman RP, Niranjan V, Walker G, et al. Efzofitimod: a novel anti-
inflammatory agent for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis.
2023;40:e2023011. https://doi.org/10.36141/svdld.v40i1.14396.
Received: 2 March 2024 / Accepted: 6 May 2024 23. Grunewald J, Grutters JC, Arkema EV, et al. Sarcoidosis Nat Rev Dis Primers.
2019;5:45. https://doi.org/10.1038/s41572-019-0096-x.
Neves et al. Advances in Rheumatology (2024) 64:57 Page 7 of 7

24. Drent M, Crouser ED, Grunewald J. Challenges of Sarcoidosis and its 36. Kouranos V, Sharma R. Cardiac sarcoidosis: state-of-the-art review. Heart.
management. N Engl J Med. 2021;385:1018–32. https://doi.org/10.1056/ 2021;107:1591–9. https://doi.org/10.1136/heartjnl-2019-316442.
NEJMra2101555. 37. Masri SC, Bellumkonda L. Sarcoid Heart Disease: an update on diagnosis
25. Janssen MTHF, Landewé RBM, Post MC, et al. Organ involvement and and management. Curr Cardiol Rep. 2020;22:177. https://doi.org/10.1007/
assessment in sarcoidosis. Curr Opin Pulm Med. 2023;29:485–92. https://doi. s11886-020-01429-4.
org/10.1097/MCP.0000000000000997. 38. Terushkin V, Stern BJ, Judson MA, et al. Neurosarcoidosis: presenta-
26. Judson MA, Baughman RP, Costabel U, et al. Efficacy of infliximab in tions and management. Neurologist. 2010;16:2. https://doi.org/10.1097/
extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J. NRL.0b013e3181c92a72.
2008;31:1189. https://doi.org/10.1183/09031936.00051907. 39. Menninger MD, Amdur RJ, Marcus RB Jr. Role of radiotherapy in the
27. Evans M, Sharma O, LaBree L, Smith RE, Rao NA. Differences in clinical treatment of neurosarcoidosis. Am J Clin Onco. 2003;26:e115. https://doi.
findings between caucasians and African americans with biopsy-proven org/10.1097/01.COC.0000077933.69101.5D.
sarcoidosis. Ophthalmology. 2007;114:325–33. https://doi.org/10.1016/j. 40. Werner J, Rivera N, Grunewald J, et al. HLA-DRB1 alleles associate with
ophtha.2006.05.074. hypercalcemia in sarcoidosis. Respir Med. 2021;187:106537. https://doi.
28. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of Sarcoidosis. org/10.1016/j.rmed.2021.106537.
An official American thoracic Society Clinical Practice Guideline. Am J Respir 41. Rastelli F, Baragetti I, Buzzi L, et al. Renal involvement in sarcoidosis: histologi-
Crit Care Med. 2020;201:e26. https://doi.org/10.1164/rccm.202002-0251ST. cal patterns and prognosis, an Italian survey. Sarcoidosis Vasc Diffuse Lung
29. Sève P, Jamilloux Y, Tilikete C, et al. Ocular Sarcoidosis. Semin Respir Crit Care Dis. 2021;38:e2021017. https://doi.org/10.36141/svdld.v38i3.11488.
Med. 2020;41:673–88. https://doi.org/10.1055/s-0040-1710536. 42. Sharma A, Kadakia J, Sharma O. Gastrointestinal Sarcoidosis. Sem Respir Med.
30. Mochizuki M, Smith JR, Takase H, et al. Revised criteria of International 1992;6:442. https://doi.org/10.1055/s-2007-1006293.
Workshop on Ocular Sarcoidosis (IWOS) for the diagnosis of ocular 43. Cremers JP, Drent M, Baughman RP et al. Therapeutic approach of hepatic
sarcoidosis. Br J Ophthalmol. 2019;103:1418. https://doi.org/10.1136/ sarcoidosis. Curr Opin Pulm Med;18:472–82. https://doi.org/10.1097/
bjophthalmol-2018-313356. MCP.0b013e3283541626.
31. Matsou A, Tsaousis TT. Management of chronic ocular sarcoidosis: challenges 44. Hangül M, Köse M, Pekcan S, Ersoy A, Unal G, Caglar HT. Childhood sarcoid-
and solutions. Clin Ophthalmol. 2018;12:519–32. https://doi.org/10.2147/ osis in the middle Anatolia of Turkey. Pediatr Pulmonol. 2023. https://doi.
OPTH.S128949. org/10.1002/ppul.26564.
32. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehen- 45. Kaufman K, Becker ML. Distinguishing Blau Syndrome from systemic
sive review and update for the dermatologist: part I. cutaneous disease. J Am sarcoidosis. Curr Allergy Asthma Rep. 2021;21:10. https://doi.org/10.1007/
Acad Dermatol. 2012;66:699e1. https://doi.org/10.1016/j.jaad.2011.11.965. s11882-021-00991-3.
33. Marchell RM, Judson MA. Cutaneous sarcoidosis. Semin Respir Crit Care Med.
2010;31:442–51. https://doi.org/10.1055/s-0030-1262212.
34. Yatsynovich Y, Dittoe N, Petrov M, et al. Cardiac sarcoidosis: a review of Publisher’s Note
Contemporary challenges in diagnosis and treatment. Am J Med Sci. Springer Nature remains neutral with regard to jurisdictional claims in
2018;355:113–25. https://doi.org/10.1016/j.amjms.2017.08.009. published maps and institutional affiliations.
35. Murtagh G, Laffin LJ, Patel KV, et al. Improved detection of myocardial dam-
age in sarcoidosis using longitudinal strain in patients with preserved left
ventricular ejection fraction. Echocardiography. 2016;33:1344–52. https://doi.
org/10.1111/echo.13281.