A review of sarcoidosis which tells about Patho physiology,clinical features,Diagnosis and management of sarcoidosis

1. CHALLENGES OF SARCOIDOSIS AND ITS
MANAGEMENT
Dr Sudharsanan M M6 Unit
Prof Dr.SUJATHA
Asst Prof Dr Balamurugan
Asst prof Dr Sivaraman
REVIEW ARTICLE

2. Published on Sep 9 2021 in NEJM

3. SARCOIDOSIS:
Sarcoidosis is an orphan, inflammatory, multisystemic disease of unknown
cause with a wide range of clinical manifestations. The disorder can affect
virtually any organ in the body — predominantly the lungs, lymphatic
system, skin, or eyes or a combination of these sites — and is characterized
by the formation of noncaseating granulomas.

4. CLASSIFICATION CRITERIA:
As per American Thoracic Society
A diagnosis of sarcoidosis is made if the following
criteria are fulfilled:
(1) a compatible clinical picture,
(2) histologic demonstration of noncaseating
granulomas and
(3) exclusion of other diseases capable of producing
a similar clinical picture.

5. EPIDEMOLOGY:
Affects both sexes with predominance among women.
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.
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.

6. ETIOLOGICAL FACTORS:
Till now there is no specific cause has been identified.
The development of sarcoidosis requires both a genetic predisposition
and environmental and sometimes occupational exposure to unknown
substances or microbial antigens.
It is generally accepted that a dysregulated immune response against one
or more disease-promoting antigens results in an inflammatory process to
eliminate the offending antigen which results either spontaneous
resoution or non caseating granuloma formation.

7. GENETIC FACTORS:
Familial clustering is reported in sarcoidosis (10% propability in sibling)
HLA GENES
HLA-DRB1*01 and HLA-DRB1*04 were protective against the
disease,
HLA-DRB1*03, *11, *12, *14, and *15 and HLA-DRB8 were risk factors
for sarcoidosis.
Moreover, HLA-DRB1*03 was associated with spontaneous resolution,
whereas HLA-DRB1*14 and HLADRB1*15 were associated with a
chronic course of the disease.

8. HLA-DRB1*03 & HLA-DQB1*02 associated with Lofgren’s
syndrome.
HLA-DQB1*06:01 with cardiac sarcoidosis
HLA-DRB1*04 with uveitis.This is protective against overall
sarcoidosis but significant risk factor for occular sarcoidosis in
patients with Heerforrdt’s syndrome.

9. NON HLA Genes:
TNF and the IL-23 receptor (IL-23G) gene.
TNF G-308A polymorphism was found to be predictive of response to
treatment with TNF inhibitors.
Ongoing genome-wide association studies,many other genes have been
identified in particular SNP ,
BTNL2, ANXA11, RAB23, OS9, CCDC88B, PRDX5, and NOTCH4.
Epigenetic changes
Methylation changes of telomeres and specific microRNAs (such as miR-
144, miR-20a, miR-302c, miR92b, and miR-206) have been found.

10. ENVIRONMENTAL AND OCCUPATIONAL
EXPOSURE:
Environmental exposures play a putative role in sarcoidosis pathogenesis by
directly triggering granulomatous inflammation and by indirectly inducing
epigenetic and immunologic changes that alter the risk of sarcoidosis.
ACCESS (A Case Control Etiologic Study of Sarcoidosis) shows positive
associations between sarcoidosis risk and certain occupations, such as
agricultural employment, exposure to insecticides, and mold/mildew work
environments,healthcare workers and firefighters.
Mycobacterium tuberculosis and Propionibacterium acnes also
implicated in development of sarcoidosis.Mycobacterial antigens such as
catalase-peroxidase protein (mKatG) and ESAT-6 are found in samples of
sarcoidosis patients.

12. PATHOGENESIS:
Granuloma formation is a hallmark of sarcoidosis disease. The
underlying immunologic events include
(1) exposure to one or more (unknown) antigens,
(2) activation of antigen presenting cells
(macrophages and/or dendritic cells)
(3) a T cell response in an effort to eliminate the antigen, and
(4) granuloma formation.

14. Macrophages:
Macrophages are important for the initial accumulation, aggregation, and
fusion of the cellular building blocks needed for granuloma formation.
This process is mediated by the strong immune modulatory capacities of
TNF-αand assisted by NKcells,which produce INF-γ.
Important mechanisms of action of TNF-α include macrophage
activation, promotion of cellular migration toward the site of inflammation
and leukocyte adhesion.
T Cells:
CD4 T cells activated predominantly (Th1 mainly,also Th17 and Th 2)
Dysfunction of Tregs (smokers has increased Tregs activity somewhat
protective against sarcoid)
BAL - CD4/CD8 ratio is increased
Immune paradox

23. Overall, there appear to be two possible immunologic scenarios in
sarcoidosis: an intense immune reaction in patients with active
disease, finally resulting in antigen clearance, or chronic disease with
less inflammation but the inability to eradicate the inciting agent and
subsequent chronic stimulation of the immune response, resulting in
organ damage such as lung fibrosis.
Exaggerated Th1,Th17,Th2 and AM2 cell response with dysfunctional Tregs
cells.

24. CLINICAL FEATURES:
Sarcoidosis can affect every organ system, with the lungs the most
commonly affected organ. Joint symptoms are quite common in
sarcoidosis, affecting up to 25% of patients.The eyes (uveitis and
retinal vasculitis), liver (abnormal liver function tests), lymph nodes
(enlarge ment), and skin (lupus pernio, papules, nodules, plaques,
and scar sarcoidosis [tattoos] are the most frequent extra
pulmonary organs affected.

25. ACUTE:
LOFGREN’S SYNDROME
HLA-DRB1*03 & HLA-DQB1*02
B/L acute symmetrical ankle joint arthritis
Erythema nodosum
B/l Hilar Lymphadenopathy
Good prognosis, 90% resolved spontaneuosly

26. HEERFORDT SYNDROME
Acute uveitis
B/l parotiditis
B/l LMN VII CN palsy
Fever
More risk for going into chronicity.

27. LUNG:
cough,breathlessness
SCADDIG staging
stage 1 - acute presentation
stage 2 - chronicity
stage 3 - clinical paradox (LN resolved and only infiltrates)

29. Sarcoid Fibrosis:
Upper lobe ILD like AS
NSIP type with Traction Bronchiectasis
Ground glass opacities
Reticulonodular pattern
Subpleural nodules
Typical inflammatory findings on HRCT include a bilateral distribution of
micronodules, perilymphatic and bronchocentric distribution, perihilar
ground-glass opacities, and varying degrees of fibrosis.
Blood - Anemia of chronic disease,lymphophenia (Immune paradox),
pancytopenia due to hyperspleenism
Drug related sarcoid in Anti TNF alpha

32. SKIN:
Lupus perinio
chronic inflammatory violaceous papulosquamous lesion
affecting nose,area under eyes and cheeks

34. Diagnosis:

36. Lymph Node Sampling
1. In patients for whom there is a high clinical suspicion for sarcoidosis
(e.g., Lo ̈fgren’s syndrome, lupus pernio, or Heerfordt’s syndrome), we suggest
NOT sampling lymph nodes
2. For patients presenting with asymptomatic, bilateral hilar lymphadenopathy, we
make no recommendations for or against obtaining a lymph node sample.
3. For patients with suspected sarcoidosis and mediastinal and/or hilar
lymphadenopathy for whom it has been determined that tissue sampling is
necessary, we suggest endobronchial ultrasound (EBUS)-guided lymph node
sampling, rather than mediastinoscopy, as the initial mediastinal and/or hilar lymph
node sampling procedure.

37. Screening for Extrapulmonary Disease
1. For patients with sarcoidosis who do not have ocular symptoms, we suggest a
baseline eye examination to screen for ocular sarcoidosis.
2. For patients with sarcoidosis who have neither renal symptoms nor
established renal sarcoidosis, we suggest baseline serum creatinine testing to
screen for renal sarcoidosis.
3. For patients with sarcoidosis who have neither hepatic symptoms nor
established hepatic sarcoidosis, we suggest baseline serum alkaline
phosphatase testing to screen for hepatic sarcoidosis.
4. For patients with sarcoidosis who have neither hepatic symptoms nor
established hepatic sarcoidosis, we make no recommendation for or against
baseline serum transaminase testing.
5. For patients with sarcoidosis who do not have symptoms or signs of
hypercalcemia, we recommend baseline serum calcium testing to screen for
abnormal calcium metabolism

38. 6. If assessment of vitamin D metabolism is deemed necessary in a patient with
sarcoidosis, such as to determine if vitamin D replacement is indicated, we
suggest measuring both 25- and 1,25- OH vitamin D levels before vitamin D
replacement.
7. We suggest that patients with sarcoidosis undergo baseline complete blood cell
count testing to screen for hematological abnormalities.
8. For patients with extracardiac sarcoidosis who do not have cardiac symptoms
or signs, we suggest performing baseline ECG to screen for possible cardiac
involvement.
9. For patients with extracardiac sarcoidosis who do not have cardiac symptoms
or signs, we suggest NOT performing routine baseline transthoracic
echocardiography (TTE) or 24-hour ambulatory ECG (Holter) monitoring to screen
for possible cardiac involvement

39. Diagnostic Evaluation of Suspected Extrapulmonary Disease
1. For patients with extracardiac sarcoidosis and suspected cardiac involvement, we
suggest cardiac magnetic resonance imaging (MRI),rather than positron emission
tomography (PET) or TTE, to obtain both diagnostic and prognostic information.
2. For patients with extracardiac sarcoidosis and suspected cardiac involvement who
are being managed in a setting in which cardiac MRI is not available, we suggest
dedicated PET, rather than TTE, to obtain diagnostic and prognostic information.
3. For patients with sarcoidosis in whom pulmonary hypertension (PH) is suspected,
we suggest initial testing with TTE.
4. For patients with sarcoidosis in whom PH is suspected and a transthoracic
echocardiogram is suggestive of PH, we suggest right heart catheterization to
definitively confirm or exclude PH.
5. For patients with sarcoidosis in whom PH is suspected and a transthoracic
echocardiogram is NOT suggestive of PH, the need for right heart catheterization
should be determined on a case-by-case basis.

43. CALCIUM IN SARCOIDOSIS:
Abnormal calcium metabolism in sarcoidosis can lead to hypercalcemia,
hypercalciuria, and their manifestations, including kidney stones and renal failure; it is
the most common cause of sarcoidosis-related renal insufficiency.
Dysfunctional calcium metabolism can also result in elevated bone resorption and
increased renal and intestinal absorption of calcium.
The mechanisms of abnormal calcium metabolism are likely multifactorial, including
increased 1a‐hydroxylase production by granulomatous macrophages, which converts
25-(OH) vitamin D to 1,25-(OH)2 vitamin D, increased expression of parathyroid
hormone–related protein in sarcoidosis macrophages.
Testing of 25-(OH) vitamin D levels may be useful in conjunction with 1,25- (OH)2
vitamin D levels in a subset of patients with sarcoidosis, such as those with severe
fatigue or exposed to chronic corticosteroids, for whom vitamin D repletion may be
beneficial.
If assessment of vitamin D metabolism is deemed necessary in a patient with
sarcoidosis, such as to determine if vitamin D replacement is indicated,suggest
measuring both 25- and 1,25-OH vitamin D levels before vitamin D replacement.

44. elevated SAA
low ACE levels less chance of having sarcoid

46. TREATMENT:
Prednisone and adrenocorticotropic hormone have both been approved for
treatment of pulmonary sarcoidosis, but no treatment for extrapulmonary
sarcoidosis, including sarcoid arthritis, has been approved by the U.S. Food and
Drug Administration (FDA).
First line therapy for most manifestations (with the exceptions of sarcoidosis
associated fatigue and smallfiber neuropathy) are corticosteroids. A dose of
prednisone 20 to 40 mg per day (0.5mg/kg) should be maintained for 1 to 3
months and then tapered to a main tenance dose of 5 to 10 mg/day, which,
empirically, is usually maintained for 1 year.

47. Secondline therapies include socalled “diseasemodifying antisarcoid drugs”
(DMASDs), including methotrexate, azathioprine, lefluno mide,
hydroxychloroquine, chloroquine, mycophenolate, and cyclosporine.Methotrexate
(MTX) is commonly prescribed, with a starting dose of 10 to 15 mg weekly,
adjusted up to 20 mg or higher if necessary and if the side-effect profile is
acceptable. It is advised to combine MTX with folic acid.Subcutaneous MTX is
recommended in the event of gastrointestinal side effects.Risk of lung fibrosis.
For refractory cases, TNF inhibitors can be used as thirdline therapy. The
two best studied agents of this class of drugs are infliximab and
adalimumab.

48. Patients with sarcoidosis might be more sensitive to calcium and vitamin D
substitution,with the associated risks of hyper calcemia and hypercalciuria,
which are present in up to 10% of patients who don’t receive vitamin D
supplements.
Bisphosphonates alone may be adequate to treat corticosteroid induced
osteoporosis.
Higher levels of 25hydroxyvitamin D (25OHD) were associated with a higher
frequency of fractures in patients with sarcoidosis.

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