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Internal Medicine

Sarcoidosis

Introduction

Inflammatory disorder of unknown cause that is characterized by noncaseating granuloma formation in affected organs, most often in the lungs.


Epidemiology

Incidence:

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Graph of sarcoidosis incidence per 100,000 individuals per year by age at diagnosis in (part a) Sweden (2003–2012, n = 8,395), (part b) Korea (2009–2015, n = 2,981) and (part c) Olmsted County, Minneapolis, MN, USA (1946–2013, n = 448). | Grunewald, J., Grutters, J. C., Arkema, E. V, Saketkoo, L. A., Moller, D. R., & Müller-Quernheim, J. (2019). Sarcoidosis. Nature Reviews Disease Primers, 5(1), 45. https://doi.org/10.1038/s41572-019-0096-x

Adverse prognostic factors:

  • Age of onset > 40 years
  • Black race
  • Cardiac involvement
  • Chronic hypercalcemia
  • Chronic uveitis
  • Cystic bone lesions
  • Lupus pernio
  • Nasal mucosa involvement
  • Nephrocalcinosis
  • Neurosarcoidosis
  • Progressive pulmonary fibrosis

Survival rate:

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Graph of survival probability after follow-up showing decreased probability of survival in patients who are in need of treatment compared with patients who do not need treatment and the general population. | Rossides, M. et al. Sarcoidosis mortality in Sweden: a population-based cohort study. Eur. Respir. J. 51, 1701815 (2018). Return to ref 46 in article

Aetiology

Genetic risk factors:

  • Family history

Environmental risk factors:

  • Mouldy environments
  • Occupational exposure to insecticides and agricultural employment
  • Iron foundry workers (exposure to silica dust)
  • Firefighters

Smoking: Decreased risk of sarcoidosis


Pathophysiology

Pathological hallmark of sarcoidosis is the presence of compact, epithelioid, non-necrotizing granulomas with varying degrees of lymphocytic inflammation.

Immunological features of granuloma formation:

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Sarcoidosis is triggered by environmental agents, primarily mycobacterial infections. Genetic, epigenetic and environmental factors interact with environmental triggers to result in the following: innate immune activation of macrophages and dendritic cells, which have upregulated major histocompatibility complex (MHC) expression and express cytokines that direct the phenotype of the adaptive immune response (step 1); upregulation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway leading to differentiation of epithelioid cells (activated macrophages that resemble epithelial cells) and changes in metabolic and immune pathways (step 2); upregulation of serum amyloid A (SAA) and heat shock proteins (HSPs) as part of an acute phase response (step 3), followed by SAA aggregation in granulomas, which promotes enhanced effector T cell responses, in part through innate immune receptors, such as Toll-like receptor 2 (TLR2); an enhanced T cell response to pathogenic tissue antigens, which in the presence of IL-12, IL-18, IL-6 and transforming growth factor-β (TGFβ) promotes polarization of T helper 1 (TH1), TH17 and TH17.1 responses in affected sites (step 4); and an impaired regulatory T (Treg) cell response (dashed arrow; step 5) allows enhanced local effector T cell responses to tissue antigens to persist, resulting in chronic sarcoidosis. | APC, antigen-presenting cell; TNF, tumour necrosis factor. | Grunewald, J., Grutters, J. C., Arkema, E. V, Saketkoo, L. A., Moller, D. R., & Müller-Quernheim, J. (2019). Sarcoidosis. Nature Reviews Disease Primers, 5(1), 45. https://doi.org/10.1038/s41572-019-0096-x

Granuloma resolution/progression:

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Granuloma resolution or progression in sarcoidosis: Exposure to an unknown antigen or antigens leads to either resolution or progression. Granuloma resolution (immune response 1) occurs when peptide antigens are presented by human leukocyte antigen (HLA)-DR3 molecules on dendritic cells or macrophages and recognized by a specific T cell receptor (TCR) β-chain variable segment 8 (TRBV8) and α-chain variable 2.3 (TRAV2.3) and CD4-positive (TRAV2.3+TRBV22+CD4+) T cells. An efficient immune response is generated that involves the production of a large range of cytokines, and the antigen is eliminated and the granuloma resolves. Conversely, granuloma progression (immune response 2) occurs if antigen recognition is not efficient, possibly because other peptides are displayed by HLA molecules other than HLADRB1*03 (HLA-DR3) or T cells are not capable of generating efficient T cell clones. Consequently, granulomas continue to grow and the disease persists. | APC, antigen-presenting cell; MHC, major histocompatibility complex. | Grunewald, J., Grutters, J. C., Arkema, E. V, Saketkoo, L. A., Moller, D. R., & Müller-Quernheim, J. (2019). Sarcoidosis. Nature Reviews Disease Primers, 5(1), 45. https://doi.org/10.1038/s41572-019-0096-x

Gross pathology:

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Gross pathology image showing sarcoidosis with honeycombing: Prominent honeycombing is present in the lower lobes accompanied by fibrosis and some honeycombing in the upper lungs. Honeycombing consists of cystically dilated airways separated by scar tissue resembling the honeycomb of bees. It is a nonspecific end stage of many types of interstitial lung disease. | Yale Rosen – https://www.flickr.com/photos/pulmonary_pathology/6076728842/in/set-72157627384045985, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=17387878

Clinical features

Pulmonary sarcoidosis (89–99%):

  • Cough, dyspnoea, wheezing and stridor

Cutaneous sarcoidosis (16–32%):

  • Papules, nodules, plaques and infiltrated scars and tattoos
  • Erythema nodosum: Skin inflammation located in part of fatty layer of skin resulting in reddish, painful, tender lumps
    • M/C anterior aspect of legs below knees
  • Lupus pernio: Skin lesions on face resembling lupus. (PATHOGNOMIC)
    • Chronic raised indurated (hardened) lesion of the skin, often purplish in color
    • Seen on the nose, ears, cheeks, lips, and forehead

Ophthalmic sarcoidosis (5–23%):

  • Anterior uveitis (M/C ophthalmic manifestation)
    • Painful and/or red eye and vision loss
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Examples of ocular sarcoidosis. (A) Scleritis in a patient with sarcoidosis. (B) Optic nerve swelling on fundoscopic exam. | Dr G. Papaliodis, Massachusetts Eye and Ear Infirmary, Boston, MA.

Hepatic sarcoidosis (12–20%):

  • Abdominal pain and elevated liver functions
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(A) Computed tomography (CT) scan of a 41-year-old Japanese woman with sarcoidosis showing hepatomegaly with multiple mottled low-density lesions. (B) 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT showing the diffuse increment of 18F-FDG uptake in the patient’s liver. | Watanabe, T., & Jodo, S. (2018). Hepatic sarcoidosis. Canadian Medical Association Journal, 190(33), E988 LP-E988. https://doi.org/10.1503/cmaj.180276

Lymph nodes (13–15%):

  • Peripheral lymphadenopathy

Spleen (5-10%):

  • Abdominal pain

Neurosarcoidosis (3–9%):

  • Facial palsy, fatigue (for example, pituitary insufficiency), gait disturbance, headache, hearing loss, numbness or paraesthesia, seizure, trigeminal neuralgia, vertigo, visual loss and weakness and/or paresis
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Left image: MRI findings (T1-weighted images) in a patient with neurosacoidosis showing thickening of infundibulum and both optic nerves (white signal marked with yellow arrows; width 6 mm). Right image: MRI brain with contrast showing near resolution of enhancement after treatment. | J Chad Hoyle, Herbert B Newton and Steven Katz – Prognosis of refractory neurosarcoidosis altered by thalidomide: a case report. Journal of Medical Case Reports 2008, 2:27. doi:10.1186/1752-1947-2-27, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5799047

Cardiac sarcoidosis (2-5%):

  • Conductance disturbances, arrhythmias, dyspnoea, fatigue (for example, cardiomyopathy) and syncope
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a) Endobronchial cobblestones (a nodular appearance of the tracheal wall mucosa). b) Diffuse reddish swelling of the earlobe due to skin localization of sarcoidosis granulomas. c) Sarcoid dactylitis (classical Perthes–Jüngling disease associated with sarcoidosis) causing cystic lesions in the hand bones. d) Lupus pernio (a chronic hardened red lesion of the skin). e) Cardiac sarcoidosis with midmyocardial delayed enhancement (arrow) on MRI. f) Radiography scan of the finger of a patient with sarcoid dactylitis. g) Skeletal muscle involvement, visualized on fluorodeoxyglucose-PET scan of the lower limbs. h) Sarcoidal reaction with nodular thickening of the skin at the site of tattooing in a patient with pulmonary sarcoidosis. i) MRI scan showing a neurosarcoidosis lesion (arrow) to the left and caudally of the optic chiasma. | Grunewald, J., Grutters, J. C., Arkema, E. V, Saketkoo, L. A., Moller, D. R., & Müller-Quernheim, J. (2019). Sarcoidosis. Nature Reviews Disease Primers, 5(1), 45. https://doi.org/10.1038/s41572-019-0096-x

Special manifestations:

  • Löfgren syndrome:
    • Acute form presenting with triad of ankle arthritis, mediastinal lymphadenopathy, and erythema nodosum.
    • Good prognosis > 90% cases resolve within 2 years
  • Heerfordt-Waldenström syndrome:
    • Extremely rare form characterized by uveitis, enlargement of the parotid and submaxillary salivary glands and paresis of the cranial nerves (especially the 7th nerve)
  • Darier-Roussy sarcoid:
    • Deep-seated nodules on the trunk and extremities.

Complications

  • Progressive pulmonary fibrosis
  • Congestive heart disease
  • Sudden cardiac death

Diagnosis

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A proposed algorithm based on expert opinion: Diagnosis usually depends on a combination of compatible clinical findings, histological evidence of non-necrotizing granulomas (for example, in transbronchial biopsy samples or ultrasonography-guided transbronchial needle aspiration (EBUS-TNA) of mediastinal lymph nodes) and exclusion of alternative causes of granulomas that result in a similar histological or clinical pattern. Bronchoalveolar lavage (BAL) with a typically increased CD4-positive (CD4+) T cell/CD8+ T cell ratio is supportive of a sarcoidosis diagnosis. | Judson, M. A. The diagnosis of sarcoidosis. Clin. Chest Med. 29, 415–427 (2008).

Skin tests:

  • Mantoux test (exclude TB)
  • Kveim test, Nickerson-Kveim or Kveim-Siltzbach test
    • Skin test used to detect sarcoidosis, where part of a spleen from a patient with known sarcoidosis is injected into the skin of a patient suspected to have the disease.
      • Positive: Non-caseating granulomas found (4–6 weeks later)
      • False-negativeIf the patient has been on treatment (e.g. glucocorticoids)

Blood panel:

  • ↑ ESR (non-specific)
  • Leukopenia
  • Hypercalcemia (10% cases)
    • Increased production of 1,25-dihydroxy vitamin D by the granuloma itself

Pulmonary function:

  • Pulmonary function tests (PFT): Restrictive pattern
  • DLCO: Reduced CO2 diffusion
  • Bronchoalveolar lavage (BAL):
    • ↑ CD4+/CD8+ ratio
    • ↑ Serum ACE levels

X-ray (Best initial test):

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Posteroanterior views of the chest showing (left) bilateral hilar adenopathy, indicative of stage I sarcoidosis, and (center) stage III sarcoidosis, and (right) single view of the chest showing stage IV sarcoidosis. | Wu, J. J., & Schiff, K. R. (2004). Sarcoidosis. American family physician, 70(2), 312–322.
  • Stage 0: Normal radiograph
  • Stage I: Bilateral hilar lymphadenopathy
  • Stage II: Bilateral hilar adenopathy and parenchymal infiltrates
  • Stage III: Parenchymal infiltrates alone
  • Stage IV: Pulmonary fibrosis

High-resolution CT (HRCT) scan  and cardiac MRI:

  • Chest: Extensive hilar and mediastinal adenopathy
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High-resolution CT imaging of pulmonary sarcoidosis: a) ‘String of beads’ appearance of peribronchovascular nodules in a patient with sarcoidosis. b) ‘Galaxy’ appearance of granulomas in a patient with sarcoidosis. | H. W. van Es, St Antonius Hospital, Netherlands.

Transbronchial biopsy (M/accurate) or USG-guided transbronchial needle aspiration (EBUS-TNA) of mediastinal lymph nodes:

  • Noncaseating granuloma (DIAGNOSTIC)
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a) Biopsy specimen taken from an enlarged mediastinal lymph node showing non-necrotizing granulomas in a patient with radiographic type I sarcoidosis on chest radiograph. Magnification 200×. b) Specimen from a consolidated mass in the lung of a patient with pulmonary sarcoidosis, showing non-necrotizing granulomas with multinucleated giant cells. Magnification ×100. Biopsy samples in both panels are stained with haematoxylin and eosin. | C. A. Seldenrijk, St Antonius Hospital, Netherlands.

18fluor-fluorodeoxyglucose-PET (18F-FDG-PET) scan:

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18F-FDG-PET findings in multi-organ involvement. a) Lung and spleen involvement; b) diffuse bone and lymph node involvement;c) marked involvement of the lymph nodes and spleen, as well as less marked involvement of the bone marrow and liver. d) Marked, diffuse muscle involvement with relatively mild involvement of the lymph nodes and liver. | Prasse, A. (2016). The Diagnosis, Differential Diagnosis, and Treatment of Sarcoidosis. Deutsches Arzteblatt International, 113(33–34), 565–574. https://doi.org/10.3238/arztebl.2016.0565

Differential diagnosis

  • Histiocytosis X (no hilar LAN)
  • Lymphoma (differentiated onbiopsy)
  • Tuberculosis (history of exposure, no skin/ocular symptoms, Mantoux test)

Management

Immunosuppressive therapy:

  • Corticosteroids (first-line treatment): Prednisone, prednisolone
  • Immunosuppressive combination therapy (2nd line treatment): Methotrexate/azathioprine
  • Anti-TNF-alpha antibody treatment: Infliximab/adalimumab
  • Other drugs:
    • Antimalarial agents: Chloroquine & Hydroxychloroquine
    • Methotrexate

    • Pentoxifylline
    • Thalidomide
    • Cyclophosphamide
    • Cyclosporine

Surveillance:

  • Stage I: initially every 6 months, then annually if stable
  • Stage II, III, IV: initially every 3-6 months, monitor indefinitely
  • Serious extrapulmonary involvement: monitor indefinitely
  • Monitor 3 years after cessation of therapy for potential relapse, subsequent follow-up not necessary if stable

Summary

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