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sarcoidosis

Sarcoidosis is a granulomatous disease with variable clinical manifestations & an unpredictable course. 2/3 of patients who present with sarcoidosis will show clinical or radiographic evidence of improvement over a period of several years. Chronic disease develops in only a minority of patients. Etiology: 1) unknown 2) cellular autoimmunity 3) some patients may develop sarcoidosis after smoking cessation [4] Epidemiology: 1) common disorder 2) slight predilection for females 3) in the US, sarcoidosis affects mostly blacks 10-17:1 over whites 4) in Europe, sarcoidosis affects mostly whites 5) disease rare among Canadian Indians & Southeast Asians 6) onset of disease at any age, most commonly age 20-40 7) sarcoidosis occurs more frequently in non-smokers Pathology: 1) mononuclear cell-mediated inflammation of affected organs 2) formation of epithelioid non-caseating granulomas a) multinucleated giant cells b) rim of T-helper cells c) granulomas infiltrate tissue of almost any organ [4] 3) organ dysfunction results from distortion of architecture of affected tissues by inflammatory cells 4) the disease involves most organs; however organ function is not uniformly affected 5) interstitial lung disease involving alveoli, small bronchi & blood vessels 6) decreased number of T-cells with proliferation of B-cells 7) increased 25-hydroxyvitamin D-1-alpha hydroxylase activity by granuloma-associated macrophages resulting in increased serum 1,25-dihydroxyvitamin D & hypervitaminosis D Genetics: - association with HLA-DR4 - susceptibility to sarcoidosis type 2 associated with polymorphism(s) in BTNL2 [7] Diagnosis: - diagnosis of exclusion [4] - multisystem involvement - non-caseating granuloma - biopsy needed except in case of classic Lofgren's syndrome Clinical manifestations: 1) acute form a) constitutional symptoms - fever - fatigue/anergy - malaise - anorexia - weight loss - night sweats b) pulmonary symptoms - dry cough - dyspnea - chest pain/discomfort c) polyarthritis (including Lofgren's syndrome) 2) insidious form a) most patients asymptomatic (disease is detected by abnormal chest X-ray) b) develops over months c) no constitutional symptoms d) pulmonary symptoms e) patients with insidious onset most commonly develop chronic sarcoidosis 3) pulmonary (>90%) [4] a) dyspnea, especially with exercise b) dry cough c) hemoptysis is rare d) pleural effusion, unilateral (1-5%) e) pulmonary fibrosis, predominantly uppper lobe (5-15%) f) pulmonary infiltrates g) pulmonary nodules [4] h) pulmonary cystic changes including aspergillomas [4] i) may present as diffuse parenchymal lung disease [4] j) often asymptomatic 4) lymphadenopathy is common a) bilateral hilar lymphadenopathy, often with mediastinal lymphadenopathy (75-90%) [4] b) peripheral or generalized lymphadenopathy very common - non painful - rarely a problem 5) skin (25%) [17] (images) a) erythema nodosum (including Lofgren's syndrome) b) papules, plaques (image) [22] - symmetric, brown-purple, round-oval - most commonly on extremities, face, scalp, buttocks - papular rash across chest c) maculopapular eruptions [29] d) subcutaneous nodules e) lupus pernio (image) [22] f) violaceous papules, nodules & plaques commonly occur around the nose, periorbital & around the mouth & at sites of trauma, including surgical scars & tattoos [4] g) nail changes (rare) include clubbing, discoloration, dystrophy, subungual hyperkeratosis, splinter hemorrhages, and onychorrhexis [27] 6) eye (25%) a) eye pain, burning b) blurred vision c) photophobia d) anterior & posterior uveitis - Heerfordt syndrome [4] - common presentation for sarcoidosis [11] e) keratoconjunctivitis sicca (lacrimal gland inflammation) f) may lead to blindness 7) upper respiratory tract a) nasal mucosa: stuffiness (20%) b) larynx involvement (5%), - dyspnea - wheezing - stridor - complete obstruction rare 8) bone marrow (40%) - mild abnormalities: anemia, neutropenia, thrombocytopenia, eosinophilia 9) spleen involvement (50-60%), splenomegaly (5-10%) 10) liver a) hepatomegaly (20-30%) b) elevated transaminases c) not clinically significant 11) kidney - nephrocalcinosis & nephrolithiasis (see management section) 12) nervous system (5%) a) unilateral facial paralysis (7th nerve) - most common - onset sudden - transient - Heerfordt syndrome [4] b) optic nerve dysfunction c) papilledema d) hypothalamic & pituitary abnormalities e) chronic meningitis f) psychiatric disturbances g) seizures h) peripheral neuropathy i) brain lesions [4] j) myelopathy [4] 13) musculoskeletal a) bone involvement (5%) - cysts within expanded bone - punched-out lesions - lytic lesions of bones of hands & feet most common, especially in terminal phalanges - may be painful b) joints (25-50%) - arthralgias & arthritis in large joints - oligoarthritis or polyarthritis [4] - polyarthritis in severe sarcoidosis may affect shoulders, wrists, knees, ankles & digits [4] - may be migratory - usually transient - asymmetric joint swelling [4] - may be chronic & deforming - tenosynovitis [4] - dactylitis [4] c) muscle dysfunction rare: - polymyositis/dermatomyositis - chronic myopathy 14) heart (5%) a) granulomas involve the heart in 25% of patients - generally subclinical [4,10] b) left ventricular wall involvement common c) arrhythmias 1] AV block, complete heart block, bundle branch block 2] ventricular arrhythmias, sudden death - monomorphic ventricular tachycardia d) cardiomyopathy 1] myocarditis 2] LV systolic dysfunction - dilated cardiomyopathy 3] restrictive cardiomyopathy is rare e) papillary muscle dysfunction f) pericarditis g) congestive heart failure h) cor pulmonale secondary to pulmonary fibrosis is rare [4] 15) endocrine: - hypothalamus & pituitary most commonly involved - central adrenal insufficiency - pituitary hypothyroidism - hypogonadism of central origin - central diabetes insipidus [4] - hypercalcemia, hypervitaminosis D 16) exocrine glands: a) parotitis, bilateral parotid gland enlargement (common) - Heerfordt syndrome [4] b) xerostomia 17) gastrointestinal involvement rarely clinically significant Laboratory: 1) complete blood count (CBC) a) lymphocytopenia b) eosinophilia may be present 2) rheumatoid factor (RF) may be positive 3) antinuclear antibodies (ANA) may be positive 5) serum globulins or serum protein electrophoresis (hypergammaglobulinemia) 6) serum calcium baseline & annually a) hypercalcemia may be present (case report of 12.1 mg/dL) [21] b) serum phosphate may be simultaneously increased c) serum PTH low for high serum calcium (hypercalcemia) & high urine calcium (hypercalciuria) [4] 7) serum creatinine & serum alkaline phosphatase baseline & annually [26] 8) serum 1,25-dihydroxyvitamin D may be elevated [22] - measure both serum 25-hydroxyvitamin D & serum 1,25-dihydroxyvitamin D [26] - patients with hypercalcemia, hypercalciuria & nephrolithiasis [4] 9) urinalysis a) sterile pyuria may be noted b) urine calcium: hypercalciuria may be present c) urine protein: mild proteinuria may be present d) urine osmolality: - urine may be inappropriately dilute (concentrating impairment) 10) erythrocyte sedimentation rate (ESR) is generally normal 12) serology: high serum antiviral titers a) Epstein-Barr virus b) rubella c) parainfluenza d) Herpes simplex 12) flow cytometry: CD4/CD8 ratio increased 13) serum angiotensin-converting enzyme: elevated ACE - of no benefit for diagnosis or management [4] 14) elevated interleukin 2 receptor soluble in serum/plasma (> 600 U/mL) [30] 15) see ARUP consult [6] Special laboratory: 1) fiberoptic bronchoscopy - endobronchial ultrasound-guided transbronchial FNA [19] 2) bronchoalveolar lavage a) increased lymphocytes b) alveolar macrophages c) a few neutrophils with pulmonary fibrosis d) non-specific findings 3) biopsy a) bronchoscopic lung biopsy 1] endobronchial biopsy 2] transbronchial biopsy a] mediastinal lymph nodes b] hilar lymph nodes 3] US-guided endobronchial biopsy preferred vs mediastinocopy [26] b) biopsy of skin nodule, scalene nodes, conjunctival lesions c) cardiac biopsy shows non-caseating granuloma in 20% d) tissue stain & culture biopsy specimens to exclude infectious cause of non-caseating granuloma e) rule-out tuberculosis & fungal infection [4] f) lacrimal gland biopsy if lacrimal gland enlargement g) presentations that do NOT require tissue biopsy (lymph node biopsy) - asymptomatic bilateral hilar lymphadenopathy - Lofgren's syndrome [4,8,26] - Heerfordt syndrome [4,26] - lupus pernia [26] 4) suppression of delayed-type hypersensitivity (skin testing) in 60% of patients 5) pulmonary function testing: a) normal, restrictive or restrictive/obstructive pattern b) DLCO is generally diminished 6) ophthalmology slit-lamp exam on all patients [26] 7) baseline electrocardiogram [26] rule out heart block on all patients - HOLTER [22] not recommended [26] 8) upper GI endoscopy to evaluate for esophageal varices for suspected hepatic sarcoidosis [4] Radiology: 1) chest X-ray [16] (images) a) 90% have abnormal chest X-ray at some time b) bilateral hilar lymphadenopathy without parenchymal changes (type 1) c) bilateral hilar adenopathy with parenchymal changes (type 2) d) diffuse parenchymal abnormalities without hilar adenopathy (type 3) e) egg shell calcification of hilar nodes f) predominantly upper lobe interstitial infiltrates g) reticular opacities h) pleural effusion i) pneumothorax j) cardiomegaly k) 50% develop permanent pulmonary abnormalities l) findings can help predict probability of spontaneous resolution [4] 2) high-resolution computed tomography of chest - identify hilar adenopathy suggested on chest E-ray - may identify early fibrosis - nodules along bronchovascular bundles 3) gallium 67 lung scan: diffuse uptake 4) X-ray of hands may show erosions & cystic changes of the phalanges* [27] 5) renal ultrasound in patients with hypercalcemia/hypercalciuria 6) MRI for neurosarcoidosis [4] 7) cardiac MRI for suspected cardiac sarcoidosis [4] - dilated cardiomyopathy [4] - suspected restrictive cardiomyopathy [26] - delayed gadolinium hyperenhancement generally of the mid myocardial wall or epicardium - findings indicative of inflammation in distribution atypical for coronary artery disease [4,10] - also useful for excluding constrictive pericarditis - 18F fluorodeoxyglucose PET scan if MRI is negative & suspicion is high [4] 8) echocardiography for suspected pulmonary hypertension [26] - right heart catheterization if confirmed [26] * image [27] Staging: - based on chest X-ray findings which roughly, but not necessarily, parallel clinical disease severity. - no evidence that disease progresses from one phase to the next - 0: normal chest X-ray with granulomas at other sites - 1: bilateral hilar lymphadenopathy & paratracheal lymphadenopathy - 2: pulmonary infiltrates with hilar lymphadenopathy - 3: pulmonary infiltrates without lymphadenopathy - 4: end-stage pulmonary fibrosis with bullous changes - 1: > 90% with spontaneous resolution* - 2 or 3: ~20% with spontaneous improvement* * without treatment [4] Complications: 1) respiratory failure (rare) 2) aspergilloma 3) blindness 4) cardiomypathy, congestive heart failure a) dilated cardiomyopathy b) restrictive cardiomyopathy 5) cor pulmonale 6) cardiac conduction system abnormalities - ventricular arrhythmias, including sudden death [4] 7) nephrocalcinosis & nephrolithiasis (see management section) Differential diagnosis: - berylliosis - multiple myeloma distinguished by paraproteinemia [21] Management: 1) do not treat asymptomatic sarcoidosis 2) pharmacologic agents a) NSAIDs for erythema nodosum or Lofgren's syndrome [31] b) glucocorticoids - uncertain benefit - topical glucocorticoid for skin lesions, anterior uveitis - inhaled glucocorticoid for nasal polyp, cough - oral glucocorticoids for - ophthalmologic disease - symptomatic pulmonary sarcoidosis [4] - neurologic sarcoidosis - hypercalcemia - significant dysfunction of other vital organ (heart, kidney) - prednisone 30-40 mg/day for 4-8 weeks - if favorable response to glucocorticoids - taper dose to lowest dose that maintains remission - maintenance usually > 15 mg qod - maintain therapy for 1 year before discontinuing - 20-50% relapse rate after discontinuation of glucocorticoids c) immunosuppressive agents, cytotoxic agents & antimalarials - consider for patients refractory to or unable to tolerate glucocorticoids - chloroquine - hydroxychloroquine - methotrexate d) pentoxifylline has been used as a steroid-sparing agent 3) surgery: - lung transplantation for severe pulmonary pathology despite appropriate medical therapy 4) prognosis - most patients with acute presentation recover without significant sequellae - Lofgren syndrome has an 80% rate of spontaneous remission & resolution [4] - chronic or recurrent disease in 15-20% - avoid vitamin D & calcium supplements - death attributed to sarcoidosis in 10% of total

Interactions

disease interactions

Specific

cardiac sarcoidosis Lofgren's syndrome neurosarcoidosis sarcoidosis early onset

General

autoimmune disease granulomatous disease

Database Correlations

OMIM correlations

References

  1. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995. page 255
  2. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 1922-1928
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 752-753
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17. 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. Dempsey OJ et al Sarcoidosis BMJ. 2009 Aug 28;339:b3206. PMID: 19717499 doi: 10.1136/bmj.b3206
  6. ARUP Consult: Sarcoidosis The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/sarcoidosis
  7. OMIM :accession 612387
  8. Hamzeh N. Sarcoidosis. Med Clin North Am. 2011 Nov;95(6):1223-34 PMID: 22032436
  9. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007 Nov 22;357(21):2153-65. PMID: 18032765
  10. Patel MR, Cawley PJ, Heitner JF et al Detection of myocardial damage in patients with sarcoidosis. Circulation. 2009 Nov 17;120(20):1969-77 PMID: 19884472
  11. Heiligenhaus A, Wefelmeyer D, Wefelmeyer E et al The eye as a common site for the early clinical manifestation of sarcoidosis. Ophthalmic Res. 2011;46(1):9-12. PMID: 21099232
  12. Chatham W. Rheumatic manifestations of systemic disease: sarcoidosis. Curr Opin Rheumatol. 2010 Jan;22(1):85-90 PMID: 19851109
  13. Thelier N, Assous N, Job-Deslandre C et al Osteoarticular involvement in a series of 100 patients with sarcoidosis referred to rheumatology departments. J Rheumatol. 2008 Aug;35(8):1622-8. Epub 2008 Jul 15. PMID: 18634144
  14. O'Regan A, Berman JS. Sarcoidosis. Ann Intern Med. 2012 May 1;156(9):ITC5-1, ITC5-2, ITC5-3 ... PMID: 22547486
  15. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part I. Cutaneous disease. J Am Acad Dermatol. 2012 May;66(5):699.e1-18 PMID: 22507585 - Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part II. Extracutaneous disease. J Am Acad Dermatol. 2012 May;66(5):719.e1-10 PMID: 22507586
  16. Kamangar A, Mosenifar Z (chest X-ray) Medscape: Sarcoidosis http://emedicine.medscape.com/article/301914-overview
  17. DermNet NZ. Sarcoidosis (images) http://www.dermnetnz.org/dermal-infiltrative/sarcoidosis.html
  18. Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2011 Mar 1;183(5):573-81. Review. PMID: 21037016 Free PMC Article
  19. Sun J, Yang H, Teng J, Zhang J, Zhao H, Garfield DH, Han B Determining factors in diagnosing pulmonary sarcoidosis by endobronchial ultrasound-guided transbronchial needle aspiration. Ann Thorac Surg. 2015 Feb;99(2):441-5. PMID: 25497069
  20. Moore SA, Abbara S, Mak GS Case 22-2016 - A 65-Year-Old Man with Syncope, Dyspnea, and Leg Edema. N Engl J Med 2016; 375:262-272. July 21, 2016 PMID: 27468063 http://www.nejm.org/doi/full/10.1056/NEJMcpc1601838
  21. Lavery K, Gilden DJ, Saint S et al A Bare-Bones Approach N Engl J Med 2017; 376:1371-1376. April 6, 2017 PMID: 28379797 http://www.nejm.org/doi/full/10.1056/NEJMcps1516629
  22. Rashid RM, Barros BS (images) Hidden Heart Disease: 19 Dermatologic Clues You Should Know. Medscape. June 13, 2017. http://reference.medscape.com/slideshow/hidden-heart-disease-6004452
  23. Wanat KA, Rosenbach M. Cutaneous Sarcoidosis. Clin Chest Med. 2015 Dec;36(4):685-702. Review. PMID: 26593142
  24. Langrand C, Bihan H, Raverot G et al Hypothalamo-pituitary sarcoidosis: a multicenter study of 24 patients. QJM. 2012 Oct;105(10):981-95. Epub 2012 Jun 30. PMID: 22753675
  25. Loffler C, Loffler U, Tuleweit A Renal sarcoidosis: epidemiological and follow-up data in a cohort of 27 patients. Sarcoidosis Vasc Diffuse Lung Dis. 2015 Jan 5;31(4):306-15. PMID: 25591142
  26. Crouser ED, Maier LA, Wilson KC et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2020 Apr 15; 201:e26 PMID: 32293205 Free PMC Article https://www.atsjournals.org/doi/10.1164/rccm.202002-0251ST
  27. Ward R, Kalus A, Schachtel A. Images in Dermatology: Nail Sarcoidosis JAMA Dermatol. 2022;158(10):1202 https://jamanetwork.com/journals/jamadermatology/fullarticle/2795311
  28. Birnie DH, Nery PB, Ha AC, Beanlands RS. Cardiac Sarcoidosis. J Am Coll Cardiol. 2016 Jul 26;68(4):411-21. PMID: 27443438 Free article. Review.
  29. NEJM Knowledge+ Rheumatology
  30. Brys ADHM, Stehouwer CDA, van de WeijerC, Magdelijns F. Not all is what it seems like: Hypercalcemia in the older patient. Geriatr Gerontol Int. 2023 Sep 25 PMID: 37746891 https://onlinelibrary.wiley.com/doi/full/10.1111/ggi.14689
  31. NEJM Knowledge+ - Bergner R, Loffler C. Renal sarcoidosis: approach to diagnosis and management. Curr Opin Pulm Med. 2018 Sep;24(5):513-520. PMID: 29965860 Review. - Hilderson I, Van Laecke S, Wauters A, Donck J. Treatment of renal sarcoidosis: is there a guideline? Overview of the different treatment options. Nephrol Dial Transplant. 2014 Oct;29(10):1841-7. PMID: 24235078 Review.
  32. Sarcoidosis https://www.nhlbi.nih.gov/health-topics/sarcoidosis