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Sarcoidosis Overview. Kenneth S. Knox, MD Assistant professor of medicine Division of Pulmonary & Critical Care Medicine Indiana University. What is Sarcoidosis ?. Nobody knows Systemic inflammatory/immunologic disorder

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Sarcoidosis overview

Sarcoidosis Overview

Kenneth S. Knox, MD

Assistant professor of medicine

Division of Pulmonary & Critical Care Medicine

Indiana University

What is sarcoidosis
What is Sarcoidosis ?

Nobody knows

  • Systemic inflammatory/immunologic disorder

  • Hallmark isgranulomatous (noncaseating) inflammation and a CD4+ T cell alveolitis in the lung

  • Thought to be in response to something

    • Occupational exposure or Environment

    • Bacteria or virus

    • Autoantigen (much like lupus and rheumatoid)


** ACCESS trial– ACase Controlled Etiologic Study of Sarcoidosis

1) Rybicki BA, Iannuzzi MC, Frederick MM, Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001 Dec 1;164(11):2085-91.

2) Baughman RP, Teirstein AS, Judson MA, Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1885-9.

3) Freemer M, King TE Jr. The ACCESS study: characterization of sarcoidosis in the United States. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1754-5.

4) Rossman M, Thompson B, Frederick M,. Sarcoidosis: association with human leukocyte antigen class II amino acid epitopes and interaction with environmental exposures. Chest. 2002 Mar;121(3)supl.

5) Pandey JP, Frederick M; ACCESS Research Group. A Case Control Etiologic Study of Sarcoidosis. TNF-alpha, IL1-beta, and immunoglobulin (GM and KM) gene polymorphisms in sarcoidosis. Hum Immunol. 2002 Jun;63(6):485-91.

6) Judson MA, Baughman RP, Thompson BW, Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis. 2003 Oct;20(3):204-11.

7) Rossman MD, Thompson B, Frederick M, HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet. 2003 Oct;73(4):720-35.

Sarcoidosis background
Sarcoidosis- background

Second most common lung disease in young adults (second only to asthma)

  • Lifetime risk .85% for US whites

  • Lifetime risk 2.4% for US blacks

  • 21.6 females and 15.3 males per 100,000 per yr ACCESS

ACCESS defined,Historical

Iu sarcoid data
IU sarcoid data

  • 398 patients with sarcoidosis (Wishard and Clarian visited in past 2 years)

  • Over 700 in database

  • Support group

  • Sarcoidosis and Immunologic lung disease program


  • Typically 20-40 yo, 35-45 with a third > 50

  • Women > Men

  • Blacks > Whites 7:1 in U.S.,4:1 in Detroit

  • Familial risk

    • sibs, aunts, uncles, grandparents OR 5.2-5.8 and parents OR= 3.8, whites > blacks

ACCESS defined,Historical

Epidemiology prognosis
Epidemiology- prognosis

  • Better prognosis

  • Lofgren syndrome

    • -E nodosum F, arthritis, nodes, +/- uveitis

  • Stage 1 X-ray

  • Younger

  • White-calcium, nodosum

  • Anterior uveitis F

Unfavorable prognosis

  • Older (over 40) F

  • Stage II ?, III, IV X-ray

  • Black –pernio (puerto rican), eye, liver, periph nodes, BM

  • Posterior uveitis- Asian

  • Unresponsive to steroid

  • Neuro F, Cardiac- Asian

  • Elevated calcium M

ACCESS defined,Historical

Environmental hypothesis

(+) Associations




Musty odors

(-) Associations



Cat/Animal dust

Feather/down pillows

Environmental Hypothesis

ACCESS defined

Environmental hypothesis1


Beryllium-similar disease

“Clustering”many reports, (ie: navy, Isle of Man)

Firefighting- anecdotes

School teachers- my experience

Geographical(“farther from the equator”)

Seasonal (“cool summer, mild winter”)“springtime dz”

cases reported worldwide.

Likely not associated

Wood dust and pine pollen




Health-care workers


Environmental Hypothesis

Infection hypothesis
Infection Hypothesis


  • Mycobacteria

  • Propionibacteria

  • Borrelia


  • Epstein-Barr

  • Human herpesvirus 8

  • CMV, Coxsackie B

Review: Current Opinion in Pulmonary Medicine 2002,8, 413-476

ATS/ERS/WASOG statement on sarcoidosis: Sarc Vasc Diff Lung Dis 1999,16

Infection hypothesis1
Infection Hypothesis

Notable, recent infectious possibilities

  • Tuberculosis (PCR study, Drake 2002)

  • Propionibacteria (Ishigi, Lancet, 1999)

  • Histoplasmosis (IU experience)

Autoimmune hypothesis
Autoimmune Hypothesis

You react to “privileged self-antigens”

  • Infection

  • Injury

** Many exposures, infections, and “injury”

can be associated with “granulomatous inflammation”

Recent etiologies
Recent etiologies

Associated with therapy “Immune-modulating”

  • HIV reconstitution syndrome

    • Foulon et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis. 2004 Feb 1;38(3):418-25.

  • IFN therapy for hepatitis

    • Pietropaoli A et al.  Interferon-alpha therapy associated with the development of sarcoidosis. Chest. 1999 Aug;116(2):569-72.


  • Genetic background

    • Familial risk (monozygotic twin studies, siblings and parents)

    • Race, ethnicity

  • Genetic background

    • HLA (DR17,DRB1*1101)

    • Other polymorphisms (TNF,Ig-KM)

    • BTNL2 truncating splice site mutation

ACCESS defined

Who gets sarcoidosis
Who gets Sarcoidosis ?




Organ involvement




Brain/spinal cord

Lymph nodes








Organ involvement

** Heterogeneous disease!


  • Nonspecific

    • Fever, sweats

    • Weakness,

    • Weight loss

    • Aches and pains

  • Psychological issues

  • Organ specific symptoms

Specific symptoms
Specific Symptoms

  • Lung: cough, short of breath, chest pain

  • Eye: blurred vision, pain, redness

  • Skin: flat rash, nodules, lupus pernio, E. nodosum

  • Heart: palpitations, skipped beats, dizziness, death

  • Central nervous system/nerves: headache, pain, weakness, memory difficulties, vision loss, hormone abnormalities

Specific symptoms1
Specific Symptoms

  • Muscles: pain

  • Bones/joints: arthritis, pain, joint swelling

  • Liver/GI: pain, diarrhea, nausea, jaundice

  • Vocal cords/salivary glands: hoarseness, swelling

  • Kidneys: kidney stones, failure, polyuria if calcium and hormone problems

Laboratory testing
Laboratory Testing

  • Bloodwork

    • Blood counts (CBC)

      • Lymphopenia (45%); leukopenia (30%)

      • Anemia up to 20%; low platelets < 2%

    • Liver (AST, GGT, Alk phos) and kidney (Cr) function, Calcium (Ca) and other chemistries

    • Proteins (IgG, albumin)

    • Tests of muscle (CK) and inflammation (ESR,CRP)

  • Urine analysis/collection

More directed testing
More Directed Testing

  • Tuberculin skin test (PPD)

  • Fungal blood work (Histoplasmosis in Indiana)

  • Angiotensin Converting Enzyme (ACE)

  • Lysozyme

Diagnosis ocular
Diagnosis- Ocular

  • Eye: anterior or posterior uveitis, mass

  • Testing: Slit-lamp eye exam, MRI

  • Diagnosis: can biopsy lid if small lesions

    • Reluctant if no visible lesion (yield < 20-50%)

25% of patients

Diagnosis and derm
Diagnosis and Derm

  • Skin: many rashes

    • Lupus pernio (biopsy)

    • Nodules, flat patches (biopsy)

    • Erythema Nodosum (biopsy non-specific)

  • Diagnosis: Appearance can be classic, biopsy to support

20% of patients

Diagnosis cardiac
Diagnosis- cardiac

  • Heart: dysrhythmia, pericardial, pulm htn if severe, causing shortness of breath

  • Testing: EKG, thallium, echo, gallium, MRI

  • Diagnosis:

    • Can biopsy heart, but not typical

    • Presumed if sarcoidosis affecting other organs

    • “Cold spots” on stress test that improve,MRI

5% symptomatic, 30% incidental

Diagnosis musculoskeletal
Diagnosis- musculoskeletal

  • Bone: pain, arthritis

  • Testing: X-ray

  • Diagnosis:

    • Can have classic features

< 5% have bone involvement; less than 1% have chronic muscle involvement

Iu liver disease
IU Liver disease

  • Hepatobiliary disease in sarcoidosis is rarely clinically overt.

  • When present, it can range from asymptomatic liver test abnormalities to cirrhosis.

  • Can be first manifestation of sarcoidosis.

  • Granulomatous hepatitis, with varying degrees of fibrosis, most common pathologic finding.

  • Male gender and splenomegaly are significantly associated with sarcoid-related liver disease.

  • Gender difference persisted after reanalysis with N=340 (Liver test abnormality group, p=0.0006).

Diagnosis of neurosarcoidosis
Diagnosis of Neurosarcoidosis

CNS: headache, memory loss, palsy, weakness, dizziness, visual, stroke

  • Testing: EEG and EMG, muscle/nerve biopsy, MRI brain and spinal cord, CSF ACE

  • Features: can be presenting sign, can occur during course of Rx, spontaneous remission

  • Diagnosis: biopsy CNS or other. Clinical…

5% symptomatic, 15% overall

Sarcoidosis overview

IU neurosarcoid data

  • 39 with documented neurosarcoidosis

    • “Neuropathy” most common

Pulmonary diagnosis of sarcoid
Pulmonary Diagnosis of Sarcoid

Lung:cough, short of breath, chest pain

  • Testing:PFTs, chest x-ray and CT scan

  • Diagnosis:usually requires biopsy

    • to exclude other things that look like sarcoid

      • (TB, lymphoma, histo, malignancy)

    • to support the diagnosis of sarcoid

  • The lung and lung lymph nodes are the most common site for biopsy (90% have thoracic at Dx)

    • Bronchoscopy (BAL, Biopsy), Mediastinoscopy

Sarcoidosis overview


  • Restrictive pattern most common (scarred lung)

    • Diffusing capacity first, then Lung capacity

  • Can have obstruction (asthma-like)

    • ACCESS >13%

  • Low Oxygen levels at rest, with exercise or sleep

  • Sarcoidosis overview

    Staging disease by Chest X-ray:

    Stage 0 Normal (5%,ACCESS 8%)

    Stage 1 Large chest lymph nodes only (50%,40%)

    Stage 2 Chest nodes and lung infiltrate (25%,37%)

    Stage 3 Lung infiltrates only (15%,10%)

    Stage 4 Fibrosis (5%,5%)

    Sarcoidosis overview



    IU clinical BAL Lab



    Sarcoidosis overview

    Tissue- granuloma shuffle

    (Classically, a “Non-necrotizing granuloma without necrosis”)

    • BEST

    • TBBx

    • Whole LN, chest

    • WORST

    • Peripheral node

    • Skin in non-specific site

    DDx: TB, Endemic fungal infection,

    Malignancy, GLUS, Wegner’s, HP

    foreign body reaction

    ** Many times supportive evidence and clinical context

    Sarcoidosis overview

    Endobronchial biopsy for sarcoidosis: a prospective study.Shorr AF, Torrington KG, Hnatiuk OW. Chest. 2001 Jul;120(1):109-14.

    Six TBB specimens were obtained, as were six EBB samples. For patients with abnormal-appearing airways, four specimens were obtained from the abnormal-appearing airways and two specimens were obtained from the main carina. In patients with normal-appearing airways, four specimens were obtained from a secondary carina and two specimens were obtained from the main carina. EBB findings were positive in 61.8% of patients, while TBB showed nonnecrotizing granulomas in 58.8% of subjects. The addition of EBB increased the yield of FOB by 20.6%. Although EBB findings were more frequently positive in abnormal-appearing airways (p = 0.014), EBB provided diagnostic tissue in 30.0% of patients with normal-appearing endobronchial mucosa.

    CONCLUSION: EBB has a yield comparable to TBB and can safely increase the diagnostic value of FOB. Pulmonologists should consider routinely performing EBB in cases of suspected sarcoidosis.

    Sarcoidosis overview

    Diagnostic value of transbronchial needle aspiration by Wang 22-gauge cytology needle in intrathoracic lymphadenopathy.Cetinkaya E, Yildiz P, Altin S, Yilmaz V. Chest. 2004 Feb;125(2):527-31.

    Diagnostic material was obtained from 16 of 21 patients with sarcoidosis (76%). In sarcoidosis, TBNA provided the only diagnostic specimen in 13 of 21 patients (62%).

    CONCLUSION: TBNA performed with a Wang 22-gauge cytology needle is an effective and safe way of obtaining cytologic specimens from intrathoracic lymph nodes and can rapidly provide diagnosis, both in malignant and benign mediastinal diseases. Hopefully, this technique will reduce further need for more invasive surgical procedures.

    Treatment options first line
    Treatment options- first line 22-gauge cytology needle in intrathoracic lymphadenopathy.


    • Can wait up to 6 months to see if spontaneous remission occurs (especially pulmonary)

    • Side effects- weight gain, glucose, cataracts, bone loss, insomnia, infection, ulcer, adrenal

    • Old dogma- early treatment alters natural course of disease unfavorably…

    Sarcoidosis overview

    Early Treatment of Stage II Sarcoidosis Improves 5-Year Pulmonary Function*

    Anne Pietinalho, MD, PhD; et al. the Finnish Pulmonary Sarcoidosis Study Group†

    Study objective:To evaluate the 5-year prognosis of patients with stage I and stage II newly

    detected (< 3 months) pulmonary sarcoidosis treated immediately after diagnosis with prednisolonefor 3 months followed by inhaled budesonide for 15 months. 79 patients with initial stage I disease and 70 patients with stage II disease.

    Treatment:Oral prednisolone for 3 months followed by inhaled budesonide for 15 months (800mg bid), or placebo tablets followed by placebo inhaler therapy. Thereafter, treatment only on anindividual basis in the case of clinical deterioration.

    Results: Placebo-treated patients more frequently required treatment with corticosteroids during the 5-year follow-up (p < 0.05). Steroid-treated patients with initial stage II(-III) disease improved more in FVC and DLCO (p < 0.05). No differences in reported adverse events or in SACE, serum calcium, or urinary calcium values were seen.

    Conclusion: Immediate treatment of pulmonary stage II(-III) sarcoidosis but not stage I disease improved the 5-year prognosis with regard to lung function variables. (CHEST 2002; 121:24–31)

    Treatment options first line1
    Treatment options- first line Pulmonary Function*

    Topical steroids as primary therapy


    • Eyedrops

    • Creams/ointments

    • Intralesional

    • Inhaled

      • Alone

      • After oral therapy for maintenance

    Treatment options first line2
    Treatment options- first line Pulmonary Function*

    Steroids are the mainstay of treatment

    • Start 20-40mg prednisone a day, need to follow closely.

    • May need more or intravenous if severe, difficulty expected, or acute disease

    • May be able to taper over first 3 months to a lower dose or every other day dosing

    Treatment options second line
    Treatment options- second line Pulmonary Function*

    If prednisone failure, intolerance, or need another controller agent


    • Liver toxicity, lung toxicity, mouth sores, abortion

    • Blood counts, Cr, and liver function monthly, biopsy?

      • Baughman RP et al. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.Sarcoidosis Vasc Diffuse Lung Dis. 2000 Mar;17(1):60-6.

        Azathioprine(Imuran- 200 max per day)

  • Low blood counts, diarrhea, small increase in malignancy

  • Blood counts and liver function monthly

    • Muller-Quernheim et al. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen.

      Eur Respir J. 1999 Nov;14(5):1117-22.

  • New treatment options second line
    New Treatment options- second line Pulmonary Function*

    If prednisone failure, intolerance, or need another controller agent

    Leflunomide (+/- MTX)

    • Liver toxicity, Blood counts, Cr, and liver function monthly


    • Low blood counts, diarrhea, small increase in malignancy

    • Blood counts, Cr and liver function monthly

    Treatment options second line1
    Treatment options- second line Pulmonary Function*

    If prednisone failure, intolerance, or need another agent

    • Hydroxychloroquine-200mg-400mg per day

      • Eye, skin, calcium, neuro, occ pulm

      • Ophthalmology every 6 months

      • ** immunomodulator (Ag processing)

    Baughman, et al. Seminars in Respiratory Infections;1998

    Jones and Callen, J Am Acad Derm; 1990

    Toxic out of favor therapies
    Toxic, out of favor therapies Pulmonary Function*

    • CSA -Stern BJ et al. Arch Neurol. 1992;49(10):1065-72

      • Kidney, CNS, hypertension, hair growth, gingival hypertrophy

      • Monitor: kidney function, lipids, electrolytes, blood pressure

    • Chlorambucil

    • Cytoxan- IV(neuro, still used)

      • 90% response (after MTX failure)

        • Lower et al. Arch Intern Med. 1997; 157:1864-68

    • Myelodysplasia, low blood counts, bladder, lung toxicity, fetal, hair loss

    • Blood counts and urinalysis.

    Treatment options
    Treatment options Pulmonary Function*

    • Antibiotics

      • Minocycline

      • Clofazamine

    • Other

      • Captopril

      • Allopurinol

      • Other immunosuppressives

    Unclear role, adjunctive, third line

    Treatment options1

    Web-based medicine- risky! Pulmonary Function*



    • Chelation

    • Supplements??

      • Melatonin, Lancet 1995

      • Fish oil??

      • Antioxidants??

      • “Enzyme therapy”

    • Marshall Plan?

    Treatment options

    • Carcinosin  • Euphrasia  • Graphites  • Leuticum (Syphilinum)  • Bacillinum  • Sepia  • Phosphorus  • Arsenicum album

    Promising therapies
    Promising therapies Pulmonary Function*

    • Anti-TNF therapy

      • Thalidomide- skin (Baughman, Chest; 2002)

      • Pentoxifylline- trial stopped, too few patients(Zabel, AJRCCM 1997)

      • Etanercept- no benefit stage II/III pulmonary(Utz, Chest; 2003),little in uveitis(Baughman, WASOG; 2002),OK for skin and arthritis(Khanna, J Rheumatol; 2003)

      • Infliximab- end of enrollment, pulmonary, promising(Yee, Ann Int Med; 2001; AJRCCM 2006)

      • Adalimumab

    Treatment guided by prognosis
    Treatment guided by prognosis Pulmonary Function*

    • Better prognosis

    • Lofgren syndrome

      • -E nodosum F, arthritis, nodes, +/- uveitis

    • Stage 1 X-ray

    • Younger

    • White -calcium, nodosum

    • Anterior uveitis F

    Unfavorable prognosis

    • Older (over 40) F

    • Stage II ?, III, IV X-ray

    • Black –pernio (puerto rican), eye, liver, periph nodes, BM

    • Posterior uveitis- Asian

    • Unresponsive to steroid

    • Neuro F, Cardiac- Asian

    • Elevated calcium M

    Sarcoidosis overview

    Quality of life- Psychosocial Pulmonary Function*

    • Sarcoidosis patients showed a lower overall QOL and general health, and suffered from more fatigue and sleeping problems than the healthy control group

    • The health status of sarcoidosis patients assessed by the Sickness Impact Profile (SIP), was impaired compared to the health status of healthy controls especially in the areas of sleep, ability to work, recreation, and social interactions.

    • Sarcoidosis patients with bodily symptoms suffered from more depressive symptoms