Sarcoidosis Overview

Kenneth S. Knox, MDAssistant professor of medicineDivision of Pulmonary & Critical Care MedicineIndiana University

What is Sarcoidosis ?

Nobody knows• Systemic inflammatory/immunologic disorder• Hallmark is granulomatous (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)

Epidemiology ** ACCESS trial– A Case Controlled Etiologic Study of SSarcoidosis 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

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

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

• Over 700 in database

• Support group

• Sarcoidosis and Immunologic lung disease program

Epidemiology

• 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

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

Better prognosis• Lofgren syndrome

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

• Stage 1 X-ray• Younger• White -calcium, nodosum

• Anterior uveitis F

ACCESS defined, Historical

Environmental Hypothesis

(+) Associations• Agriculture• Insecticides/pesticides• Mold/Mildew• Musty odors

(-) Associations• Tobacco• Children• Cat/Animal dust• Feather/down pillows

ACCESS defined

Environmental Hypothesis

Uncertain • 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• Metals• Silica• Talc• Health-care workers• Pets

Infection Hypothesis

Bacteria– Mycobacteria – Propionibacteria– Borrelia

Virus– 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 Hypothesis

Notable, recent infectious possibilities

• Tuberculosis (PCR study, Drake 2002)• Propionibacteria (Ishigi, Lancet, 1999)• Histoplasmosis (IU experience)

Autoimmune Hypothesis

You react to “privileged self-antigens”

• Infection

• Injury

** Many exposures, infections, and “injury” can be associated with “granulomatous inflammation”

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.

Genetics

• 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 ?

Infectious

Sarcoidosis = OR X Genetic X ??

Environment

Organ involvement• Lung• Eye• Skin• Brain/spinal cord• Lymph nodes• Heart

• Kidneys• Liver/spleen• Muscles/nerves• Joints/bones• Hematologic • Metabolic

** Heterogeneous disease!

Symptoms

• Nonspecific– Fever, sweats– Weakness, – Weight loss– Aches and pains

• Psychological issues

• Organ 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 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

• 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

• Tuberculin skin test (PPD)• Fungal blood work (Histoplasmosis in Indiana) Angiotensin Converting Enzyme (ACE) Lysozyme

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

• 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

• 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

• 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

• 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 NeurosarcoidosisCNS: 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

IU neurosarcoid data

• 39 with documented neurosarcoidosis– “Neuropathy” most common

AFRICAN AMERICANn=19

CAUCASIANn=20

Cranial nerve lesions

11 (58%) 7 (35%)

Peripheral neuropathy

8 (42.1%) 14 (70%)

Brain lesions 10 (53%) 7 (35%)

Spinal cord lesions

4 (21%) 2 (10%)

Brain+Spinal cord (CNS)

14 (74%) 9 (45%)

> than 1 part of nervous system

8 (42.1%) 8 (40%)

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

Lung

PFTs• 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

Lung

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%)

Lymphocytesubsets

IU clinical BAL Lab

TNF

IFN

Tissue- granuloma shuffle

BEST• TBBx• Whole LN, chest

WORST• Peripheral node• Skin in non-specific site

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

** Many times supportive evidence and clinical context

DDx: TB, Endemic fungal infection, Malignancy, GLUS, Wegner’s, HPforeign body reaction

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.

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

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.

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.

Treatment options- first line

CONSIDER NOT TREATING!– 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…

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 newlydetected (< 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 line

Topical steroids as primary therapyMILD DISEASE– Eyedrops– Creams/ointments– Intralesional– Inhaled

• Alone• After oral therapy for maintenance

Treatment options- first line

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

If prednisone failure, intolerance, or need another controller agent

Methotrexate (5-20mg/week)– 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

If prednisone failure, intolerance, or need another controller agent

Leflunomide (+/- MTX)– Liver toxicity, Blood counts, Cr, and liver

function monthly

Mycophenolate – Low blood counts, diarrhea, small increase in

malignancy– Blood counts, Cr and liver function monthly

Treatment options- second line

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;1998Jones and Callen, J Am Acad Derm; 1990

Toxic, out of favor therapies

• 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

• Antibiotics

– Minocycline– Clofazamine

• Other – Captopril– Allopurinol– Other immunosuppressives

Unclear role, adjunctive, third line

Treatment options

Web-based medicine- risky!• http://www.gethealthyagain.com/

• http:// www.ivillagehealth.com

• Chelation• Supplements??

Melatonin, Lancet 1995

Fish oil??

Antioxidants??

“Enzyme therapy”

• Marshall Plan?

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

Promising therapies• 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

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

Better prognosis• Lofgren syndrome

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

• Stage 1 X-ray• Younger• White -calcium, nodosum

• Anterior uveitis F

Quality of life- Psychosocial• 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