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Sarcoidosis Overview Kenneth S. Knox, MD

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1 Sarcoidosis Overview Kenneth S. Knox, MD
Assistant professor of medicine Division of Pulmonary & Critical Care Medicine Indiana University

2 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)

3 Epidemiology ** ACCESS trial– A Case 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 Dec 1;164(11): 2) Baughman RP, Teirstein AS, Judson MA, Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med Nov 15;164(10 Pt 1): 3) Freemer M, King TE Jr. The ACCESS study: characterization of sarcoidosis in the United States. Am J Respir Crit Care Med Nov 15;164(10 Pt 1): 4) Rossman M, Thompson B, Frederick M,. Sarcoidosis: association with human leukocyte antigen class II amino acid epitopes and interaction with environmental exposures. Chest 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 Jun;63(6): 6) Judson MA, Baughman RP, Thompson BW, Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis Oct;20(3): 7) Rossman MD, Thompson B, Frederick M, HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet Oct;73(4):

4 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

5 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

6 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 and parents OR= 3.8, whites > blacks ACCESS defined, Historical

7 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

8 Environmental Hypothesis
(+) Associations Agriculture Insecticides/pesticides Mold/Mildew Musty odors (-) Associations Tobacco Children Cat/Animal dust Feather/down pillows ACCESS defined

9 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

10 Infection Hypothesis Bacteria Virus Mycobacteria Propionibacteria
Borrelia Virus Epstein-Barr Human herpesvirus 8 CMV, Coxsackie B Review: Current Opinion in Pulmonary Medicine 2002,8, ATS/ERS/WASOG statement on sarcoidosis: Sarc Vasc Diff Lung Dis 1999,16

11 Infection Hypothesis Notable, recent infectious possibilities
Tuberculosis (PCR study, Drake 2002) Propionibacteria (Ishigi, Lancet, 1999) Histoplasmosis (IU experience)

12 Autoimmune Hypothesis
You react to “privileged self-antigens” Infection Injury ** Many exposures, infections, and “injury” can be associated with “granulomatous inflammation”

13 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 Feb 1;38(3): IFN therapy for hepatitis Pietropaoli A et al.  Interferon-alpha therapy associated with the development of sarcoidosis. Chest Aug;116(2):

14 Genetics Genetic background 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

15 Who gets Sarcoidosis ? Infectious Sarcoidosis = OR X Genetic X ??

16 Organ involvement Lung Eye Skin Brain/spinal cord Lymph nodes Heart
Kidneys Liver/spleen Muscles/nerves Joints/bones Hematologic Metabolic ** Heterogeneous disease!

17 Symptoms Nonspecific Psychological issues Organ specific symptoms
Fever, sweats Weakness, Weight loss Aches and pains Psychological issues Organ specific symptoms

18 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

19 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

20 Laboratory Testing Bloodwork Urine analysis/collection
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

21 More Directed Testing Tuberculin skin test (PPD)
Fungal blood work (Histoplasmosis in Indiana) Angiotensin Converting Enzyme (ACE) Lysozyme

22 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

23 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

24 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

25 Diagnosis- musculoskeletal
Bone: pain, arthritis Testing: X-ray Diagnosis: Can have classic features < 5% have bone involvement; less than 1% have chronic muscle involvement

26 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).

27 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

28 IU neurosarcoid data 39 with documented neurosarcoidosis
AFRICAN AMERICAN n=19 CAUCASIAN n=20 Cranial nerve lesions 11 (58%) 7 (35%) Peripheral neuropathy 8 (42.1%) 14 (70%) Brain lesions 10 (53%) Spinal cord lesions 4 (21%) 2 (10%) Brain+Spinal cord (CNS) 14 (74%) 9 (45%) > than 1 part of nervous system 8 (40%) 39 with documented neurosarcoidosis “Neuropathy” most common

29 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

30 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

31 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%)

32 IU clinical BAL Lab TNF Lymphocyte subsets IFN

33 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


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

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

37 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…

38 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)

39 Treatment options- first line
Topical steroids as primary therapy MILD DISEASE Eyedrops Creams/ointments Intralesional Inhaled Alone After oral therapy for maintenance

40 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

41 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 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 Nov;14(5):

42 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

43 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;1998 Jones and Callen, J Am Acad Derm; 1990

44 Toxic, out of favor therapies
CSA -Stern BJ et al. Arch Neurol. 1992;49(10): 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: Myelodysplasia, low blood counts, bladder, lung toxicity, fetal, hair loss Blood counts and urinalysis.

45 Treatment options Unclear role, adjunctive, third line Antibiotics
Minocycline Clofazamine Other Captopril Allopurinol Other immunosuppressives

46 Treatment options Web-based medicine- risky! Chelation Supplements??
Chelation Supplements?? Melatonin, Lancet 1995 Fish oil?? Antioxidants?? “Enzyme therapy” Marshall Plan? • Carcinosin   • Euphrasia   • Graphites   • Leuticum (Syphilinum)   • Bacillinum   • Sepia   • Phosphorus   • Arsenicum album

47 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

48 Treatment guided by 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

49 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

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