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Sarcoidosis “The Great Mimicker” Richard F. Duff III, MD Pulmonary/Critical Care Medicine Sarcoidosis of Boeck • First recognized as a skin lesion by Jonathan Hutchinson in 1869 • First recognized in lymph nodes by Ziegler in 1881 • Besnier 1889 “lupus pernio” • Boeck published 1899 • Generalized disease • Affects skin, bones, organs • Resembled sarcoma – “multiple benign sarcoid of the skin” Sarcoidosis of Boeck • Initially thought infectious process – Related to tuberculosis • Schaumann first real description as generalized disease 1914 – “lymphogranulomatosis benigna” Sarcoidosis • Affects people of all racial groups • All ages – Usually develops before age 50 – Peak incidence ages 20-39 – 0.06/100000 children < 4 yrs old • Highest annual incidence in Northern European countries followed by Japan • Blacks 3x > Whites • tends to occur later in life (4th decade) • More likely to be chronic and/or fatal Sarcoidosis • Bimodal distribution in females • 20’s and 60’s • Socioeconomic status does not affect risk • Lower incomes associated with more severe disease • Great Mimicker • Affects any organ, most commonly lung, eyes, skin • Environmental? (airborne antigens) – Wood burning stoves, Tree pollen, Insecticides, Inorganic particles, Metal workers, Military, Firefighters 2001 WTC bombing, molds, mycobacterium Sarcoidosis • No formal twin study completed – Appears to be higher in monozygotes • Siblings born to parents with sarcoid at risk – Ocular or hepatic involvement (3%) • Genes – Class I HLA-B8 – Class II HLA-DRB1, DQB1 Sarcoidosis genes Known To Date Chromosome 6p Chromosome 3p White Germans Chromosome 5p, 5q Chromosome 3p, 5q11.2 Black Americans Chromosome 5p15.2 Protective Chromosome 1p36 Radiographic resolution Chromosome 18q22 Cardiac/Renal involvement Pathophysiology of Sarcoidosis • • • • Biochemistry Organ involvement Immune pathophysiology Aggravating/Alleviating factors Immunopathogenesis • Granulomas are fundamental abnormality – Organized collections of macrophages and epithelial cells surrounded by lymphocytes – Multinucleated giant cells – Increased CD4:CD8 • IL-2, INF-Y, TNF-a – Immune paradox; anergy • CD25 Organ involvement • Granulomas can involve ANY organ – 90% intrathoracic lymph nodes • • • • Lung Skin Eye combo Organ involvement • Lung – Dyspnea – Wheezing – Vague chest discomfort • Scadding stages are degrees of radiographic involvement and do not correlate with changes in PFT’s Organ involvement • Lung – Fibrosis – Abscess/mycetoma – Bronchiectasis – Hemoptysis – Pulmonary hypertension • 20% at rest, 40% with exertion Organ involvement • Pulmonary fibrosis 20-25% patients – MMP 8 and 9 increased in BAL – Lower metalloproteinase 1 levels – TH2 IL 4, 10, 13, fibronectin, and CCL18 Sarcoidosis scadding stage IV Sarcoidosis with mycetoma Organ involvement • Skin/Bone – Not life threatening, but morbidity can be high… • Emotionally devastating • Nape of neck, back, extremities, face • 25% pts • Singular lesions or crops – Lupus pernio • Nose, cheeks, lips, ears • Erodes cartilage • May have bone involvement • Women > men • Usually extrapulmonary disease and chronic Organ involvement • Skin/bone – Erythema nodosum • 10% • Lasts 3 weeks • Septal panniculitis if biopsied – Neither confirms nor negates diagnosis of sarcoidosis Organ involvement • Liver and Spleen – 10% – Cholestatic syndrome (infrequent) – Blacks twice more likely than whites – Cirrhosis, portal hypertension, hepatic failure < 1% Organ involvement • CNS • 25% at autopsy, 10% with symptoms – Cranial nerve palsies – Headache – Ataxia – Cognitive dysfunction – Weakness – Seizures • Precede diagnosis in up to 74% • Solitary manifestation 10-15% Organ involvement • Ophthalmologic – Eye and Adnexa involved 20-80% – Anterior uveitis most common manifestation; 65% • Glaucoma, Vision loss (chronic) – Posterior uveitis 30% • Usually accompanied by CNS involvement Organ involvement • Cardiovascular – Cardiac granulomas 25% autopsy, 5% symptoms • LV free wall followed by IV septum – Conduction system – Manifested as cardiomyopathy, tachy/bradyarrythmias • Palpitations, syncope, death – Endomyocardial biopsy yield < 20% Organ involvement • Renal – Hypercalciuria 40% – Hypercalcemia 10% – Nephrolithiasis 10% • Sarcoid granulomas contain 25-hydroxyvitamin D-1ahydroxylase1,25 hydroxyvitamin D • Renal failure more likely due to intrarenal calcinosis than granulomatous nephritis Organ involvement • Bone and Joints – Lesions scattered throughout skeleton – Confused with metastasis – Lupus pernio – Arthralgias more common than frank arthritis Diagnosis of Sarcoidosis • • • • • Clinical Presentation Laboratory Radiology Histology PFT’s Clinical findings • CXR during routine screening exam • Fatigue, night sweats, weight loss • Lofgrens syndrome – Arthritis (usually medium joint), erythema nodosum, hilar lymphadenopathy – Good prognosis Diagnosis • Clinical, radiographic findings, and histology – Non-caseating granulomas in the absence of organisms or particles (AFB, Fungi, Berylium) • Unless Lofgrens syndrome • Bronchoscopic TBBx ~85% yield • EBUS TBNA ~82% yield • Kviem Siltzbach preparation (not used anymore) True positives > 50%, false positives near 0 • Response to CS does not = Sarcoidosis Radiology • CXR is usually suggestive – Scadding stages do not reflect chronology of disease • CT not always needed, unless D/DX or road map for biopsy – PET CT esp if without lung involvement Radiology • Gadolinium cardiac MRI • PET CT Laboratory values • ACE controversy – Produced by granulomas – Elevated in 60% pts – Lacks sensitivity and specificity • PPV 84%, NPV 74% – Poor therapeutic guide Laboratory values • CSF – Non-specific lymphocytosis – 1/3 oligoclonal immunoglobulin bands • Difficult to differentiate from MS! Laboratory values • 24 hour urine excretion for calcium – Normal is 100-300mg/day (for normal diet) • If high, consider checking 1,25 vit D levels and iCA • Thiazide diuretics lower urine calcium levels PFT’s • • • • 65% Restrictive pattern with reduced FVC 50% concomitant obstruction 83% airway hyperreactivity 80% return to normal after two years ECG Treatment of Sarcoidosis • Organ involvement and derangement • Options for therapy Treatment • None at all unless organ function threatened or deranged • Prednisone 20-40 mg/day – Evaluate response in 1-3 months • + Reduce dose 5-15mg/day for 9-12 months • - Non-adherence, fibrosis, inadequate dose Treatment Treatment • Immunosuppressive/Cytotoxic drugs – Anecdotal or small sample size – MTX is best steroid sparring alternative – Hydroxychloroquine for hypercalcemia, skin, or neurologic involvement – Minocycline for skin Treatment • MTX – Structurally similar to folic acid, inhibits DHFR • Decreased synthesis of thymidylate, purine nucleotides, amino acids – Does not penetrate CNS • Can be given intrathecally – Myelosuppression, hemorrhagic enteritis, neurotoxicity, pneumonitis, hepatotoxicity, alopecia • Toxic effects reduced by co-administration of folinic acid Treatment • Thalidomide, pentoxyfylline, Infliximab, Etanercept – Suppress TNF-a • • • • case reports for refractory disease Hypersensitivity rxn’s, headache, serum sickness Sepsis Development of malignancy Treatment • Hydroxychloroquine – Removes excess Fe stores from liver • Decreases DNA and RNA synthesis – Decreases leukocyte chemotaxis – Decreases T-lymphs response to mitogens – Dermatitis, myopathy, ***Irreversible retinal degeneration – Ophthalmology eval Q 6 months Treatment • Transplant – 3% of all lung – 1% of all heart and liver – Sarcoidosis can re-occur in allografts Sarcoidosis Prognosis • 2/3 remission within a decade of diagnosis • 50% remission within three years • 1/3 unrelenting disease with organ impairment • Relapse after one or more years of remission is uncommon • <5% Die – Respiratory failure, cardiac, neurologic involvement Sarcoidosis Management • • • • Screening Complications of disease Complications of therapy When to refer