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* For Best Viewing: Open in Slide Show Mode Click on icon or From the View menu, select the Slide Show option * To help you as you prepare a talk, we have included the relevant text from ITC in the notes pages of each slide © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Terms of Use The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-forprofit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets constitutes copyright infringement. © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. in the clinic Sarcoidosis © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Who is at risk? Varying incidence among ethnic groups African American lifetime risk: 2.4% White American lifetime risk: 0.85% More common if Scandinavian, Irish, German, W. Indian descent Relatively rare if Japanese, Spanish, Portugese descent Family history: Familial clustering in 5%-19% of cases Age: >80% of cases present between ages 20-40 years Gender: marginally more common in women © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Is there a role for screening? Screening is not recommended Even for family members of an index case Due to… Variable prognosis No evidence early diagnosis affects prognosis © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What symptoms and clinical findings should prompt a clinician to consider sarcoidosis? Common signs and symptoms Cough (usually nonproductive) Fever and weight loss Chest pain (central substernal) Painful ankle swelling Painful red nodules on shins Eye pain or blurred vision Lung or thoracic lymph nodes almost always involved Lofgren syndrome: common presentation (fever, bilat hilar LAD, ankle swelling, erythema nodosum) Uveoparotid fever: hallmark presentation © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Figure 1. A patient with lupus pernio sarcoidosis Violaceous plaques and nodules on the cheeks, bridge of nose, and nares Lesions responded to treatment with prednisone and methotrexate © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Physical exam in suspected sarcoidosis Skin lesions: Erythema nodosum, lupus pernio, sarcoid lesions on old scars, tattoos (“Koebner phenomenon”) Parotid enlargement Lymphadenopathy Normal lung examination (usual) Hepatosplenomegaly Neurologic (especially VII nerve palsy): typically involves cranial neuropathies, neuroendocrine disease parenchymal brain disease, and peripheral, often small-fiber, neuropathy Eyes (red, painful): Ocular disease; uveitis, retinal vasculitis Cardiac: Any cardiac symptoms should raise suspicion (particularly syncope and palpitations, CHF symptoms) © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. CLINICAL BOTTOM LINE: Risk Factors and Clinical Features... More common in distinct ethnic groups Symptoms Protean systemic and/or organ-specific Can affect any organ system Characteristic presentations Fever } Bihilar lymphadenopathy Ankle swelling Erythema nodosum Lofgren syndrome Asymptomatic bihilar lymphadenopathy Ocular involvement: painful red eyes indicates uveitis Cutaneous symptoms: erythema nodosum, lupus pernio © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. How is sarcoidosis diagnosed? Do all suspected cases require biopsy? Diagnosis of exclusion! Diagnosis Generally Requires: o typical noncaseating granulomata on biopsy PLUS o exclusion of other causes of granulomatous inflammation (e.g., tuberculosis) Confident diagnosis only at 3-6 months follow-up: if evolves in typical manner © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. How is sarcoidosis diagnosed? Do all suspected cases require biopsy? Biopsy needed if: Presentation atypical (r/o cancer, TB, other infection) Systemic corticosteroids required Clinical course doesn’t stabilize or improve in 3-6 months Biopsy may not be needed if: Classical Lofgren syndrome, Heerfordt syndrome, or asymptomatic BHL (high likelihood self-limited disease) Biopsy of erythema nodosum lesions not helpful (shows panniculitis, not typical granuloma) © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. How is sarcoidosis diagnosed? Do all suspected cases require biopsy? Biopsy easily accessible sites preferentially: Unexplained skin lesions or peripheral LAD Otherwise: intrathoracic LAD or lung Transbronchial bx: yield up to 90% if radiographic infiltrates Mediastinoscopy bx – 100% yield, but more invasive Endobronchial endoscopic US – guided or TBNA options © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What imaging studies should be ordered in the evaluation of a patient with sarcoidosis? Chest x-ray Only routine imaging recommended Scadding staging system correlates with prognosis Not recommended for routine use: High-resolution CT Consider for atypical cases + differentiate from other conditions CT and PET scans Monitor disease activity, progression, treatment response © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Stages of sarcoidosis C A B D E © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Are pulmonary function tests useful in evaluating patients with sarcoidosis? Results often normal, even in parenchymal lung disease Most common abnormalities Restrictive ventilatory defect with reduced FVC Reduced DLCO Airflow obstruction with FEV1/FVC <70% seen in ≈16% Serial spirometry and measurement of DLCO can be useful for: following response to therapy following disease progression © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What additional investigations should be ordered? Complete blood count: anemia and leukopenia in >20% Renal function Serum calcium: hypercalcemia up to 10% 24-h urine test calcium levels: hypercalciuria up to 30% Liver function tests Tuberculin skin test Total immunoglobulins ECG: indicated in all patients Neuorosarcoidosis evaluation: if unexplained neurologic symptoms or seizures © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What other conditions should be considered in the differential diagnosis? Infectious causes of granulomatous disease Lymphoma, other cancers ANCA-associated vasculitis Coccidiomycosis (can present like Lofgren syndrome) Alternate causes of parenchymal pulmonary infiltrates Consider alternative diagnosis if… Age >40 years Weight loss >10% body weight Crackles on lung exam Tender lymph nodes Positive tuberculin skin test Asymmetrical BHL on chest x-ray © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. When is consultation required? Pulmonologist: All cases of suspected disease Ophthalmologist: All newly diagnosed cases Cardiologist: Possible or confirmed cardiac sarcoidosis Neurologist: Possible neurosarcoidosis © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. CLINICAL BOTTOM LINE: Diagnosis... Diagnosis of exclusion Definitive diagnosis requires 6 months follow-up Chest x-ray + eval for extrapulmonary involvement Clinical Dx: typical Lofgren syndrome, asymptomatic BHL Biopsy required? choose most accessible, least invasive site Differential diagnosis Cancer and infection, particularly lymphoma and TB © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Which patients with pulmonary sarcoidosis require treatment? Wait on treatment if symptoms are mild Disease often resolves or remains stable Withhold systemic treatment 3-6 months, if possible Use NSAIDs for EN or ankle arthralgias Use inhaled steroids for dry cough Treat persistent, severe or worsening pulmonary symptoms Use oral corticosteroids Avoid potentially toxic Rx if likely to resolve spontaneously Controversial: whether to treat asymptomatic patients with progression of pulmonary disease on chest x-ray © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Which patients with extra-pulmonary sarcoidosis require treatment? Treat promptly: disease involving critical organ function Active uveitis Cranial nerve abnormalities Pituitary or hypothalamic dysfunction Meningitis Seizures or other manifestations of CNS involvement Cardiac dysfunction or dysrhythmias from granulomas Also treat… Symptomatic hypercalcemia or interstitial nephritis Disfiguring facial lesions © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What is the role of nonsystemic steroids? Pulmonary parenchymal sarcoidosis Inhaled corticosteroids: adjunct therapy for bronchospasm or cough Efficacy is uncertain & routine use not recommended Mild ophthalmologic disease Topical steroids alone Skin lesions Topical or intralesional steroids To reduce size and prominence, but may thin skin Don’t use potent fluorinated steroids on face Rhino-nasal sarcoidosis Intranasal steroids © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What is the role of systemic steroids for the treatment of pulmonary sarcoidosis? Immunomodulatory therapy Effective but not FDA-approved for sarcoidosis Oral prednisone Consensus: start 20 – 40 mg / every other day Evaluate response after 1 to 3 months Continue therapy for ≥1 year (taper to lowest effective dose) Long-term use for sarcoidosis is controversial Use alternative if no response or intolerable SEs © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. When should nonsteroidal pharmacologic treatment be used for pulmonary sarcoidosis? Cytotoxic agent (methotrexate) or other immunosuppressant Use long-term only if induces unequivocal improvement Folic acid reduces myelosuppression with methotrexate Chloroquine or hydroxychloroquine Cutaneous or mucosal disease Control of hypercalcemia Those who with hyperglycemia on corticosteroids TNF inhibition with infliximab Progressive sarcoidosis (intolerant of non-responsive to steroids & cytotoxic agents) Cytoxan, chlorambucil, cyclosporine Severe progressive sarcoidosis refractory to steroids and less toxic immunosuppressive agents © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. How long should pharmacologic therapy be continued in pulmonary sarcoidosis? Initial therapy with prednisone: 9 to 12 months Periodically attempt to taper to lowest effective dose Frequently treatment is required for >2 years Life-long treatment may be needed if repeated relapse © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. How should extrapulmonary sarcoidosis be treated? Myocardial sarcoidosis Corticosteroids, tapering over months or years Consider steroid-sparing agents Facial nerve palsy or other neurologic disorders Prednisone, tapering over months or years Adding cytotoxic agent may improve response Posterior uveitis, lacrimal, and orbital sarcoidosis Systemic corticosteroids; IV methylprednisolone if vision threatened or changing rapidly Hypercalciuria and hypercalcemia Prednisone, tapering to lowest effective dose Alternative: hydroxychloroquine © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Which patients require life-long therapy? Patients with repeated relapse 80% relapse, often within 2 years of tapering corticosteroids 10 mg prednisone daily or every other day prevents relapse No evidence for similar long-term, low-dose cytotoxic agents © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What other pharmacologic therapies are available? Antimicrobial: bronchiectasis from chronic sarcoidosis Antifungal: hemoptysis associated with aspergilloma Vitamin D, calcium, nasal calcitonin, and bisphosphonates: osteoporosis related to steroid therapy NSAIDs: musculoskeletal symptoms and pain from EN Ketoconazole (600-800 mg/day): hypercalcemia Pulmonary hypertension therapy- Rx of unproven benefit and requires expert evaluation © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What nonpharmacologic interventions should be considered? Rehabilitation program for advanced lung disease Oxygen therapy for hypoxemia at rest or with exercise Vaccination for pneumococcal pneumonia and influenza Pacemaker or implantable defibrillator for cardiac sarcoidosis © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. Which patients should be referred for organ transplantation? Patients with… Severe functional impairment Severe end organ damage Progressive deterioration despite appropriate medical Rx Ideal time for lung transplantation is imprecise Refer before condition deteriorates to point when survival time is less than time on waiting list © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. How should sarcoidosis be monitored? Intensive longitudinal clinical surveillance for ≥ 5 years Track organ system involvement Regular spirometry; repeat oximetry to adjust oxygen Consider repeat chest imaging if clinical deterioration occurs Annual blood tests and EKG & Holter monitoringa Target signs and symptoms that frequently occur Those affecting pulmonary system, eyes, skin Refer patient to opthamologist Ocular involvement may be asymptomatic © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. When should patients with sarcoidosis be hospitalized? Respiratory failure Onset of cardiac symptoms (particularly syncope) Symptomatic hypercalcemia New or progressive neurologic disease Acute vision loss Acute renal failure Severe treatment side effects © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What is the prognosis of patients with sarcoidosis? Resolution: ≥50% Persistent fibrosis: 25% May cause symptoms but no progression Chronic progressive disease: 25% Fatal: 5% (usually pulmonary/cardiac impairment) Predictors of good prognosis EN; stage 1 CXR; asymptomatic presentation Predictors of poor prognosis Lupus pernio; cardiac, neurologic, or bone involvement; nephrolithiasis © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. What education do patients with sarcoidosis require? Information on organ involvement Information on symptoms to be alert for Treatment risks and possible side effects Measures to counteract toxicity of medications Prognostic information © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. CLINICAL BOTTOM LINE: Treatment... Observe for 3-6 months before therapy, if possible Spontaneous remission can occur 1st-line Rx, when warranted: prednisone 9-12 months Treat promptly Symptomatic neurologic, cardiac, or eye sarcoidosis or symptomatic hypercalcemia Treat mild skin or eye disease with topical corticosteroids Use alternative Rx: disease refractory or toxicity unacceptable Methotrexate Consider infliximab if intolerable SEs or continued disease progression © Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1.