46 F Fitzpatrick type V skin, emigrated from Sri Lanka (1978) via Zambia (1992), married, 2 children, daycare worker. RFR: bilateral ankle/knee pain, night sweats, fever x 2½ weeks. PMH: Type 2 Diabetes No known microvascular disease; + macrovascular Glyburide 5 mg po bid; previously metformin. Coronary Artery Disease CCS I angina; silent MI’s x 2 detected on EKG. Cardiac catheterization 95% LAD lesion (Feb 22/02). ECASA 81 mg po qd; Nitro patch 0.6 mg qd. Reactive Airways Disease Hysterectomy Ovaries preserved. Hypertension Diltiazem 300 mg po qd Hypercholesterolemia Pravachol 20 mg po qd HPI: Jan 02 Noted by GP to have dropping Hgb; placed on iron. Feb 22 cardiac catheterization; persistent pain in right groin. Feb 24 fever and right knee pain with swelling. Feb 28 bilateral knees and ankles. March 1 seen in ER; dopplers -ve, increased WBC and treated with Keflex x 10 days. March 14 progression to inability to ambulate; repeat Dopplers –ve; Painful R elbow. Knee tap: WBC 1089; 70% Neuts; 19% lymphs; 11% Monos; no growth. Sent home on Indocid. March 16 continued fever, painful joint involvement, admitted. Physical Examination: – Unwell looking moderately obese woman in some respiratory distress. BP 120/70, p88R, resps 32, O2 sat 98%, T38 Bilateral conjunctivitis. Axillary and inguinal lymphadenopathy (1-2 cm, soft, mobile, non-tender). Bibasilar early inspiratory crackles. Dullness at bases. Right Dupuytren’s contracture Hepatomegaly 18-19 cm; no splenomegaly. Peripheral oedema Bilateral knee effusions, stress tenderness both ankles; Right elbow held in flexion. Hyperpigmented, indurated nodules on dorsum of right foot and pulp spaces of RMT #2 and #3. Laboratory Investigations: Hemoglobin 87 HCT 0.252; MCV 77.4; RDW 15.4 Fecal occult blood negative. Ferritin 521; saturation 0.05; TIBC 37; iron 2 Hemoglobin A2 0.025; no hemoglobin H. Blood film – hypochromasia, few rouleaux. WBC 14.9 Neutrophilia 12.7 (Left shift); Eosiniphilia 0.44. No urine eosinophils. CD4:CD8 Platelets 506 ESR 137 Haptoglobin 5.6; fibrinogen 6.98, thrombin 11.4 INR 1.35; Albumin 18. Creatinine, BUN, transaminases, Electrolytes, Ca, Mg, P04 normal. LD 250 HbA1C 0.077 Serum immunoelectrophoresis normal; globulins elevated 39. Urinalysis benign Repeat R knee taps: 16/03 – 2250 WBC; 51%N; 49%L (yellow, cloudy). 23/03 – 1911 WBC; 48%N; 29%L; 23%M (yellow, cloudy). Pertinent Laboratory Negatives: ANA, RF, ANCA. C3, C4 normal CK normal HbSAg negative; Monospot –ve; Rubella immune. HIV negative Tb skin test negative; no anergy panel performed. Blood Cultures x 4 (extended incubations) Right Knee fluid cultures x 3 (extended incubations). Urine Cultures x 2 Tissue Culture Skin lesion from Right foot (extended incubations) Imaging Studies: – Xrays: Cardiomegaly (CXR); Right knee effusion (RKX). – Arteriogram: No pseudoaneurysm. – CT thorax: Left aortic arch nodes up to 1.4 cm; bilateral axillary nodes 1cm; increased linear patchy opacities in bilateral lung peripheries (?pneumonitis vs BOOP); bilateral small pleural effusions. – CT Abdo/pelvis: No groin hematoma; Bilateral inguinal nodes 1.5 cm; Right hip effusion; trace of ascites. – Abdo U/S: Hepatomegaly (18.5 cm), moderately echogenic. – MRI Right leg: Subcutaneous oedema in soft tissues; high T2 signal in all muscle groups (?cellulitis/myositis?). Normal bone marrow and cortex. – Repeat Dopplers (21/03): Negative for DVT. – EKG: NSR; old inferior and anterior infarcts. – Echo: Grade I LV; no vegetations; no regurgitant valves. Tissue Biopsies: – Inguinal Lymph Node: Aspirate Pending. – Skin Lesion Right Foot: Predominanly lobular panniculities without vasculitis. Small granulomas without caseation are present within the fat lobules. Both neutrophilic and lymphocytic infiltrates. GMS, PAS and modified Warthin-Starry stains negative for fungal and mycobacteria. No foreign material or crystals on polarized light. Mostly Septal With Vaculitis Venules: Leukocytoclastic vasculitis Veins: Superficial thrombophlebitis Arteries: Cutaneous polyarteritis nodosa Mostly Lobular With Vasculitis Venules: Erythema nodosum leprosum Lucio’s phenomenon Neutrophilic pustular panniculitis associated with rheumatoid arthritis. Mostly Septal Without Vasculitis Lymphocytes/Plasma Cells: With granulomata – necrobiosis lipoidica No granulomata – scleroderma Arteries: Erythema induratum of Bazin Crohn’s Disease Granulomatous infiltrate: Mucin – subcutaneous granuloma annulare Fibrin – rheumatoid nodule Cholesterol clefts – necrobiotic xanthogranuloma None of above but has radial granulomas – Erythema nodosum Mostly Lobular Without Vasculitis: Few or No Inflammatory Cells: Sclerosing panniculitis Calciphylaxis Oxalosis Sclerema neonatorum Lymphocytes Predominate: Cold panniculitis Lupus panniculitis/Lupus profundus Panniculitis in dermatomyositis Neutrophils Predominate: Pancreatic panniculitis Ά1-antitrypsin deficiency Infective panniculitis Factitial panniculitis Histiocytes Predominate: Subcutaneous sarcoidosis Traumatic panniculitis Lipoatrophy/Post-steroid panniculitis Infective panniculitis Factitial panniculitis Subcutaneous fat necrosis of the newborn Gout panniculitis Crystal-storing histiocytosis Cytophagic histiocytic panniculitis Postirradiation pseudosclerodermatous panniculitis. 46 F Multisystem Disease: Skin: Lobular panniculitis without vasculitis with non-caseating granulomata and negative stains/cultures. Joints: bilateral knees, ankles, right hip. Lung: Linear opacities and small pleural effusions. Lymphatics: para-aortic, axillary, inguinal. Muscle: Diffuse myositis both legs. Liver: Hepatomegaly. Ocular: Conjunctivitis, sicca Fever Acute Phase Reactants, WBC, L-shift, mild eosinophilia. Normocalcemic SARCOIDOSIS Sarco = flesh; Eidos = like; Osis = condition Multisystem disorder of unknown origin characterized by the accumulation of lymphocytes and mononuclear phagocytes that induce the formation of noncaseating epithelioid granulomas with secondary derangement of normal tissue or organ anatomy and function. Acute sarcoid = less than 2 years. Chronic sarcoid = lasting longer than 2 years. Diagnosis is one of exclusion: – Requires 3 criteria – 1) Compatible clinical or radiologic picture, or both 2) histologic evidence of non-caseating granulomas 3) Negative special stains and cultures for acid-fast bacilli, fungi and bacteria. Epidemiology: Incidence peaks in winter and early spring. Women greater incidence. African ethnicity greater incidence. More common in non-smokers. Immunology: ?local presentation of antigen by macrophages to CD4 (T H1) phenotype expressing ά/β T-cell receptors resulting in both cellular redistribution of immune cells as well as in situ proliferation. Up regulation of E-selectin on endothelial cells, compartmentalized CD4 cells, increased IL-2, -8, TNF-ά, IFN-γ induces granuloma formation (epithelioid giant cells). Rim of CD8+ cells. As granuloma matures, switches to TH2 (IL-4) profile causing a fibroproliferative phase. Etiology: Speculative – Familial cases – positive association with HLA-1, -B8, -B13, -DR3 and –B27. Rare autosomal dominant granulomatous syndrome (Blau Syndrome – 16p12-q21) – lacks pulmonary involvement. High rate of detection of HHV-8 in sarcoid tissue. Unlikely mycobacterial (gets better with steroids; no reduction with BCG; anti-tb meds ineffective). Clay, talk, pine pollen, oxalosis, beryllium can cause similar picture. Sarcoid – Cutaneous manifestations • 25-37% • Often occuras at onset of disease. • Does not show correlation with extent of disease in general. • Skin lesions – more likely to have lymphadenopathy & hepatosplenomegaly than if no skin lesions. • May portend prognosis. • Classified as: • Specific (lesions contain granulomas) • Non-specific (lesions are reactive processes and do not contain granulomas). Specific Lesions: Maculopapular sarcoid Nodular sarcoid Plaque sarcoid Darier-Roussy Nodules (Subcutaneous) Scar sarcoid Lupus pernio Acquired ichthyosis Ulcerative sarcoid Rare variants: Psoriasiform, Hypopigmented, Verrucous, folliculitis, Eruptive, Lichenoid, Erythrodermic, Cicatricial alopecia, Erythematous plaques of palms and soles, Nodular fingertip lesions, Unilateral lower extremity edema, granulomatous cheilitis, palmar erythema, morpheaform, angiolupoid, perforating, lupus-erythematosus-like, umbilicated, rosacea-like syndrome. < TD> Non-specific Skin Lesions Erythema nodosum Lofgren’s Syndrome: EN + bilateral hilar adenopathy +/migratory polyarthritis, fever and iritis. Good prognosis (83% remit in 2 years). Calcifications Prurigo Erythema multiforme Clubbing Onychodystrophy +/- underlying bone cysts Subungual hyperkeratosis/onycholysis. Constitutional Symptoms 33% fever, weight loss, fatigue +/- night sweats Ocular 22-50% Granulomatous uveitis (anterior (80%)>posterior) Uveitis – acute or chronic (adhesions) Keratoconjunctivitis, retinal hemorrhages, band keratopathy, proptosis. Peripheral Lymphadenopathy 75% Cervical, axillary, epitrochlear and inguinal Upper Respiratory Tract 5-20% Nasal granulomas. Laryngeal involvement 5%. Lungs >90% dyspnea, dry cough, chest pain (intensified after alcohol), hemoptysis, asymptomatic. 4 Stages: Stage 0: normal Stage I: bilateral hilar lymphadenopathy with right paratracheal adenopathy without pulmonary infiltrates. Stage II: bilateral hilar lymphadenopathy with pulmonary infiltrates. Stage III: pulmonary infiltrates without hilar adenopathy. Stage IV: end-stage fibrosis, bullae and honey-combing. Heart 5% - conduction disturbances; MI; pericardial disease; sudden death (27% on autopsy); cor pulmonale. Liver 20% hepatomegaly (autopsy granulomas 63-87%) Usually asymptomatic Spleen 15% splenomegaly; usually silent (50% on autopsy) Kidneys 4-40% From hypercalcemia/hypercalciuria; granulomatous infiltration of the renal parenchyma, glomerular disease or renal arteritis secondary to granulomas. Salivary Glands 6% parotidomegaly; subclinical 50% (but usually only with hilar adenopathy); sarcoidal ranula; tongue, tonsils. Rheumatologic 25-39% joint involvement; 2 forms – acute and chronic (<6 months). May precede other manifestations by years Knees > ankles > elbows > wrists > small joints of hands (typically 2-6 joints). Periarticular swelling > effusions Synovial fluid often non-inflammatory Tenosynovitis and heel pain may occur Chronic: knees, PIPs (associated with chronic cutaneous sarcoid lesions). transient or chronic dactylitis. Cystic lytic lesions often noted in middle & distal phalanges of hands; trabecular changes that give the bone a honeycomb appearance; always associated with chronic skin lesions. Muscular Progressive proximal muscle weakness; myopathic pattern EMG, increased CpK. Neurological 5% Mononeuritis multiplex, Guillian-Barre, pure motor, pure sensory polyneuropathies, meningitis, seizure, arachnoiditis, myasthenia gravis-like symptoms, myelopathy. Uhthoff phenomenon reported (visual loss after exposure to heat). CNVII > but any cranial nerve. Endocrine Pituitary & hypothalamus – diabetes, hyperthyroidism. May see elevated prolactin. Intermittent hypercalcemia – 17-19%. Laboratory: Anemia 5% Leukopenia – reflects bone marrow involvement – 28% Eosiniphilia 24-34% ESR 66%; Elevated haptoglobin 40%. Hypercalcemia (increased intestinal Ca absorption due to production of (3H)1,25(OH)2D3 – 19% ACE 60% (false + DM, alcoholic liver disease, Hep C, tuberculosis, leprosy, lymphoma, hyperthyroidism, Whipple’s, PBC, silicosis, histoplasmosis, berylliosis, Gaucher’s); serum lysozyme, B2-microglobulins. Cutaneous anergy 66% CD4:CD8 – normal 1.8:1; low-activity sarcoid 1.4:1; highintensity alveolitis 0.8:1. Hypergammaglobulinemia 50% Bronchoalveolar lavage – fluid lymphocyte count >7% lymphocytes; CD4/CD8 >3.5. 67Gallium scan may demonstrate panda or lambda signs (from parotid & lacrimal gland granuloma gallium uptake [panda] and bilateral hilar lymph node involvement [lambda]). Kviem-Siltzbach test (90% with hilar adenopathy). Sarcoidosis Syndromes: Lofgren’s Syndrome Hilar lymphadenopathy, erythema nodosum, migratory polyarthritis, fever, iritis. Darier-Roussy Type Presence of subcutaneous non-painful nodules. Heerfordt-Waldenstrom Syndrome Fever, parotid enlargement, anterior uveitis, facial nerve palsy (can get lethargy, papilledema, meningism) Mikulicz’s Syndrome Bilateral sarcoidosis of the parotid, submandibular, sublingual and lacrimal glands. Treatment: – 60% experience spontaneous resolution (83% with acute). An additional 10-20% have resolution with steroids. Major goal: prevent fibrosis. Steroids first line: – Help prevent fibrosis. Scarring cutaneous lesions Hypercalcemia Severe lung disease Liver disease Cardiac inflammation Posterior uveitis Neurosarcoidosis Severe sarcoidosis of other organs Rheumatology Guidelines: Prednisone 0.5 mg/kg/day; single daily dose, tapered by 5 mg q2 weeks until at 0.15 mg/kg/day, maintained for 4-8 months, then tapered off completely. Follow PFTs. Steroid sparing: Methotrexate. Arthritis: colchicine, salicylates. Dermatology Guidelines: Systemic Sarcoidosis: Prednisone 1 mg/kg/d x 4-6 weeks followed by a slow taper over 23 months. Hydroxychloroquine 2-3 mg/kg/day x 12 weeks (30-50% success). MTX 15 mg/week in 3 divided doses at 12 hour intervals x 9-11 months (94% success). Thalidomide (TNF blocker) Infliximab (Ab against TNF-ά); Etanercept (receptor for TNF). Cutaneous Sarcoidosis: Superpotent topical corticosteroids (+/- occlusion). Intralesional triamcinolone qmonthly Intralesional chloroquine (50 mg/mL monthly) Minocycline 200 mg qd; doxycycline 100 mg bid Carbon dioxide laser Pulse dye laser Allopurinol 100-300 mg qd for 4 weeks Thalidomide 200 mg/d x 2 weeks followed by 100 mg/d x 11 weeks, then 100 mg every other day. PUVA Oral isotretinoin 1 mg/kg/day x 8 months. Systemic steroids, hydroxychloroquine, MTX. Basic Sarcoidosis Work-up: History/PE CBC, BUN, Cr, LFTs, electrolytes, Ca. Urinalysis ACE levels CXR PFTs (spirometry, volumes, diffusion measurements) Tuberculin test with anergy panel. Ophthalmologic examination with both slit-lamp and fundus. Histology.