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Case Report A 44-year-old African-American woman presented with complaints of worsening dyspnea and chest discomfort for several months Review of systems revealed long-standing dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea. Physical exam was significant for JVD, decreased breath sounds in the lung bases, tachycardia, and lower extremity edema to the knees. Notably, the exam was lacking rales and an S3 gallop. Differential Diagnosis? Chest radiograph revealed an enlarged cardiac sillouette and bilateral pleural effusions (Figure 1). Bedside echocardiography revealed a pericardial effusion (Figure 2). Data Laboratory findings included a macrocytic anemia (MCV 114.6 fL, HCT 22.2%) with a high corrected reticulocyte count (14.5) and normal B12 and folate levels. Auto-immune hemolytic anemia was confirmed by a decreased haptoglobin (<14 mg/dL), an elevated LDH (1411 U/L), and the detection of a warm IgG autoantibody. ANA testing revealed a 160 titer and an anti-DNA DS level of 101 IU. Right heart catheterization revealed tamponade physiology. Discussion This case represents a rare presentation in a patient with SLE. The patient's symptoms were secondary to both tamponade and hemolytic anemia, perhaps two of the most morbid of the diagnostic criteria. The eventual diagnosis may have been delayed were it not for careful attention to the physical exam and prompt diagnostic testing to validate those findings. Standard treatment for congestive heart failure based solely on reported symptoms would have greatly increased her morbidity, and could have been fatal. This case emphasizes the importance that our history AND physical examinations guide our diagnostic and therapeutic measures. Systemic Lupus Erythematosus July 13, 2009 Julie Schwartzman, MD Associate Program Director, Rheumatology Director of Arthritis and Lupus Clinics SLE: Subsets Discoid LE Drug Induced SLE Neonatal SLE Antiphospholipid Syndrome SLE Benign, incomplete Subacute cutaneous, ANA negative, Ro + lupus DNA positive, complement fixing, hypocomplementic Drug Induced SLE Hydralazine Procainamide Minocycline (ANCA+) Chlorpromazine Isoniazid Penicillamine Methyldopa Interferon-alpha SLE: Demographics Affects .5 million (.2%) vs 1.5 million (.6%) of US population (epidemiologic vs LFA random digit dialing telephone survey) Female:Male ratio of 10:1 Closer to 2:1 during childhood and after menopause, suggesting hormonal influence Disease in males is often more severe 70% of SLE: females between ages 15-45 African American to Caucasian ratio 3:1 Highest prevalence in Afro-Caribbean females 1:250 Demographics Genetic factors HLA-A1, B8, Dr3 - C4A null genes - Fc receptor polymorphisms -gene linked to chromosome 1 Environmental factors - Concordance for monozygotic twins is 30% (70% of genetically identical twins will not share the disease) Child of SLE mother risk of SLE 1:15 (7%) ANA positive in 5-20% of population. 10 times more likely to have false positive ANA than disease Null alleles that cause a deficiency of one of the early complement components — C1q, C2, or C4 — are a strong risk factor for lupus. Family studies have identified genes that are more likely to occur in patients with lupus than in their healthy relatives. Many of these genes encode components of the immune system. SLE: ETIOLOGY AUTOANTIBODY PRODUCTION GENERATION OF CIRCULATING IMMUNE COMPLEXES EPISODIC COMPLEMENT ACTIVATION SLE: Pathobiology Autoantibodies (AIHA, AITP, Anti-neuronal antibody, APS) Immune complex disease (microangiitis and vasculitis) Neutrophil and endothelial cell adhesive interaction with leukoaggregation Thrombophilia: Antibody mediated thrombosis in secondary APLS with micro and macrovascular noninflammatory occlusion SEROLOGY ANA (Titer and pattern: diffuse, speckled, rim, nucleolar, centromere) double stranded-DNA- highly specific, correlates with disease activity Sm- highly specific for SLE, no correlation with disease activity RNP- also seen in MTCD/UCTD Ro (SS-A)/La (SS-B)- neonatal lupus, SS, subacute cutaneous lupus, photosensitivity (Ro) C3 C4 POSITIVE ANA SLE Non SLE CTD (RA, SS, PSS, CREST, DM/PM) DRUG-INDUCED NORMALS (FALSE POSTIVE) LYMPHOPROLIFERATIVE DISORDER CHRONIC INFECTION (HIV, Leprosy) 1982 ACR Classification Criteria Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Immunologic disorder Anti-nuclear antibody Require four simultaneously or serially Mucocutaneous Manifestations * Malar rash * Discoid rash * Photosensitivity *Oral ulcers Vasculitis Periungual erythema Alopecia (*classification criteria) “Butterfly” or Malar Rash 1. Malar rash: Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds Discoid Rash 2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions IgG Deposition at Dermo-epidermal Junction in Discoid Lupus Photosensitivity “allergic to the sun” 3. Photosensitivity: Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation Oral Ulcers 4. Oral ulcers: Oral or nasopharyngeal ulceration, usually painless Subacute Cutaneous Lupus Erythematosus Left, Papulosquamous lesions are characterized by erythematous scaling papules and plaques that resemble psoriasis. The distribution in light-exposed areas suggests photosensitivity. Right, The annular polycyclic lesions have an erythematous, slightly scaling border with central clearing. Cutaneous Vasculitis with Infarcts Alopecia Arthritis 5. Arthritis: Non-erosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion 80% Single or multiple joints Reducible deformities Pain may be out of proportion with appearance Jaccoud’s arthritis Serositis 6. Serositis a) Pleuritis--convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion OR b) Pericarditis--documented by ECG or rub or evidence of pericardial effusion Peritonitis - diffuse abdominal pain, nausea and vomiting, ascites is rare Lupus Serositis Pleuritis Chest X-ray Peritonitis Abdominal X-ray Pericarditis Chest X-ray Renal 7. Renal disorder a) Persistent proteinuria greater than 0.5 grams per day OR b) Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed Lupus Nephritis (WHO Classification) I Normal glomeruli a) Nil by all techniques b) Normal by light but deposits on EM or IF II Mesangial nephritis III Focal glomerulonephritis IV Diffuse proliferative glomerulonephritis V Membranous nephritis VI Membranoproliferative glomerulonephritis VII Advanced sclerosing glomerulonephritis Lupus Nephritis (light microscopy) Mesangial nephritis Diffuse proliferative glomerulonephritis Focal glomerulonephritis Membranous glomerulonephritis Lupus Nephritis (immunofluorescent staining) Staining with anti-Ig FITC Lupus Nephritis (Electron Microscopy) A – subepithelial deposits B – intramembranous deposits C – basement membrane D – epithelial foot processes Neurologic disorder 8. Neurologic disorder a) Seizures--in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance OR b) Psychosis--in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance Neuropsychiatric Lupus Seizures Psychosis Headache Coma Dementia Aseptic meningitis Chorea Ataxia Depression Cranial neuropathy Peripheral neuropathy Mononeuritis multiplex Stroke syndrome Transverse myelitis SLE Brain gross specimen photomicrograph fibrin thrombus leukoaggregation Left, Gross specimen reveals multiple cerebral infarctions. Right, Photomicrograph demonstrates occlusion of small vessels by both leukoaggregation (A) and a fibrin thrombus (B) as the causes of the infarctions. Vasculitis was not found Hematologic Manifestations 9. Hematologic disorder a) Hemolytic anemia--with reticulocytosis OR b) Leukopenia--less than 4,000/mm on 2 or more occasions OR c) Lymphopenia--less than 1,500/mm on 2 or more occasions OR d) Thrombocytopenia--less than 100,000/mm in the absence of offending drugs 10. Immunologic disorder a) Anti-DNA OR b) Anti-Sm OR c) Positive finding of antiphospholipid antibodies 11. ANA: in the absence of drugs known to be associated with "drug-induced lupus" syndrome Classification Criteria 4/11 criteria >90% sensitivity and specificity Criteria designed for classification, especially for entrance into laboratory studies and clinical trials but not for diagnosis For mild and early disease may not be as sensitive Examples: patient with malar rash and +ANA patient with GN, +ANA and elevated dsDNA Abs Mortality 90% survive 5 years, 80% 10 years Worse if renal disease AA more aggressive and treatment resistant disease Bimodal distribution of etiology Early: disease activity and infection Late: disease activity, ESRD, arteriosclerotic and thromboembolic CAD in SLE Risk is 10-times increased in SLE patients, 50-times increased in SLE pts 35-44 yrs old Factors contributing to increase: Steroid therapy Hyperlipidemia HTN Smoking Coagulation abnormalities Homocystinemia Obesity Vasculopathy from Immune Injury>>increased circulating endothelial cells activation *All modifiable risk factors are important targets of intervention by both PMD and Rheum MD APLS The anti-phospholipid Ab syndrome (APS) is vascular thrombosis and/or pregnancy morbidity developing in persistently anti-phospholipid antibody (aPL)-positive individuals. The most commonly used aPL tests are the lupus anticoagulant test, the anti-cardiolipin antibody ELISA, and/or the anti- b2-glycoprotein I ELISA. APS is present if more than 1 clinical and 1 lab criteria met ANTIPHOSPHOLIPID SYNDROME Sapporo Criteria, Sydney revision Miyakis, J Thromb Haemost. 2006 4:295-306 Clinical • Thrombosis: one or more confirmed episodes: venous, arterial or small vessel (exclude other causes, male 55+ female 65+) • Confirmed by imaging or Doppler or histopathology and without evidence of inflammation in vessel wall on histopathologic confirmation ANTIPHOSPHOLIPID SYNDROME Sapporo Criteria, Sydney revision Miyakis, J Thromb Haemost. 2006 4:295-306 Clinical • Pregnancy: – one or more unexplained deaths >10 wk – one or more pre-eclampsia/placental insufficiency < 34 wk – 3 or more unexplained consecutive spontaneous abortions <10 wk – exclude other causes ANTIPHOSPHOLIPID SYNDROME Sapporo Criteria, Sydney revision Miyakis, J Thromb Haemost. 2006 4:295-306 Laboratory • Medium/high IgG or IgM aCL, b2GP1 dependent on 2+ occasions 12 wk apart • LAC 2+ occasions 12 wk apart –prolonged PL-dependent screening test –failure to correct with mixing –shortening with excess PL –exclusion of other coagulopathies ANTIPHOSPHOLIPID SYNDROME Sapporo Criteria, Sydney revision Miyakis, J Thromb Haemost. 2006 4:295-306 aPL-associated findings (individual diagnosis) • cardiac valve disease • livedo reticularis • thrombocytopenia • nephropathy Current Recommendations Vascular Thrombosis prevention {Asymptomatic aPL + No treatment} Venous thrombosis Warfarin INR 2.0-3.0 Arterial thrombosis Warfarin INR 3.0 Recurrent thrombosis Warfarin INR 3.0-4.0+ASA CAPS Anticoagulation + corticosteroid + IVIG or plasmapheresis Erkan, Lockshin, Rheum Dis Clin North Am 2006;32:129-48 Lim, Crowther, Eikelboom, JAMA 2006;295:1050-1057 ANTIPHOSPHOLIPID ANTIBODY SYNDROME PREGNANCY ASA 81 mg, Prednisone 20-40 mg, sc Heparin, sc LMWH (IVIG) CAPS (Catastrophic APS) Heparin, steroids, pheresis, IVIG, cytoxan SLE: CLINICAL FEATURES CONSTITUTIONAL CUTANEOUS JOINTS SEROSAL CYTOPENIAS RENAL NEUROLOGIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME TREATMENT Sunscreen Topical Steroids NSAIDs Antimalarials STEROIDS CYTOTOXICS Calcium, Vitamin D, Folate supplementation INFLUENZA VACCINE (annual) PNEUMOCCOCAL VACCINE (decade) Treatment Avoid possible disease triggers: sulfa Rx, sun, high estrogen Prevent atherosclerosis Prevent OP Prevent clots in patients with APL Ab (not already on AC): ASA, avoid unnecessary surgeries and vascular catheterizations, avoid exogenous estrogen Treat infections promptly Treat fatigue: r/o hypothyroidism, metabolic disturbances, myopathy, anemia, depression Use of Steroid Therapy ACUTE LUPUS CRISIS ACTIVE NEPHRITIS ACUTE ACTIVE CNS ACUTE CYTOPENIAS (AIHA,AITP) REFRACTORY SEROSITIS VASCULITIS SEVERE CONSTITUTIONAL (fever, fatigue, wgt loss, synovitis, anemia) CYTOTOXIC THERAPY Azathioprine (Imuran): purine inhibitor, cytotoxic, decreases cell proliferation < USES: nephritis, cytopenia> Methotrexate: inhib DHFR and DNA synthesis suppressing lymphocyte proliferation, also down regulates inflammatory pathways by increasing extracellular Adenosine (potent neut inhibitor) <USES: articular> Leflunomide (Arava): inhibits pyrimidine synthesis Steroid sparing (constitutional, serositis, immune cytopenias) Articular Mycophenolate mofetil (cellcept): inhibits lymphocyte production and migration, <USES: Nephritis> Cyclophosphamide (cytoxan): alkylates DNA USES: Nephritis, CNS, immune cytopenias, vasculitis CONSTITUTIONAL SYMPTOMS Reassurance Rest/exercise NSAID Antimalarials Steroids (e.g. Prednisone < 0.25 mg/kg/day) TCA/SSRI/Behavioral or cognitive therapy Referral to Lupus Foundation, Support Groups CUTANEOUS Sun avoidance/sunblock Steroids (topical and intralesional) Hydroxychloroquine (plaquenil) Chloroquine (aralen) Quinacrine (atabrine) Dapsone Retinoids (isotretinoin) Clofazamine Azathioprine ARTICULAR NSAID Antimalarials (HCQ, CQ) Methotrexate Azathioprine Leflunomide Steroids (e.g. Prednisone < .25 mg/kg/day) HEMATOLOGIC (AIHA/AITP) Steroids (e.g. Prednisone 1 mg/kg/day; Decadron 40 mg day x 4 days) Danazol Dapsone Vincristine Cyclophosphamide Intravenous immunoglobulin (IVIG) Pheresis Rituximab Splenectomy CSF (Epogen, Neupogen) SEROSITIS NSAID (e.g. Indomethacin) Antimalarials (HCQ, CQ) Steroids (e.g. Prednisone < .5 mg/kg/day) Aspiration VASCULITIS Steroids (e.g. Prednisone 1 mg/kg/day) Cyclophosphamide Plasmapherisis (especially TTP/HA) Intravenous immunoglobulin (IVIG) Nephritis Goals: To induce remission with a stringent immunosuppressive tx combining moderate to HD GC and a cytotoxic drug, given for short period of time (3-12 mo, induction phase) To achieve a response and To maintain this response in the long term by prescribing a safer immunosuppressive Rx for a longer period (5-10yrs, maintenance phase) Definition of Response, Nephritis Fair clinical response: 50% reduction of proteinuria and stabilization of renal function VS: Complete remission – absence of proteinuria and completely nl UA Only 5-20% SLE pts experience complete remission in 6mo Current Management of Lupus Glomerulonephritis Steroids oral daily or QOD Prednisone Pulse solumedrol Pulse cytoxan Cyclophosphamide Azathioprine Cyclosporine Methotrexate Plasmapheresis synchronized Intravenous gammaglobulin Mycophenolate mofetil 2 chlorodeoxyadenosine Fludarabine Recombinant human DNAse ACE inhibitors/ARB Low protein diet Combination pulse solumedrol plus cytoxan MMF Sequential:pulse cytoxan to MMF or imuran NERVOUS SYSTEM Steroids (e.g. Prednisone 1 mg/kg/day) Cyclophosphamide IVIG Psychotropics (e.g. Haloperidol) TCA/SSRI NOVEL THERAPY Immunoablative chemotherapy with or without autologous stem cell transplant B-cell toleragen (Single signal anergy) B cell depletion (Rituximab/antiCD20, Epratizumab/antiCD22) Complement inhibitors (anti-C5, C5aRecptor antagonists, soluble CR1) Adhesion molecule inhibitors (anti-ICAM 1 antiCD11b/CD18) Co-stimulatory pathway inhibitors (CTLA-4Ig inhibitor of B7(CD80,86)-CD28, anti-CD40ligand) PITFALLS ANA positive Fibromyalgia Steroids for musculoskeletal symptoms Excessive duration of steroids Inadequate monitoring of disease activity Poor compliance Diagnostic or therapeutic delays: renal biopsy, initiation of cytotoxic therapy Role of the Primary Care Physician Assessments to Order Initial: CBC, SMA-20, ANA, dsDNA, C3/C4, ESR, CRP, UA, Rheumatoid Factor, Vit D 25OH If possible overlap or other: centromere, Scl-70, CPK, aldolase If Signficant Arthritis: XRAYS If prior diagnosis of SLE, patient seeking continuation of care: Subserologies: Ro, La, Sm, RNP, LAC, Cardiolipin Ab Reasons for Referral to Rheumatology To confirm a diagnosis To assess disease activity and severity To provide general disease management To manage uncontrolled disease To manage organ involvement or lifethreatening disease To manage/prevent treatment toxicities Other circumstances: APLS, pregnancy, surgery Follow Up Visits Frequency depends on activity, severity, and extent of SLE, response to treatment, type of treatment, need for toxicity monitoring At routine visits, CBC, SMA, UA should be checked, even in patients with previously normal values Patients with known renal disease should also have either 24 hour urine or spot protein/creatinine checked every 6-8 weeks Follow Up Active disease can be diagnosed by Assessment of clinical features such as rash, arthritis, serositis, etc Laboratory features: dsDNA Ab, complement levels, CBC Imaging: CXR, ECHO, etc Severe or Life Threatening Complications Monitoring for Specific Medications Patients on chronic steroid therapy must also be on Calcium/Vitamin D Anticipate the need for possible bisphosphonate therapy, check DEXA Role of the Primary Care Physician Patients may have more frequent access to their primary care physician as compared to Rheum or Renal Services Understand the importance of disease severity: lupus and it’s treatments are highly toxic and clinical status can decline rapidly Do not hesitate to call the Rheumatology Consult Service when initiating work-up or to discuss continued care Case Report 19 yo HF no PMH p/w 3 weeks of intermittent fevers (Tmax 103.4), weakness, retrosternal discomfort, proximal muscle weakness. Denies weight loss, chills, HA, CP, SOB, GI/GU sx. DDX? Case Presentation Initial PE: HR 92, RR 22, O2 sat 99% on RA Positives: trace alopecia, UE/LE 2/5 Initial labs: pancytopenia, SMA-10 WNL, AST/ALT 560/340, bilis nl, alb 2.3, UA: 3+prot and blood, EKG tachy, CXR NL CPK: 3750, LDH 1221, ECHO: small effusion Case Report Subsequent Data: ANA 1:1280, +dsDNA, C3 28, C4 6 +Sm/RNP Patient with clinical picture and lab data consistent with acute presentation of SLE, with acute cytopenia, myositis, serositis, and nephritis