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Zhanna Servetnyk, MD

Zhanna Servetnyk, MD, House Staff, Department of Medicine, St. Luke-Roosevelt Hospital, Columbia University of Physicians College of Physicians and Surgeons, New York, NY Disclosure: Zhanna Servetnyk, MD, has disclosed no relevant financial relationships. Dr. Servetnyk does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr. Servetnyk does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
Constantine Albany, MD

Constantine Albany, MD, House Staff, Department of Medicine, St. Luke-Roosevelt Hospital, Columbia University of Physicians College of Physicians and Surgeons, New York, NY Disclosure: Constantine Albany, MD, has disclosed no relevant financial relationships. Dr. Albany does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr. Albany does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.
Ira S. Meisels, MD

Ira S. Meisels, MD, Assistant Professor of Clinical Medicine, Senior Attending in Medicine (Nephrology), St. Luke-Roosevelt Hospital, Columbia University of Physicians College of Physicians and Surgeons, New York, NY Disclosure: Ira S. Meisels, MD, has disclosed no relevant financial relationships. Dr. Meisels does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr. Meisels does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

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Craig A Goolsby, MD

Craig A. Goolsby, MD, Director, eMedicine Case of the Week; Staff Physician, Department of Emergency Medicine, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX Disclosure: Craig A. Goolsby, MD, has disclosed no relevant financial relationships.
Usama Basit, MD, MBBS

Usama Basit, MD, MBBS, Reviewer, eMedicine Interactive Case Studies (CME Case of the Week), Rawalpindi, Pakistan Disclosure: Usama Basit, MD, MBBS, has disclosed no relevant financial relationships.
Ali K Abu-Alfa, MD, FASN

Ali K. Abu-Alfa, MD, FASN; Associate Professor of Medicine, Director, Peritoneal Dialysis Program, Yale School of Medicine, Department of Internal Medicine, Section of Nephrology Disclosure: Ali K. Abu-Alfa, MD, FASN, has disclosed no relevant financial relationships.
Luis M. Soler, BA

Luis M. Soler, BA, Associate Editor, eMedicine/Medscape, New York, NY Disclosure: Luis M. Soler, BA, has disclosed no relevant financial relationships. CME Reviewer(s)
Laurie E. Scudder, DNP, NP

Accreditation Coordinator, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC; Nurse Practitioner, School-Based Health Centers, Baltimore City Public Schools, Baltimore, Maryland Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

A 41-Year-Old Woman With Shortness of Breath, Hematuria, and Lymphadenopathy CME

Zhanna Servetnyk, MD; Constantine Albany, MD; Ira S. Meisels, MD
CME Released: 09/08/2010; Reviewed and Renewed: 04/11/2012; Valid for credit through 04/11/2013

Background

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A 41-year-old black woman presents to the emergency department (ED) with a 5-day history of increasing shortness of breath along with a mild, nonproductive cough. She denies having any fever, chills, chest pain, or palpitations. No sick contacts are identified, and she denies any recent travel. On further questioning, the patient reports that she first experienced shortness of breath 1 year ago, and that it has been gradually progressive since then. Her shortness of breath has particularly worsened over the last 5 days, to the point that it is limiting her daily activities; this has prompted her to come to the ED. She does not attribute the shortness of breath to any precipitating event. Her past medical history is significant for asthma and hypertension, as well as for several episodes of presumed bronchitis/pneumonia last year; she recalls being treated with antibiotics as an outpatient by her primary care provider. She also has a history of heavy menstrual periods, for which she has been on oral contraceptive pills (OCPs). Her family history is positive for diabetes mellitus and ischemic heart disease. Except for the OCPs, she is nonadherent to the rest of her regular medications, which include an angiotensin-converting enzyme (ACE) inhibitor, an inhaled corticosteroid, and a beta-2 agonist. She quit smoking 10 years ago, after a 20-pack-year history. She denies any alcohol or illicit drug use, and she has no known allergies (drug or otherwise). On physical examination, she appears to be in no acute distress. She is morbidly obese, with a body mass index (BMI) of 45. Her blood pressure is 170/95 mm Hg, her heart rate is 106 bpm, her respiratory rate is 18 breaths/min, and her temperature is 98.6F (37C). She has an oxygen saturation of 97% while breathing room air. Pertinent findings on chest examination include fine crackles at the lung bases, with decreased vocal fremitus. Auscultation of the rest of the chest reveals no abnormalities. Her cardiovascular examination shows normal first and second heart sounds, with no jugular venous distention, murmurs, rubs, or gallops. There are, however, several enlarged, nontender cervical and axillary lymph nodes bilaterally. She has no rashes. The neurologic examination is nonfocal. Her peripheral pulses are palpable. Examination of her lower extremities elicits mild bilateral pitting pedal edema. The rest of her examination reveals no significant findings. An electrocardiogram is performed that is remarkable for sinus tachycardia. The initial laboratory workup reveals a creatinine of 1.6 mg/dL (141.44 mol/L), proteinuria (>300 g/L), and hematuria (50-100 red blood cells per high-power field). She is found to have anemia, with a hemoglobin and hematocrit of 8.1 g/dL (81 g/L) and 25.4% (0.254), respectively. Her mean corpuscular volume is 77

m (77 fL), with iron levels of less than 10 g/dL, a total iron binding capacity of 197 g/dL (35.26 mol/L), and a ferritin level of 68 ng/mL (152.8 pmol/L). The D-dimer is positive at 4.73 g/mL (4.73 mg/L), and the erythrocyte sedimentation rate (ESR) is elevated at 50 mm/hr. A chest x-ray (Figure 1) obtained during the ED visit shows a right-sided pleural effusion and a patchy linear opacity at the base of the left lung that is consistent with atelectasis/scar tissue. Computed tomography (CT) scanning of the thorax shows bilateral small pleural effusions that are greater on the right than the left, significantly enlarged axillary and subpectoral lymph nodes bilaterally, and a small pericardial effusion. Ultrasonography of the kidneys, ureters, and bladder reveals no obstruction.

Keeping the history in mind, what is the most likely diagnosis? Hint: Asymptomatic azotemia and proteinuria are often a part of the picture in this disease. COPD exacerbation Pulmonary embolism Systemic lupus erythematosus Sarcoidosis Congestive heart failure Save and Proceed

Discussion
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Figure 2. Figure 3.

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The constellation of serositis, hypertension, diffuse lymphadenopathy, azotemia, and proteinuria in this patient was highly suspicious for a systemic autoimmune disease. Further laboratory workup revealed a positive result for antinuclear antibodies (ANA) 1:640, including those against double-stranded DNA (ds-DNA); IgG titer of 300 IU/mL, and an anti-Smith finding (156 EU/mL) which, when correlated with the clinical picture, are consistent with a diagnosis of systemic lupus erythematosus. Other relevant findings included a decreased complement level, with C3 and C4 levels of 46.2 mg/dL (0.462 g/L) and 5.3 mg/dL (0.053 g/L), respectively; a positive Coombs test; hypoalbuminemia (3.1 g/dL [31 g/L]); and a negative lupus anticoagulant antibody finding. Biopsy of the kidney was performed, which showed diffuse proliferative lupus nephritis class IV, with moderate activity and no chronicity; moderate interstitial inflammation was also seen (Figures 2 and 3). Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that primarily affects the connective tissue. Because the disease affects the connective tissue, multiple organ systems, including the skin, joints, kidneys, lungs, nervous system, serous membranes, and/or other organs of the body are affected as well. As is typical of other autoimmune disorders, the immune system attacks the bodys own cells and tissue, which results in a continuous inflammatory response and tissue damage. SLE is more common, and more severe, in nonwhite patients. The highest prevalence among ethnic groups is in blacks. SLE is up to 10 times more common in women than in men and typically occurs during child-bearing age, with a peak age of onset between 15 and 45 years. The disease course is as variable as it is unpredictable, with periods of illness, or "flares," alternating with periods of remission. Estrogen may play a role in the pathophysiology of SLE, but this has not yet been proven conclusively. Women exposed [2] to estrogen-containing OCPs, however, do have an increased risk of developing SLE, especially if they started using them recently. SLE is characterized by a wide spectrum of signs and symptoms due to the ongoing presence of a variety of antigens, autoantibodies, and immune complexes, which result in accumulated tissue damage to the point of clinical manifestation. The American College of Rheumatology (ACR) diagnostic criteria for lupus includes 11 manifestations. These criteria include: Serositis (pleuritis, pericarditis) Oral ulcers Arthritis (nonerosive) Photosensitivity (exposure to UV radiation causes skin manifestations) Blood dyscrasias (hemolytic anemia, leukopenia, thrombocytopenia) Renal manifestations (proteinuria, casts)
[1]

Positive ANA finding Immunologic disorders (anti-Smith antibodies positive, antiphospholipid antibody positive, false positive test for syphilis, presence of antidouble-stranded DNA antibodies) Neurologic manifestations (seizures, focal signs, psychosis) Malar (butterfly) rash Discoid rash The presence of 4 or more of these criteria, either serially or simultaneously, is diagnostic of SLE. About 80% of patients have skin involvement manifesting as photosensitivity, malar (butterfly) and discoid rash (thick, red, scaly patches on the skin), ulcers in the oral and nasal cavities or in the vagina, or alopecia, all of which are part of ACR diagnostic criteria. However, an absence of skin manifestation, as described in this patient, should not lower clinical suspicion for lupus because its symptoms vary and come and go unpredictably. Diagnosing SLE can thus be elusive, with some patients suffering from unexplained symptoms of untreated SLE for years, such as the initial (and chronic) complaints of fever, malaise, joint pains, myalgias, and fatigue, as well as temporary loss of cognitive abilities. When SLE is diagnosed, it is important to establish the severity and potential reversibility of the illness in order to institute appropriate therapy. Treatment options usually focus on the suppression of symptoms rather than treating the cause, since there is not an actual [4] "cure" for the disease. Renal disease remains the most serious complication of SLE. It affects 30%-60% of patients. Renal involvement is characterized by proteinuria (> 0.5 g/24h) and/or active urinary sediment (> 5 red blood cells per high-power field, pyuria, or cell casts). In patients with inactive sediment and > 500 mg/day of proteinuria, monitoring is recommended with urinalysis every 3-6 months for 3 years; every 3 months is preferred in patients with antidouble-stranded DNA antibodies and/or [5] hypocomplementemia. Prompt renal biopsy is required in all lupus patients with evidence of kidney involvement to determine the histologic subtype of lupus [6] nephritis. The typical histologic picture is of a membranous glomerulonephritis, with "wire-loop" abnormalities that result from the granular appearance (on immunohistochemical staining) of immune-complex deposition along the glomerular basement membrane. [7] The World Health Organization (WHO) classification of glomerulonephritis in SLE includes grades I to VI. Pathology reports also reflect the extent of inflammatory (reversible) and chronic (irreversible scarring) changes. In general, treatment for lupus nephritis is not recommended in patients with class I or II disease or in those with extensive irreversible changes. In contrast, aggressive immunosuppression is recommended for patients with disease class III, IV, or V with inflammatory proliferative lesions, because a [8] majority of those individuals, if untreated, develop end-stage renal disease (ESRD). However, ESRD is seen in fewer than 5% of SLE cases, due to earlier detection and subsequent prompt management of the disease. Lupus nephritis tends to be an ongoing disease, with flares often requiring repeat biopsy and repeated treatment over time. Pleural inflammation is a common feature of SLE and is the most common pulmonary manifestation of SLE. It causes chest pain, [9] shortness of breath, and cough. Pleural effusions are typical findings and are usually ANA-positive exudates with low complement. Less frequent pulmonary complications of SLE include interstitial lung disease and pulmonary hypertension. The most common hematologic manifestation of SLE is anemia, usually normochromic normocytic, which is often overlooked in young menstruating women. Iron deficiency may also develop. Leukopenia and thrombocytopenia are common as well, which may be due to the primary disease process or may be a side effect of the subsequent pharmacologic treatment for the disease. Leukopenia [10] almost always consists of lymphopenia, not granulocytopenia. Patients with SLE may also have signs and symptoms of a thrombotic disorder known as antiphospholipid syndrome, wherein autoantibodies to phospholipids are present in the serum. Serum levels of anticardiolipin antibodies should also be checked in patients suspected of having SLE. The presence of these antibodies may result in a false positive test for syphilis. Lymphadenopathy is not an uncommon presentation in SLE; it occurs in 15%-26% of [11,12] patients. However, diffuse lymphadenopathy is very rare and is reported in very few cases. It is not one of the ACR criteria for the diagnosis of SLE. Lymph node biopsy may be warranted to exclude alternative diagnoses. The patient in this case underwent lymph node biopsy, which showed no evidence of lymphoproliferative disorder. A number of research protocols (Systemic Lupus Activity Measure [SLAM], SLE Disease Activity Index [SLEDAI], etc) have been [13-15] designed in order to accurately monitor disease activity, which all use combinations of history, physical examination findings, and laboratory data. Meanwhile, the search for reliable markers of disease activity continues. Complement activation products, soluble T-cell activation markers, antibodies to C1q, and the use of nucleosomes have been reported but not validated for universal clinical [16] use. Currently, widely used indicators include antidouble-stranded DNA antibodies, complement levels, hemoglobin levels, platelet count, urine analysis, and serum levels of creatinine and albumin. Because there is great variability in SLE's presentation and course, predicting a flare in a particular patient should take into account laboratory findings that correlate with flares in the past. Treatment of SLE is aimed at controlling acute flares and using maintenance strategies that suppress symptoms to an acceptable level, while preventing further organ damage. For milder manifestations of SLE, such as arthritis, dermatitis, and constitutional symptoms, NSAIDs, hydroxychloroquine, and low-dose steroids have been used with success. Severe forms of the disease, including those with more life-threatening courses (including lupus nephritis), require a combination therapy of high-dose systemic glucocorticoids and cyclophosphamide or mycophenolate mofetil to induce remission, followed by longer-term, intense [17] immunosuppressive therapy to maintain response. The patient in this case began treatment with high-dose oral corticosteroids and mycophenolate mofetil. After 1 week, her condition
[3]

improved, with significantly decreased shortness of breath. She was discharged to home with renal, rheumatologic, and primary care outpatient follow-up.

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You are evaluating a patient who presents with a number of symptoms indicating possible SLE. Which of the following symptoms would NOT cause you to suspect SLE in this patient? Photosensitivity Arthritis Proteinuria Lymphadenopathy Anemia You are examining a patient who was diagnosed with SLE last year. Today, at your office, she is asymptomatic and her urine analysis shows no proteinuria and 1-3 RBCs per high-power field, with no casts. What is the appropriate time frame for her kidney function follow-up? When she develops symptoms In 1 month In 3 months In 12 months First perform a biopsy, and then arrange for follow-up every three months Save and Proceed

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1. Manson JJ, Rahman A. Systemic lupus erythematosus. Orphanet J Rare Dis. 2006;1:6. 2. Bernier MO, Mikaeloff Y, Hudson M, Suissa S. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum. 2009;61:476-481. 3. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725. 4. Balow JE., Kidney disease in systemic lupus erythematosus. Rheumatol Int. 1991;11:113-115. 5. Falk RJ. Treatment of lupus nephritis--a work in progress. N Engl J Med. 2000;343:1182-1183. 6. Faurschou M, Starklint H, Halberg P, Jacobsen S. Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol. 2006;33:1563-1569. 7. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65:521-530. 8. Kasper DL, Braunwald E, Hauser S, Longo D, Jameson JL, Faci AS. Harrison's Principles of Internal Medicine. 16th ed. Chicago, IL: McGraw-Hill;2004:1960-1967. 9. Paran D, Fireman E, Elkayam O. Pulmonary disease in systemic lupus erythematosus and the antiphospholpid syndrome. Autoimmun Rev. 2004;3:70-75. 10. Sultan SM, Begum S, Isenberg DA. Prevalence, patterns of disease and outcome in patients with systemic lupus erythematosus who develop severe haematological problems. Rheumatology (Oxford). 2003;42:230-234. 11. Kitsanou M, Andreopoulou E, Bai MK, Elisaf M, Drosos AA. Extensive lymphadenopathy as the first clinical manifestation in systemic lupus erythematosus. Lupus. 2000;9:140-143. 12. Shapira Y, Weinberger A, Wysenbeek AJ. Lymphadenopathy in systemic lupus erythematosus. Prevalence and relation to disease manifestations. Clin Rheumatol. 1996;15:335-338. 13. Alarcn GS, Calvo-Aln J, McGwin G Jr, et al. Systemic lupus erythematosus in a multiethnic cohort: LUMINA XXXV. Predictive factors of high disease activity over time. Ann Rheum Dis. 2006;65:1168-1174. 14. Uribe AG, Vil LM, McGwin G Jr, Sanchez ML, Reveille JD, Alarcn GS. The Systemic Lupus Activity Measure-revised, the Mexican Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and a modified SLEDAI-2K are adequate instruments to measure disease activity in systemic lupus erythematosus. J Rheumatol. 2004;31:1934-1940. 15. Bae SC, Koh HK, Chang DK, Kim MH, Park JK, Kim SY. Reliability and validity of systemic lupus activity measure-revised (SLAM-R) for measuring clinical disease activity in systemic lupus erythematosus. Lupus. 2001;10:405-409. 16. Liu CC, Ahearn JM. The search for lupus biomarkers. Best Pract Res Clin Rheumatol. 2009;23:507-523.

17. Houssiau FA, Ginzler EM. Current treatment of lupus nephritis. Lupus. 2008;17:426-430. Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Medscape CME Case Presentations 2010 MedscapeCME

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