Department of Dermatology:INVESTIGATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUSAssessed by:Prof Dr Abdel Aal ElKamshoushi

1. NURAMALINA BINTI YAHAYA (10-5-257)2. NOOR HAKIMAH HIDAYAH BT MOHD RAHIM (10-5-258)3. NURHAKIM BIN IBRAHIM (10-5-259)4. MEDHAT AHMED ELSAYED YOUSSEF (1037)

INVESTIGATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUSIntroductionSystemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. It can affect nearly every organ system in the body which the symptoms may vary widely between individuals.The classic presentation of a triad of fever, joint pain and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLELaboratory Findings(By Nuramalina Binti Yahaya 10-5-257)There is no definitive test for diagnosing SLE but some laboratory test can be very helpful in supporting the diagnosis of SLE.There are several standard laboratory studies of SLE:1. Complete blood count, CBCIt is very essential test because all cellular elements of blood can be affected.It helps screen for leucopenia, lymphopenia, anaemia, thrombocytopenia and prolonged activated partial thromboplastin time (aPTT).

2. Serum creatinine may be used in the diagnosis of kidney affection in SLE

3. Urinalysis The result will be low serum albumin with persistent proteinuria and membranous GN.

Also with microscopic analysis, red and white blood cells casts in urinary sediment may be present in proliferative GN.Other laboratory tests that may be used are:1. Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)It is nonspecific finding of SLE as it indicates systemic inflammation. However, it can be used in order to monitor the patient because when both markers are markedly elevated, suspect of increase activity of infectious process are occurred.

2. Complement levels.Measuring the complement level are also can be used because C3 and C4 may decrease in patient with active SLE due to consumption of immune complex-induced inflammation.

3. Liver function testLiver test result may be mildly elevated in acute SLE or in response of certain drug treatment.

4. Creatine kinase assayCreatine kinase level may be elevated in myositis and overlap syndromes.

5. Spot protein/ spot creatinine ratio [1]

Tests for Autoantibodies (ANA Test):(By Noor Hakimah Hidayah BT Mohd Rahim 10-5-258)

Antinuclear Antibodies (ANAs). 1. A primary test for SLE checks for antinuclear antibodies (ANA), which attack the cell nucleus. Its sensitivity = 99%; specificity = 49%.

2. High levels of ANA are found in more than 98% of patients with SLE. Other conditions, however, also cause high levels of ANA, so a positive test is not a definite diagnosis for SLE:-

2.1 Antinuclear antibodies may be strongly present in other autoimmune diseases (such as scleroderma, Sjgren syndrome, or rheumatoid arthritis).2.2 They also may be weakly present in about 20 - 40% of healthy women.2.3 Some drugs can also produce positive antibody tests, including hydralazine, procainamide, isoniazid, and chlorpromazine.

3. A negative ANA test makes a diagnosis of SLE unlikely but not impossible. High or low concentrations of ANA also do not necessarily indicate the severity of the disease, since antibodies tend to come and go in patients with SLE.

4. In general, the ANA test is considered a screening test:

4.1 If SLE-like symptoms are present and the ANA test is positive, other tests for SLE will be administered.4.2 If SLE-like symptoms are not present and the test is positive, either look for other causes, or the results will be ignored if the patient is feeling healthy.

ANA Subtypes.

5. Anti-double stranded DNA (Anti-ds DNA) is more likely to be found only in patients with SLE. It may play an important role in injury to blood vessels found in SLE, and high levels often indicate kidney involvement. Anti-ds DNA levels tend to fluctuate over time and may even disappear.

6. Anti-Sm antibodies are also usually found only with SLE. Levels are more constant and are more likely to be detected in African-American patients. Although many lupus patients may not have this antibody, its presence almost always indicates SLE.

7. When the ANA is negative but the diagnosis is still strongly suspected, a test for anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB) antibodies may identify patients with a rare condition called ANA negative, Ro lupus. These autoantibodies may be involved in the sun-sensitive rashes experienced by patients with SLE and are also found in association with neonatal lupus syndrome, in which a pregnant mother's antibodies cross the placenta and cause inflammation in the developing child's skin or heart.

8. Antiphospholipid antibodies. Around half of patients with SLE have antiphospholipid antibodies, which increase the risk for blood clots, strokes, and pregnancy complications. If suspects SLE blood abnormalities, tests may be able to detect the presence of the two major antiphospholipid antibodies: lupus coagulant antibody and anticardioplin antibody.

9. As with the ANA, these antibodies have a tendency to appear and disappear. Patients who have these autoantibodies as well as blood clotting problems or frequent miscarriages are diagnosed with antiphospholipid syndrome (APS), which often occurs in SLE but can also develop independently. [2]

Diagram 1 : Clinical associations of autoantibodies in SLE patients

Diagram 2 : ANAs in SLE

Radiography Investigations of SLE(By Nurhakim Ibrahim bin Ibrahim)There are certain radioimaging technique that can be used to help in the diagnosis.Joint radiographyJoint radiography often provides little evidence of systemic lupus erythematosus (SLE), even in the presence of Jaccoud arthropathy ('reversible' joint deformities) with deformity or subluxations such swan neck appearance. The most common radiographs in SLE show periarticular osteopenia and soft-tissue swelling without erosions. And when the x ray is done in the hip joint, there is probability to find the avascular necrosis due to prolonged used of steroid as a treatment.

Chest radiography and chest CT scanningThese modalities can be used to monitor interstitial lung disease and to assess for pneumonitis, pulmonary emboli, and alveolar hemorrhage when we use to do the chest imaging.

This chest x-ray is taken from a patient with lupus demonstrates a right-sided pleural effusion (yellow arrow) and atelectasis with scarring in the left lung base (blue arrow). In severe complications, a fibrothorax may develop.EchocardiographyEchocardiography is used to assess for pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks endocarditis

Libman-Sacks endocarditis is the most characteristic cardiac manifestation of lupus. It is characterized by clusters of verrucae on the ventricular surface of the mitral valve. These lesions consist of accumulation of immune complexes, platelets, and mononuclear cells. This can lead to heart failure, valvular dysfunction, emboli, and secondary infective endocarditis. Diagnosis is best made via echocardiography, which may reveal the characteristic valvular masses (arrows). [IVS = interventricular septum; LA = left atrium; LV = left ventricle.]

Brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA)Brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) is used to evaluate for central nervous system (CNS) lupus white-matter changes (see the following image), vasculitis, or stroke, although findings are often nonspecific and may be absent in as many as 42% of cases with neuropsychiatric symptoms

This brain magnetic resonance image (MRI) demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with long-standing systemic lupus erythematosus (SLE).

Cardiac MRIThere are some investigators have suggested that cardiac MRI (CMR) provides an excellent alternative to clinical assessment, electrocardiography, and echocardiography for diagnosing SLE myocarditis. They reported that patients who were positive for infectious myocarditis on CMR were more symptomatic than those with active SLE disease and that more than 50% of patients with CMR-positive myocarditis had a concurrent positive endomyocardial biopsy. [3]

Clinical Manifestations and Investigations for Systems affected in SLE: (By Medhat Ahmed Elsayed Youssef 1037)Renal SystemKidney involvement in SLE is common, with 74% of patients being affectedat some time in the course of disease, and is a poor prognostic indicator. Renalpathology is generally attributed to the deposition of circulating immunecomplexes or in situ formation of these complexes in glomeruli and resultsin the activation of complement and subsequent recruitment of inflammatorycells. In addition to glomerular inflammation, necrosis, and scarring, renal pathology is characterized by vascular lesions, including thrombotic microangiopathyand extraglomerular vasculitis, and tubulointerstitial disease, including tubular atrophy and interstitial fibrosis. Hypertension may be a consequence of significant renal involvement. Most cases of lupus nephritis present a complex immunopathologic picture, but, in general, the pattern of renal disease reflects the site of depositionof immunoglobulins and the quality of the effector mechanisms they induce. Mesangial deposition of immunoglobulin induces mesangial cell proliferation and is associated with microscopic hematuria and mild proteinuria Subendothelial deposition of immune complexes results in proliferative and exudative inflammation, together with hematuria, mild to moderate proteinuria, and reduced glomerular filtration rate. Subepithelial deposition of immune complexes adjacent to podocytes and along the glomerular basement membrane can result in membranous nephritis with nephrotic-range proteinuria. In addition, antiphospholipid antibodies maysupport the development of thrombotic or inflammatory vascular lesions within or external to glomeruli.A World Health Organization classification of lupus nephritis lesions wasfirst published in 1975 with subsequent revisions. These classifications were reviewed and rigorously reexamined in the revised International Society ofNephrology and Renal Pathology Society classification criteria for lupus glomerulonephritis (GN) (Table 274-3). Class I and II GN involves mesangial deposition of immune complexes (class I without and class II with mesangial hypercellularity), class III describes focal GN involving less than 50% of total glomeruli, class IV includes diffuse GN involving 50% or more of glomeruli, class V designates membranous lupus nephritis, and class VI is characterized by advanced sclerotic lesions. Classes III and IV have subdivisions for active and sclerotic lesions, and class IV also has subdivisions for segmental and contributes to nephrotic syndrome. This complication can be evaluated by renal ultrasound.

Cardiovascular SystemPericarditis and valve nodules were among the first clinical manifestations described in SLE. It is only recently that the extent of premature atherosclerotic disease has been well documented. Pericarditis (Chapter 77) is the most common cardiac manifestation, but it is sometimes recognized only on imaging studies or at autopsy. It is a component of the generalized serositis that is often a feature of SLE and is associated with local autoantibodies and immune complexes. Pericarditis is usually manifested as substernal chest pain that is improved by bending forward and can be exacerbated by inspiration or coughing. The symptoms and effusions associated with pericarditis are quite responsive to moderate-dose (20 to 30 mg/day of prednisone) corticosteroidtreatment. Structural valve abnormalities in SLE range from sterile nodules originally described by Libman and Sacks to nonspecific valve thickening. The nodules are immobile and usually located on the atrial side of the mitral valve and sometimes on the arterial side of the aortic valve. Right-sided lesions are rare.These structural changes may in some cases result in valvular regurgitation. Although valve nodules are detected in most patients with SLE at autopsy, clinically significant valvular heart disease is much less common (1 to 18%). The verrucous valvular lesions of Libman and Sacks are most likely inflammatory in nature and may be associated with the presence of antiphospholipid antibodies. Premature and accelerated atherosclerosis is increasingly recognized as being prevalent in lupus patients, and preclinical atherosclerotic carotid plaque has been documented in 37% of SLE patients as opposed to 15% of age- and sex-matched controls. Traditional cardiovascular risk factors apply, but the diagnosis of SLE is itself a significant risk factor for premature atherosclerosis. Although the lupus-specific mechanisms that confer additional risk for atherosclerosis have not been defined, it is likely that chronic inflammation associated with immune system activation contributes to the accumulation of vascular damage. Mortality from atherosclerosis may be up to 10 times greater in patients with SLE than in age- and sex-matched controls. Although not specific to SLE, Raynauds phenomenon (Chapter 80), characterized by episodic vasospasm and occlusion of the digital arteries in response to cold and emotional stress, is a feature in up to 60% of SLE patients and contributes to pain and sometimes necrosis of the distal ends of extremities. The character of the digits classically changes from pallor to cyanosis and then to rubor as vascular perfusion becomes impaired. In addition, small arteries, arterioles, and capillaries can be affected by vasculitis and fibrinoid necrosis with clinical manifestations that include periungual telangiectases,abdominal pain, and neuropsychiatric symptoms.Pulmonary SystemPleuritis is the most frequent manifestation of pulmonary involvement in SLE and occurs in about 30% of patients at some point in their disease course. Pleuritis is characterized by pain on respiration and exudative effusions.Parenchymal disease is less common but may be based on several distinct mechanisms, including pneumonitis in the absence of documented infection and sometimes involving alveolar hemorrhage (in up to 12% of patients), pulmonary embolism secondary to peripheral thrombosis, or pulmonary hypertension with increased pulmonary resistance and impaired diffusing capacity.Neuropsychiatric InvolvementClinical features of SLE that involve the nervous system include both neurologic psychiatric manifestations. The central and peripheral nervous systems can be affected by the disease. The American College of Rheumatology has identified 19 neuropsychiatric syndromes that can be associated withSLE, and validation of these neuropsychiatric findings has been substantiated in several independent studies (The most common manifestations) that are probably attributable to SLE cerebritis include cognitive dysfunction,present in 17 to 66% of SLE patients; psychosis or mood disorder, the former reported in up to 8% of patients; cerebrovascular disease in 5 to 18% of patients; and seizures, present in 6 to 51% of patients. Headaches arealso common. Because none of these CNS manifestations are found exclusively in SLE, it can be difficult to be certain that a neuropsychiatric complaint or symptom can be attributed to SLE. Evaluation of neuropsychiatric lupus depends on a careful clinical history and physical and laboratory examinations and, in some cases, imaging studies imaging is useful for detecting intracranial abnormalities, which are seen in 19 to 70% of patients and include white matter lesions, cerebral infarction, venous sinus thrombosis, and sometimes atrophy. More sophisticated imaging techniques such as magnetic resonance angiography and magneticresonance spectroscopy can be used to assess cerebral blood flow or neuronalmetabolism.Cranial nerve and ocular involvement, most likely based on vasculopathy and focal ischemia, can sometimes affect vision. Ocular examination of the retina can reveal cotton-wool spots as a result of retinal ischemia or necrosis. Although rare, transverse myelopathy, frequently associated with antiphospholipid antibodies, can have devastating consequences, including paraplegia. Sensorimotor neuropathies, often asymmetrical, are morecommon (up to 28%) and are based on damage to small nerve fibers with vasculopathy in the small arteries that supply the nerve fibers. As is the case with lupus nephritis, the pathophysiologic mechanisms that account for the neuropsychiatric manifestations of SLE are diverse and complex. Recent data suggest that autoantibodies cross-reactive with neuronal cell surface glutamate receptors and DNA may mediate excitotoxic death of neurons and are proposed to contribute to cognitive dysfunction. Antibodies directed against ribosomal P protein have also been associated with neuropsychiatric lupus, and antiphospholipid antibodies can contribute to a procoagulant state, vascular thrombosis, and cerebral ischemia. Cerebral vasculopathy has been clearly demonstrated by angiographic and pathologic studies. Noninflammatory small vessel vasculopathy is the mostcommon lesion and can be associated with microinfarcts. Inflammatory mediators, including the cytokines interleukin-6 and interferon-, and matrix metalloproteinases may also contribute to the neuropsychiatric manifestations of SLE.Gastrointestinal SystemAlthough uncommon, vasculitis of the gastrointestinal tract or mesentery can result in pain and bowel necrosis. Less common than pleuritis and pericarditis, peritonitis can manifest as peritoneal effusion and abdominal pain. Pancreatitis occurs in less than 10% of patients but may also be due to vascular pathology. Lupoid hepatitis, a syndrome that was named for the presence of positive ANAs in patients with chronic active hepatitis, is a misnomer because elevated transaminases are only rarely seen in lupus patients.LymphadenopathyAbout one third of SLE patients demonstrate diffuse lymphadenopathy at some time during the course of their disease. The nodes are often nontender, and lymphoma is sometimes considered in the differential diagnosis. Biopsy usually reveals follicular hyperplasia, although some histopathologic findings appear similar to the histiocytic necrotizing lymphadenitis that is a feature of Kikuchis disease, a self-limited syndrome characterized by fever and lymphadenopathy.Recent multicenter studies have determined the frequency of malignancies in patients with SLE and have found a significant increase in hematologic malignancies, particularly non-Hodgkins lymphoma. Splenomegaly is sometimes seen in SLE, and spleen pathology is characterized by a classic onion-skin histology that appears as concentric circles of collagen matrix surrounding splenic arteries and arterioles.Lupus Pregnancy and Neonatal LupusWhether pregnancy increases the likelihood of lupus exacerbation has been debated, with differences on this point presented by different investigators. However, abundant data indicate that patients with SLE have worse fetal outcomes than healthy individuals. Gestational hypertension, fetal growth restriction, and fetal distress are increased in patients with SLE and may lead to fetal loss or premature delivery. Preeclampsia can contribute to a poor outcome in both the mother and fetus and can be difficult to distinguish from a lupus flare associated with lupus nephritis. Neonatal lupus is a distinct entity that can occur in infants of mothers with or without a diagnosis of SLE. The syndrome is characterized by cutaneous lesions and congenital heart block in the infant and the presence of antibodies to the Ro (SSA) or La (SSB) RNA-binding proteins (or both) in the mother. Mortality in babies with a congenital heart block is 15 to 31%. Deposition of anti-Ro IgG in the fetal heart, indicative of transplacental transfer of maternal autoantibody, and dense connective tissue encompassing the conduction system have been demonstrated in autopsy specimens. Prenatal testing of lupus mothers for the presence of anti-Ro and anti-La antibodies is appropriate, and careful monitoring with fetal echocardiography starting at week 16of pregnancy can detect conduction defects. Fluorinated corticosteroids such as dexamethasone have been effective in reversing heart block in some cases.Antiphospholipid Antibody SyndromeAntiphospholipid antibodies represent a distinct class of autoantibodies that are seen in about one third of SLE patients but can also be present in individuals who do not carry a diagnosis of SLE . Althoughthese antibodies were initially thought to be specific for phospholipids exposed in cell membranes, particularly after flipping of the membranes of apoptotic cells, extensive data support their primary reactivity with phospholipid-binding proteins, particularly 2GPI. Whether in primary antiphospholipid syndrome or in SLE, antiphospholipid antibodies have been associated with venous and arterial thromboses. In addition to vascularthromboses, clinical manifestations of antiphospholipid syndrome include thrombotic microangiopathic glomerular disease, cardiac valve lesions, livedo reticularis, thrombocytopenia, hemolytic anemia, and CNSdisease. Recent data indicate that these autoantibodies can contribute to fetal loss and growth restriction by binding to the placenta, activating the complement system, and inducing inflammation. Catastrophic antiphospholipid syndrome, triggered by the acute onset of multisystemic (three or more organs) thrombosis, is resistant to anticoagulation treatment and is fatal in approximately 50% of cases.Investigations for Follow up of Disease:It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include hemoglobin levels, platelet counts, urinalysis, and serum levels of creatinine or albumin. There is great interest in identification of additional markers of disease activity. Candidates include levels of anti-DNA antibodies, several components of complement (C3 is most widely available), activated complement products (including those that bind to the C4d receptor on erythrocytes), IFN-inducible genes, soluble IL-2, and urinary adiponectin or monocyte chemotactic protein 1. None is uniformly agreed upon as a reliable indicator of flare or of response to therapeutic interventions. The physician should determine for each patient whether certain laboratory test changes predict flare. If so, altering therapy in response to these changes has been shown to prevent flares. In addition, given the increased prevalence of atherosclerosis in SLE, it is advisable to follow the recommendations of the National Cholesterol Education Program for testing and treatment, including scoring of SLE as an independent risk factor, similar to diabetes mellitus. [4]

REFERENCES

[1] http://www.webmd.com/lupus/guide/laboratory-tests-used-diagnose-evaluate-sle?page=2

http://emedicine.medscape.com/article/332244-overview

[2] http://umm.edu/health/medical/reports/articles/systemic-lupus-erythematosus

http://www.docstoc.com/docs/445715/Systemic-Lupus-Erythematosus-Definition

http://en.wikipedia.org/wiki/Systemic_lupus_erythematosus#Laboratory_tests

[3] http://emedicine.medscape.com/article/332244-overview

http://emedicine.medscape.com/article/332244-clinical

http://radiopaedia.org/articles/musculoskeletal-manifestations-of-systemic-lupus-erythematosus

[4] Goldmans Cecil Medicine 24th Edition