CASE PRESENTATIONS
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A CASE REPOST OF CHRONIC URTICARIA IN SYSTEMIC LUPUS ERYTHEMATOSUS ASSOCIATING TRANSVERSE MYELITIS Sanda-Maria Deme1, Dragos Catalin Jianu2, Stefania Kory Calomfirescu3 1 General Medicine Faculty, Neurology Department, “Vasile Goldiş” West University, Arad, Romania 2 Neurology Department, “Victor Babeş” University of Medicine and Pharmacy, Timisoara, Romania 3 Neurology Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
ABSTRACT Transverse myelitis may occur in isolation (idiopathic), or in the setting of another illness. Idiopathic transverse myelitis is assumed to be a result of abnormal activation of the immune system against the spinal cord. We report a 40-year-old woman with chronic urticaria and acute transverse myelitis associated with systemic lupus erythematosus. The urticaria appeared in her adolescence and after 26 years was followed by photosensitivity, peripheral polyarthritis and acute transverse myelitis, with positive antiphospholipid and antinuclear antibodies. Both chronic urticaria and acute transverse myelitis have been described associated appearing as the first manifestation of systemic lupus erythematosus. Transverse myelitis is a rare and still poorly understood condition reported in about 2 % of patients with systemic lupus. Key words: transverse myelitis, urticaria, systemic lupus erythematosus
Transverse myelitis is a neurological disorder caused by inflammation across both sides of one level, or segment, of the spinal cord. The segment of the spinal cord at which the damage occurs determines which parts of the body are affected. Damage at one segment will affect function at that segment and segments below it. The term myelitis is a nonspecific term for inflammation of the spinal cord; transverse refers to involvement across one level of the spinal cord. It occurs in both adults and children and the spinal cord. It occurs in both adults and children and the incidence per year varies from 1 – 5 per million people. In people with transverse myelitis, inflammation usually occurs at the thoracic level, causing problems with leg movement, bowel and bladder control.
CLINICAL SYMPTOMS Transverse myelitis symptoms develop rapidly over several hours to several weeks. Approximately 45 % of patients worsen maximally within 24 hours. Inflammation within the spinal cord interrupts the medullar pathways and causes the common presenting symptoms: • limb weakness, • sensory disturbance, • bowel and bladder dysfunction, • back pain and radicular pain (pain in the distribution of a single spinal nerve). Almost all patients will develop leg weakness of varying degrees of severity, but upper limbs are involved in a minority of cases depending upon the
Author for correspondence: Stefania Kory Calomfirescu, MD, “Iuliu Haţieganu” University of Medicine and Pharmacy, 43 Victor Babes Street, Cluj-Napoca, Romania email:
[email protected]
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level of spinal cord involvement. Sensation is generally diminished below the level of spinal cord involvement. Pain, temperature, the sensation, the appreciation of vibration are generally diminished, sometimes the last two might be spared.
CAUSES OF TRANSVERSE MYELITIS Transverse myelitis may occur in isolation (idiopathic), or in the setting of another illness. Idiopathic transverse myelitis is assumed to be a result of abnormal activation of the immune system against the spinal cord. A list of illnesses associated with transverse myelitis includes: 1. Parainfections (occurring at the time of and in association with an acute infection or an episode of infection)
– Viral: herpex simplex, herpes zoster, cytomegalovirus, Epstein-Barr virus, enteroviruses (poliomyelitis, Coxsackie virus, echovirus), human T-cell, leukemia virus, human immunodeficiency virus, influenza, rabies – Bacterial: Mycoplasma pneumoniae, Lyme borreliosis, syphilis, tuberculosis 2. Postvaccinal – Rabies, cowpox 3. Systemic – Systemic lupus erythematosus autoimmune disease – Sjogren’s syndrome – Sarcoidosis 4. Multiple Sclerosis 5. Paraneoplastic syndromes 6. Vascular causes – Thrombosis of spinal arteries – Vasculitis secondary to heroin abuse – Spinal arterio-venous malformation
The cause of idiopathic transverse myelitis is unknown, but most evidence supports an autoimmune process. This means that the patient’s own immune system is abnormally stimulated to attack the spinal cord and cause inflammation and tissue damage. Examples of autoimmune diseases which are more common include rheumatoid arthritis, in which the immune system attacks the joints, and multiple sclerosis, in which myelin, the insulating material for nerve cells in the brain, is the target of autoimmune attack. Transverse myelitis often develops in the setting of viral and bacterial infections, especially those which may be associated with a rash (rubeola, varicella, variola, rubella, influenza, and mumps). Approximately one third of patients with TM report a febrile illness (flu-like illness with fever) in close
temporal relationship to the onset of neurologic symptoms. Transverse myelitis may be a relatively uncommon manifestation of several autoimmune diseases including systemic lupus erythematosus, Sjogren’s syndrome, and sarcoidosis. Systemic lupus erythematosus is an autoimmune disease of unknown cause which affects multiple organs and tissues in the body. Features of this illness include arthralgias and arthritis, rasches, kidney inflammation, low blood counts (including white and red blood cells, platelets), oral ulcers and the presence of abnormal autoantibodies (antibodies which are directed against the person’s own tissues) in the blood. The fully developed syndrome of systemic lupus erythematosus is easy to recognize. But, this illness may begin with just one or two signs and is then more difficult to diagnose.
DIAGNOSIS OF TRANSVERSE MYELITIS The general history and physical examination are first performed, but often do not give clues about the cause of spinal cord injury. The first concern of the physician who evaluates a patient with complaints and examination suggestive of a spinal cord disorder is to rule out a mass-occupying lesion which might be compressing the spinal cord. Potential lesions which might compress the cord include tumor, herniated disc, stenosis of the spinal cord canal, and abscess. The easiest test to rule out such a compressive lesion is magnetic resonance imaging of the appropriate levels of the cord. If the MRI shows no mass lesion outside or within the spinal cord, then the patient with spinal cord dysfunction is thought to have transverse myelitis or vascular problems. The MRI can sometimes show an inflammatory lesion within the cord. The physician would next send blood for general laboratory tests and studies fir systemic lupus erythematosus and Sjogren’s syndrome, HIV infection, vitamin B12 level to rule out deficiency and a test for syphilis. The next test which is commonly performed is a lumbar puncture to obtain fluid for studies, including white cell count and protein to look for inflammation, cultures to look for infections of various types, and tests to examine for abnormal activation of the immune system (immunoglobulin level and protein electrophoresis). A MRI of the brain is often performed to screen for lesions suggestive of MS. If none of these tests are suggestive of a specific cause, the patient is presumed to have idiopathic transverse traverse myelitis
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or parainfectious transverse myelitis, if there are other symptoms to suggest an infection.
SYSTEMIC LUPUS ERYTHEMATOSUS SYMPTOMS AND DIAGNOSIS Systemic lupus erythematosus is an autoimmune disorder that involves multisystem microvascular inflammation with the generation of autoantibodies. Although the specific cause of systemic lupus erythematosus is unknown, multiple factors are associated with the development of the disease. These include genetic, racial, hormonal, and environmental factors. Many immune disturbances, both innate and acquired, occur in systemic lupus erythematosus. The development of autoantibodies involves a defect in apoptosis that causes increased cell death and a disturbance in immune tolerance. The redistribution of cellular antigens during apoptosis leads to a display of plasma and nuclear antigens on the cell surface. Thus, dysregulated lymphocytes begin targeting normally protected intracellular antigens. Immune complexes form in the microvasculature, leading to complement activation and inflammation. Moreover, antobody-antigen complexes deposit on the basement membranes of skin and kidneys. In active systemic lupus erythematosus, this process has been confirmed based on the presence of complexes of nuclear antigens such as DNA, immunoglobulins, and complement proteins at these sites. Antinuclear antibodies (ANAs) are present in the serum in virtually all patients with active systemic lupus erythematosus, and antibodies to native doublestranded DNA (dsDNA) are relatively specific for the diagnosis of systemic lupus erythematosus. Systemic lupus erythematosus is a chronic autoimmune disease that can affect almost any organ system. Its presentation and course is highly variable, ranging from indolent to fulminant with several clinical manifestations such as: • Constitutional: – Nonspecific fatigue, fever, arthralgias and weight changes are the most frequent symptoms in new cases or recurrent active systemic lupus erythematosus flares. – Fatigue, the most common constitutional symptom, can be due to active systemic lupus erythematosus, medications, lifestyle habits, or affective disorders. Fatigue due to active systemic lupus erythemato-
sus generally occurs in concert with other clinical and laboratory markers. – Fever, another common yet nonspecific symptom, may also be due to many causes. Active systemic lupus erythematosus, infection, and drug fever are the most common etiologies. Careful history taking may help to differentiate these. – Weight loss may occur with active disease. Weight gain may also be due to corticosteroid treatment or active disease such as nephrotic syndrome anasarca. • Musculoskeletal: – Arthralgia, myalgia, and arthritis represent the most common presenting symptoms in systemic lupus erythematosus. – Small joints of the hands, wrists, and knees are involved most frequently. – Migratory asymmetrical pain is often out of proportion with swelling. • Dermatologic: – Cutaneous manifestations of systemic lupus erythematosus comprise 3 diagnostic criteria and multiple other clues to a potential diagnosis of lupus. – Malar rash describes an erythematosus rash over the cheeks and nasal bridge that lasts from days to weeks and is occasionally painful or pruritic. – A report of a photosensitive rash may be elicited from patients if they are asked if they have any unusual rash or symptom exacerbation after sun exposure. – Discoid lesions often also develop in sunexposed areas but are plaquelike lesions with follicular plugging and scarring. They may be part of systemic lupus or may represent discoid lupus without organ involvement, which is a separate diagnostic entity. – Alopecia is a common yet less specific feature of systemic lupus erythematosus that often affects the temporal regions or creates a patchlike pattern of hair loss. – Asking patients if they note any hand color change or pain with cold exposure may yield a history of Raynaud phenomenon. A painful triphasic blue, white, and red color change is a classic description. Although it is not a specific finding for systemic lupus erythematosus, Raynaud phenomenon may
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be seen in up to 20-30 % of patients with SLE. – Other skin lesions related to but not specific to systemic lupus erythematosus include livedo reticularis, panniculitis (lupus profundus), bullous lesions, vasculitic purpura, and urticaria. • Renal: – The kidney is the most commonly involved visceral organ in systemic lupus erythematosus. Although only approximately 50 % of patients develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in almost all patients. – Glomerular disease usually develops within the first few years after onset and is usually asymptomatic. – Acute nephritic disease may manifest as hypertension and hematuria. – Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia. – Acute or chronic renal failure may cause symptoms related to uremia and fluid overload. • Neuropsychiatric: – Widely varying nomenclature has been used to describe systemic lupus erythematosus-related CNS manifestations, although broader syndromes are commonly reported. – Headache is the most common neurological symptom often with migraine or complex migraine features, although a clear association with systemic lupus erythematosus is debated. – Mood disorders such as anxiety and depression are frequently reported. – Cognitive disorders may be variably apparent in patients with systemic lupus erythematosus. Formal neuropsychiatric testing reveals deficits in 21-67 % of patients with systemic lupus erythematosus. Whether this represents true encephalopathy, neurological damage, medication effects, depression, or some other process is unclear. – Psychosis related to systemic lupus erythematosus may manifest as paranoia or hallucinations. – Delirium represents a spectrum of fluctuating altered consciousness characteristic
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of systemic lupus erythematosus. Delirium may be caused by central nervous system vasculitis, encephalopathy, or the manifestations previously called organic brain syndrome. – Seizures related to systemic lupus erythematosus may be generalized or partial and may precipitate status epilepticus. – Stroke and transient ischemic attack may be related to antiphospholipid antibody syndrome or vasculitis. – Movement disorders include chorea and parkinsonism; additionally, transverse myelitis with spastic paraparesis is a rare but serious complication of systemic lupus erythematosus. – Myelopathy, optic neuropathy, or other demyelinating disorders may occur. – Mononeuritis may result in focal peripheral deficits such as foot drop. Sensory neuropathy or mixed polyneuropathy may also be reported. – Aseptic meningitis may occur. • Pulmonary: – Pulmonary manifestation of systemic lupus erythematosus may manifest acutely or indolently, representing many different complications. – Pleurisy with pleuritic chest pain with or without pleural effusions is the most common feature of acute pulmonary involvement. – Shortness of breath or dyspnea may be due to many causes. Serositis due to pericardial or pulmonary effusions, pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, complement-mediated pulmonary leukoaggregation, or infection may be related to lupus disease. – Pulmonary hypertension without underlying parenchymal lung disease rarely occurs with symptomatic dyspnea or right heart failure. – Hemoptysis may herald diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication of systemic lupus erythematosus. • Gastrointestinal: – Gastrointestinal symptoms secondary to primary systemic lupus erythematosus and adverse effects or medication are
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common among persons with systemic lupus erythematosus. – Abdominal pain in systemic lupus erythematosus is significant because it may be directly related to active lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction. – Nausea and dyspepsia are frequent symptoms in patients with active systemic lupus erythematosus and are sometimes difficult to correlate with objective evidence of gastrointestinal involvement. – Jaundice due to autoimmune hepatitis may be reported. • Cardiac: – Heart failure or chest pain symptoms must be carefully examined in patients with systemic lupus erythematosus. – Pericarditis that manifest as chest pain is the most common cardiac manifestation of systemic lupus erythematosus and may occur with or without a detectable pericardial effusion. – Libman-Sacks endocarditis is noninfectious but may manifest with symptoms similar to those of infectious endocarditis. – Myocarditis may occur in systemic lupus erythematosus with heart failure symptomatology. – Accelerated ischemic coronary artery disease is associated with systemic lupus erythematosus and may present as atypical angina equivalents in this predominantly female population. – Coronary vasculitis that manifests as angina or infarction is rarely reported. Coronary thrombosis related to antiphospholipid antibodies is also rare. • Hematologic: – History of multiple cytopenias such as leucopenia, lymphopenia, anemia, or thrombocytopenia may suggest systemic lupus erythematosus, among other etiologies. – Leukopenia and, more specially, limphopenia are common in systemic lupus erythematosus; this and hypocomplementemia may predispose persons with systemic lupus erythematosus to frequent infections.
– Thrombocytopenia may be mild or part of a thrombotic thrombocytopenic purpura (TTP)-like syndrome. – Anemia is occasionally overlooked in young menstruating women.
CASE REPORT A 40-year-old woman attended to hospital complaining of non-scarring alopecia and ascending paresthesia and paraparesis in the lower limbs which rapidly evolved to paraplegia. She also referred urinary and bowel dysfunction. Beginning at the age thirteen, she related episodes of itching and fugacious reddish papules and plaques in the skin soon after hot baths. Since 28 years of age, these lesions have been recurring at yearly intervals, persisting for 3 to 12 months in spite of the use of corticosteroids and hydroxyzine. A couple of years later, she noticed photosensitivity and, at 36 years, a spontaneous abortion occurred. In 2002, she developed recurrent headaches and migratory arthralgias involving the temporomandibular, elbow, wrist, metacarpophalangeal, interphalangeal, coxofemoral, knee, ankle and metatarsophalangeal joints, in addition to episodes of asymmetric peripheral polyarthritis, coinciding with a positive HEp-2 eim ANA indirect immunofluorescence test. On admission, she was conscious and well-oriented, with Cushingoid facies and urticaria lesions predominantly on the trunk. Body mass index: 25.3 kg/m2. Skin temperature was 36.5º C. The heart was rhytmic, 88 bpm, and there were no murmurs. Blood pressure: 140/90 mmHg. The lungs were clear and the respiratory rate 20 ipm. There was a discrete abdominal distension and tympanism, with bilateral sensory abolition below the epigastrium level. The liver and spleen were normal, and there was leg weakness and muscle flaccidity, with ankle jerk and plantar hyporeflexia, mainly on the right side. Erythrocyte count 4.65 x 106/mm3, hemoglobin 13.4 g/dl, hematocrit 41.5 %, mean cell volume 89.2 fl, leukocyte count 17,500/mm3 (neutrophils: bands 11 %, segmented 83 %, eosinophils and nasophile 0 %, lymphocytes 14 %, monocytes 2 %), platelets 224,000/mm3. Erythrocyte sedimentation rate (ESR) 7 mm. INR 1.03, prothrombin time 12.3 sec, albumin 3.4 g/dL, globulins 2,53 g/dL (a1 0.26, a2 0.51, β 0.68, g 1.08 g/dL); glucose 104 mg//dL, urea 19 mg/dL, creatinine 0.9 mg/dL, sodium 137
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mEq/L, chloride 104 mEq/L, calcium 1.21 mmol/L; TSH 1.32 μU/mL; antibodies antithyroglobulin negative, and antiperoxidase 10 U/mL; complement levels C3 134 mg/dL and C4 50 mg/dL; acid a1-glycoprotein 83 mg/dL. Rheumatoid factor and C-reactive protein titers were normal. Anti-Ro (SS-A) and anti-RNP were positive; anti-La (SS-B) and anti-Sm were negative; antibodies anticardiolipin IgM and IgG were negative. Hepatitis B and C and syphilis tests were negative. The urinalysis was normal. The cerebrospinal fluid (CSF) was clear, with 8 cells (neutrophils 51 %, lymphocytes 47 %, monocytes 2 %); protein 90 mg/dL, glucose 57 mg/ dL, chloride 123 mEq/L; serologic tests were negative for herpesvirus, cytomegalovirus, toxoplasmosis, syphilis, cysticercosis and schistosomiasis; Gram-stained smear and routine cultures resulted negative. The radiographic studies of the thorax, hands and knees revealed normal. The complete neuro-ophtamologic evaluation resulted normal. An electroneuromyography study showed absence of motor unities recruitment in the lower right limb, without signs of peripheral neuropathy. The uncontrasted computed tomography of thoracic spinal cord resulted normal, while in magnetic resonance imaging (MRI) the T2-weighed images after gadolinium disclosed multiple focal areas of hyper signal, aspect suggestive of spinal cord demyelinating neuropathy. Moreover, the nerve conduction evoked responses to visual and auditory stimuli, and dysfunction of the sensory fast conducting fibers mainly and FLAIR images of the cranium with gadolinium revealed multiple bilateral focal areas of abnormal enhancement in the white matter, more conspicuously in the posterior parietal lobes and in the left temporal lobe, a finding compatible with demyelization and vasculitis. The skin biopsy disclosed edema, lymphangiectasia, perivenular infiltrate predominantly of mononuclear cells, some degranulated mast cells and rare eosinophilis. The direct immunofluorescence tests with IgA, IgG, IgM and C3 were negative and leukocytoclasia, fibrinoid necrosis and deposits of immunocomplexes were not found in the sample. The diagnoses of chronic urticaria and transverse myelitis associated with systemic lupus erythematosus were well established. The treatment for transverse myelitis was initiated immediately after the establishment of this diagnosis, in order to halt eventual progression of cord compression, and consisted of pulse therapy with methylprednisolone (20 mg/kg/day) during five days, which resulted in
rapid clinical improvement. The patient remains symptomless and she is under outpatient surveillance.
DISCUSSION Transverse myelitis is related to other autoimmune disorders of the nervous system, including Guillain-Barré syndrome, multiple sclerosis and acute disseminated encephalomyelitis. Acute transverse myelitis is a monophasic disorder, the recurrence of which raises the question of multiple sclerosis (MS) or other multifocal CNS disease. We now report three patients with a previously undescribed syndrome of relapsing isolated acute transverse myelitis. Each had two to five attacks over periods of 3 to 8 years, characterized by ascending paresthesias, urinary retention, sensory loss with a thoracic or cervical level, paraparesis, hyperreflexia, and bilateral Babinski signs. MRI demonstrated areas of increased signal intensity on T2- and proton density-weighted scans and decreased signal intensity on T1-weighed scans of the cervical or thoracic spinal cord consistent with an inflammatory or demyelinating process. All patients had normal complete myelograms, oligoclonal IgG bands were consistently absent from the cerebrospinal fluid, cranial MRIs were normal, and there was no other clinical or laboratory evidence of MS, collagen-vascular disease, or active viral infection. They were treated with high doses of intravenous corticosteroids, stabilized between episodes, and had partial or complete recovery. The recognition of these three patients at a single medical center in a 1-year period suggests that relapses of acute transverse myelitis may not be rare. Transverse myelitis is a rare and still poorly understood condition reported in 1-2 % of patients with systemic lupus erythematosus, and is associated with the presence of antiphospholipid antibodies. Urticariform lesions may occur associated with collagen diseases and the diagnosis of SLE must be discarded in patients with chronic urticaria. Although without clear distinction among the acute and chronic forms and the urticarial vasculitis occurrence or urticaria was identified in 44 % of 73 patients with SLE. In the study of López de Maturana et al, 72 % of 32 patients with pathological diagnosis of cutaneous vasculitis were women, with a mean age of 43.5 years, and palpable purpura, erythematosus maculae and urticaria were the most frequently
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observed skin lesions, while connective tissue diseases and systemic vasculitis were the most commonly associated diseases. Autoimmunity plays an important role in the development of chronic urticaria associated with systemic lupus erythematosus and both conditions may be influenced by the use of corticosteroids. Urticaria can not be considered among the diagnostic criteria for SLE. However it may represent one of the first complains of such a patient. In such patients are also involved neuropsychiatric changes. In about 80 % of patients with systemic lupus erythematosus occur seizures and psychosis, in addition to anxiety and depression, dementia, deficit of cranial nerves, headache, peripheral neuropathy, cerebellar dysfunction, chorea, Guillain-Barré syndrome, strokes, aseptic meningitis, and myelopathy.
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In this particular patient, the lupus anticoagulant was negative, and the anticardiolipin antibodies were positive. In general, the antiphospholipid antibodies may be detected in 30-50 % of patients with systemic lupus erythematosus, while the incidence of antiphospholipid antibodies in systemic lupus erythematosus patients with transverse myelitis has been somewhat higher, as reported to 5564 %.
CONCLUSION The association of transverse myelitis and skin eruption (urticaria), in patients whom had the urticaria treated with corticosteroids may be suspect of developing lupus erythematosus. Both urticaria and the transverse myelitis might be signs of the lupus disease.
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