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     TOC  |  Rheumatology  

SLE - Systemic Lupus Erythematosus                               DX  |  SX  | RX  
Systemic lupus erythematosus (SLE) is a multisystem, potentially fatal autoimmune disease that can involve the skin, joints, muscles, heart, lung, kidneys, peripheral nerves, central nervous system (CNS), and blood. The severity is largely determined by which organs are involved, patients with CNS or renal involvement often having the most serious disease. The diagnosis of SLE is made if patients fulfill at least 4 of the 11 criteria designated by the American College of Rheumatology.

Criteria for the classification of SLE
(If any 4 or more of 11 criteria are met)

  1. Malar rash
  2. Discoid rash
  3. Photosensitivity
  4. Oral ulcers
  5. Arthritis
  6. Serositis
  7. Renal diseas: >0.5 f/d proteinuria, or >3+ dipstick proteinuria, or cellular casts
  8. Neurologic disease: seizures, or psychosis (without other cause)
  9. Hematologic disorders:
  10. Immunologic abnormalities:
  11. Positive ANA test.

(REF: Arthritis Rheum 1982 Nov;25(11):1271-7 )

L = Lymphopenia, leukopenia, anemia, thrombocytopenia
U = Urine abnormality as proteinuria or cellular casts
P = _leuropericarditis
U = Ulcers of mouth
S = Skin discoid or malar rash, photosensitivitiy

A = Arthritis
N = Neurologic Sx as seizure, psychosis
A = Autoantibodies as ANA, Anti-DNA, ANti-Sm, Anti-CardioLipin Ab

The 1982 revised criteria for the classification of systemic lupus erythematosus
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ

The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.


Drugs assoc. with lupus-like syndrome:
Symptoms include fever, arthritis, and serositis but not renal or CNS disease and normally resolve in 6 to 8 weeks after the drug is stopped. In 90% of the cases an anti-histone antibody can be identified. Specific skin manifestations, particularly those of SCLE, may also be associated with use of thiazides, diltiazem, griseofulvin, sulfonylureas, and carbamazepine.

   


Constitutional Symptoms:
are frequent, especially fatigue, which is reported by 80 to 100% of patients. Fever and weight loss occur in more than 60% of patients as well. Lymphadenopathy is a common manifestation of SLE.

Skin Manifestations
including the typical malar rash & the Discoid lupus erythematosus (DLE) lesions that are scarring and occur either alone or in association with SLE.
Subacute cutaneous LE (SCLE) includes two types of lesions: psoriasiform and annular polycyclic.

Renal Manifestations
Renal disease is common in most patients with SLE and can be asymptomatic until there's advanced disease.
The excretion of more than 500 mg of urinary protein /24 hours (or greater than 3+ proteinuria on dipstick testing), the presence of casts (including RBCs, hemoglobin, granular, tubular, or mixed), hematuria (more than 5 RBCs /hpf) or pyuria (more than 5 WBCs/hpf ), or an elevated serum creatinine level is evidence of renal disease and should prompt the clinician to a more thorough investigation of renal status and referral to a specialist.

The World Health Organization (WHO) classification of lupus nephritis is the standard by which most lesions are classified and can prognosticate survival of the kidney.
Mesangial abnormalities (WHO class II) - in 40% of the patients,
Focal glomerulonephritis (class IIIA and class IIIB) -in 20% of the patients,
Diffuse proliferative glomerulonephritis (class IV) - in 40% of the patients, and
Predominant membranous lesion (class V) - in less than 10 % of the patients.
Class I and class II lesions require no treatment. Class III lesions can undergo transition to a more proliferative and diffuse process, necessitating treatment. The consequences of nephrotic syndrome, hypertension, hyperlipidemia, and hypercoagulability, seen with both class IV and class V lesions, can increase mortality in these patients. Class V (membranous) lesions usually have a slowly progressive course, and treatment varies, including steroids or immunosuppressives, neither of which have been shown to alter the course of the disease. Class IV (diffuse proliferative) lesions affect more than 50% of the glomeruli, with progression to renal failure in most cases.

Musculoskeletal Manifestations
common, including acute arthritis, typically involving the small joints of the hands, wrists, and knees, is usually episodic and symmetrical in distribution.  Avascular necrosis (AVN) is seen in 5% of SLE patients, affecting the hip most commonly but also the shoulder, knee, and ankle.

Cardiac Manifestations
Pericarditis is the most common cardiac Sx (precordial chest pain and a pericardial rub), 20 to 30% in most large series.
Myocarditis presenting as dysrhythmias and/or cardiomegaly is a less common manifestation .
Libman-Sacks endocarditis, with sterile verrucous vegetations on the mitral valve, is less common.
Premature atherosclerosis is a major cause of morbidity and mortality in SLE.

   

Pulmonary Manifestations
include pleuritis, pulmonary alveolar hemorrhage, pneumonitis, pulmonary infiltrates, chronic interstitial lung disease, shrinking lung syndrome, pulmonary hypertension, and pulmonary embolism. Acute pneumonitis frequently responds to corticosteroids (1 mg per kg per day). Pulmonary alveolar hemorrhage is a rare but serious manifestation and carries a high mortality. Very aggressive treatment is required for improved survival, and cytotoxic agents or plasmapheresis may be necessary.

Patients with chronic interstitial lung disease can present with typical symptoms of restrictive lung disease, including nonproductive cough, dyspnea on exertion, and basilar rales on physical examination. Pulmonary hypertension may be a finding in many of the collagen-vascular diseases and occurs in 1 to 2% of SLE patients. Pulmonary hypertension can present insidiously with progressive exertional dyspnea, and early disease can be detected by an abnormal carbon monoxide diffusing capacity (DL CO) on pulmonary function testing. Pulmonary embolus is a serious potential complication of antiphospholipid (APL) antibody syndrome (discussed later) in patients with SLE.  Pleuritic chest pain in an SLE patient cannot be assumed to be due to SLE serositis. In an SLE patient with a normal chest film, pulmonary embolus must be excluded.

Gastrointestinal Manifestations
Abdominal pain, anorexia, nausea, and vomiting are common gastrointestinal manifestations of SLE. Serositis is the most common underlying causative disorder and frequently responds to moderate doses of corticosteroids. The presenting manifestation of mesenteric vasculitis can be lower abdominal pain accompanied by frank or occult rectal bleeding, and perforation of the bowel can result. If the diagnosis of mesenteric vasculitis is suspected, intensive investigation should be undertaken, with appropriate treatment with high doses of steroids. Acute pancreatitis can occur in SLE patients, manifesting as abdominal pain, nausea, vomiting, and elevated serum amylase.

Neuropsychiatric Manifestations
Diffuse manifestations are the most common CNS presentation in NP-SLE patients (60% of cases).

The most common histologic finding in the brain of SLE patients is a vasculopathy, with associated microinfarcts. True vasculitis is rare. The evaluation of an SLE patient with CNS manifestations includes cerebrospinal fluid (CSF) evaluation for routine studies, antineuronal antibodies (seen in patients with diffuse manifestations), quantitative CSF immunoglobulins, and oligoclonal bands (elevations commonly seen in active CNS SLE disease). Magnetic resonance imaging (MRI) can sometimes demonstrate small, high-signal-intensity vascular lesions but cannot define active disease.

Treatment of the diffuse manifestations may include administration of antiseizure drugs or antipsychotics but usually requires high-dose steroids (1 mg per kg per day) or pulse high-dose steroids (1 gram per day for 3 days). Refractory cases sometimes respond to intravenous cyclophosphamide, plasmapheresis, or a combination of these. Focal manifestations seen in association with APL antibodies are treated with anticoagulation, in addition to the aforementioned medications.

Hematologic Manifestations
Cytopenias, including anemia, leukopenia, lymphopenia, and thrombocytopenia, are frequent findings in SLE.

Malignancy
Malignancy continues to increase in SLE patients with increasing use of alkylating agents. Over 100 cases of non-Hodgkin's lymphoma have been reported, and there is an increased frequency of gynecologic cancers. In one series, the mean time from onset of treatment to cancer was only 4.1 years. Frequent surveillance, including Papanicolaou smears and mammograms, is important.

Antiphospholipid Antibodies
A variety of clotting abnormalities, including the presence of the lupus anticoagulant, manifested as a prolonged activated partial thromboplastin time (APTT) that does not normalize with mixing studies. Patients with the lupus anticoagulant, a false-positive result on VDRL testing, or a high titer of anticardiolipin antibodies fall under the umbrella term of "APL antibody-positive" and are predisposed to thrombotic events. The APL antibody syndrome describes the association of these APL antibodies with arterial and venous thrombosis, recurrent fetal loss, and immune thrombocytopenia. Management of SLE patients with APL antibodies who have never had a thrombotic event is usually with low-dose aspirin therapy. Once patients have had a thromboembolic event, lifelong anticoagulation with warfarin is established, with an INR (International Normalized Ratio) of 3.0, to prevent recurrent events.

   


Frequency of lab. abnormalities in SLE:

(REF: Medicine 1985;64:285)


RX for SLE:                     REF:  Harrison Online 2-2003
There is no cure for SLE.  Complete sustained remissions are rare.  
Goal of Rx:  to control acute, severe flares and to develop maintenance strategies in which symptoms are suppressed to an acceptable level, usually at the cost of some drug side effects.
Approximately 25% of SLE patients have mild disease with no life-threatening manifestations, although pain and fatigue may be disabling. These patients should be managed without glucocorticoids.

Arthralgias, arthritis, myalgias, fever, and mild serositis may improve on nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates.

The dermatitides of SLE, fatigue, and lupus arthritis may respond to antimalarials. Doses of 400 mg hydroxychloroquine daily may improve skin lesions in a few weeks. Side effects are uncommon and include retinal toxicity, rash, myopathy, and neuropathy. Regular ophthalmologic examinations should be performed at least annually, since retinal toxicity is related to cumulative dose. Other therapies include sunscreens (an SPF rating 15 is recommended), topical or intralesional glucocorticoids, quinacrine, retinoids, and dapsone. Recent studies suggest that daily oral doses of dihydroepiandrosterone may lower disease activity in patients with mild SLE.   Systemic glucocorticoids should be reserved for patients with disabling disease unresponsive to these conservative measures.

Life-threatening, severely disabling manifestations of SLE that are responsive to immunosuppression should be treated with high doses of glucocorticoids (1 to 2 mg/kg per day). When disease is active, glucocorticoids should be given in divided doses every 8 to 12 h.
Acutely ill lupus patients, including those with proliferative GN, can be treated with 3 to 5 days of 1000 mg intravenous "pulses" of methylprednisolone, followed by maintenance daily or alternate-day glucocorticoids. Disease flares are probably controlled more rapidly by this approach, but it is unclear whether long-term outcome is changed.

The use of cytotoxic agents (azathioprine, chlorambucil, cyclophosphamide, methotrexate, mycophenolate mofetil) in SLE is probably beneficial in controlling active disease, reducing the rate of disease flares, and reducing steroid requirements. Patients with lupus nephritis have significantly less renal failure and better survival if treated with combinations of glucocorticoids plus intravenous cyclophosphamide; azathioprine as the second drug is less beneficial but is also effective in preventing renal failure.

Algorithm for the treatment of SLE  

REF:
Harrison Online 2-2003
Rakel: Conn's Current Therapy 1999
Patient Fact Sheet on SLE from ARA 
New Approaches for Treatment of SLE - Annals of Internal Medicine, 15 December 1998 by Philip M. Bulman and Gene Hunder
Rational Approach to Dx of SLE 1999 Richard Wernick, MD, Carolyn Coyle, MD
     [Hospital Medicine 35(4):16-22, 1999]

           


Classification of Vasculitis  Correspondence (NEJM 12-2-1999;341:23)

Arthritis Rheum 1990 Aug;33(8):1101-7

The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis.

Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, Calabrese LH, Fries JF, Lie JT, Lightfoot RW Jr, et al  NIAID, NIH, Bethesda, MD.

Criteria for the classification of Wegener's granulomatosis (WG) were developed by comparing 85 patients who had this disease with 722 control patients with other forms of vasculitis. For the traditional format classification, 4 criteria were selected:  abnormal urinary sediment (red cell casts or greater than 5 red blood cells per high power field), abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates), oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. The presence of 2 or more of these 4 criteria was associated with a sensitivity of 88.2% and a specificity of 92.0%. A classification tree was also constructed with 5 criteria being selected. These criteria were the same as for the traditional format, but included hemoptysis. The classification tree was associated with a sensitivity of 87.1% and a specificity of 93.6%. We describe criteria which distinguish patients with WG from patients with other forms of vasculitis with a high level of sensitivity and specificity. This distinction is important because WG requires cyclophosphamide therapy, whereas many other forms of vasculitis can be treated with corticosteroids alone.

Arthritis Rheum 1990 Aug;33(8):1065-7

The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction.

Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, Leavitt RY, Lie JT, Lightfoot RW Jr, Masi AT, et al  -  Mayo Clinic, Rochester, MN.

           

02252003