SYSTEMIC LUPUS ERYTHEMATOSUS



SYSTEMIC LUPUS ERYTHEMATOSUS

Diagnosis

Systemic lupus erythematosus is a multi-system disease which can be diagnosed in a patient who fulfills at least four out of the following eleven criteria (present for at least six weeks).

1. Malar rash (butterfly rash) – a light red rash over the cheeks and nasal area.

2. Photosensitivity – a significant rash or malaise which follows relatively brief exposure to the sun.

3. Discoid lupus – a scarring hyperpigmented plaque often present on the face or upper extremities. Most frequently occurs in patients with discoid lupus without systemic involvement. Approximately 10% of these patients develop systemic lupus.

4. Oral ulcers – these can be asymptomatic.

5. Serositis - pleuritis, pericarditis, or peritonitis.

6. Arthritis - generally non-deforming and transient.

7. Nephritis.

8. Neurologic – peripheral, central or cognitive.

9. Hematologic – leukopenia, thrombocytopenia, or hemolytic anemia.

10. FANA

11. SM, double-stranded DNA, anti-cardiolipin antibodies, lupus anticoagulant.

These criteria have been proven useful in epidemiologic studies. The probability of lupus in a general population is less than 5% with zero, one or two criteria. With three criteria positive, approximately 10% of patients have lupus. With three clinical criteria plus a positive FANA, 60% of respondents have lupus and FANA with four clinical criteria gives over 80% positive diagnosis of lupus. These criteria are also useful to review when evaluating the clinical activity of a lupus patient. It is usually apparent from interview or inspection if there are skin rashes, serositis, arthritis or neurologic abnormalities. Since hematologic and renal abnormalities are often asymptomatic, the patient should be screened on a regular basis with a CBC, creatinine and urinalysis. If the patient has no obvious clinical complaints and these labs are normal, there is a high likelihood that their disease is quiescent.

Epidemiology

Ninety percent of patients are female with an age of 15-40. Elderly patients occas develop lupus and generally have more pulmonary disease and Sjögren’s syndrome with less arthritis. The overall prevalence of lupus in the population is approximately 1 in 2000. In young women, it is approximately 1 in 750. In black women it is 1 in 250. Patients with a positive family history of lupus, approximately 1 in 20 have the disease.

Etiology

A variety of abnormalities have been found in B-cell and T-cell function. Patient with lupus have an impaired antibody induction and increased spontaneous antibody production. They also have impaired hypersensitivity with decreased numbers of T-cells and variable function of the T-cells. There is clearly a genetic predisposition to lupus as evidenced by race (increased in Blacks and Asians), the increased family incidence, and an increased incidence of HLA DR2 and DR3 as compared to the general population. There is evidence for hormonal influence (increased incidence in females). There is also may be some environmental triggers. Drugs induce lupus-like syndrome. The sunlight also can trigger flares of lupus probably through antigen exposure from sun damage in the skin.

Antinuclear Antibodies

The first lab test for lupus was the LE prep, initially described by hematologists at the Mayo Clinic in the 1950’s. The test is performed by placing a patient’s serum in with a mixture of bare nuclei, polys and complement. If the patient’s serum contains antibodies to DNA, these will attach to the bare nuclei and be engulfed by the white cells with opsonization from complement. The sensitivity and specificity of this test is approximately 70-80%. The fluorescent antinuclear antibody (FANA) is a more accurate test with a sensitivity and specificity are in the high 90s. In this test, the patient’s serum is poured on top of an epithelial cell plate with exposed nuclei. The serum is then washed off leaving behind any antibodies attached to the epithelial cell nuclei. Then fluorescently tagged rabbit antibodies directed at the human FC region are added to the mixture which illuminates the patient’s antibodies attached to constituents of the nucleus.

It has been found that there are five major patterns of fluorescent staining of nuclei. The diffuse or homogenous pattern is most common and least specific. The speckled pattern is seen primarily in connective tissue disease. The nucleolar pattern is seen in scleroderma and myositis. An anticentromere pattern is seen in CREST. A rim pattern is rarely see in active lupus. Unfortunately, the patterns are not specific enough to accurately categorize disease (except in CREST). Therefore, procedures have been developed which separate out the various components of the nucleus and test for antibodies to each component. When nuclei are broken apart, the initial separation is into components which precipitate in saline and those which are extracted (extractable nuclear antigens—ENA).

Precipitate

1) Histones – antibodies to histones are seen in approximately 60% of lupus patients and 90% of patients with drug induced lupus.

2) DNA – antibodies to double stranded DNA are seen in lupus and the titer correlates with activity of lupus (particularly renal activity). Antibodies to single stranded DNA are not used since they are nonspecific.

ENA

1) SM – antibodies to SM are seen in 30% of SLE and are very specific for lupus.

2) RNP – antibodies to ribonuclear protein are seen in approximately 60% of lupus and 100% of MCTD.

3) SSA (RO) – seen in 30% of lupus, 70% Sjogren’s, cutaneous lupus and mothers of babies with fetal heart block.

4) SSB (LA) – seen in 60% of Sjogren’s and 15% of lupus.

5) Jo-1- seen in 20% of polymyositis/dermatomyositis. Associated with increased pulmonary disease.

6) SCL-70 – seen in scleroderma. Associated with increased pulmonary disease.

In summary, the FANA is very useful as a screening test, with a positive titer set at 1:160 to achieve a sensitivity of 98% and a specificity of 95%. However, even at 1:160, in an unscreened population only 1 of 40 individuals with a positive FANA will have lupus, since the incidence is 1 in 2000, and at 95% specificity 5% of normal will have a positive FANA. The only clinically useful pattern is the centromere—which indicates CREST. Once the patient has a positive FANA, there is no reason to repeat it. The antibody to double stranded DNA is very useful in evaluating the clinical activity of lupus and plays a role in the diagnosis for lupus. The other antibodies to nuclear antigens do not tend to vary in titer or positivity over time, so should only be performed once.

Serositis

Pleuritis and pericariditis are common, diagnosed with usual studies. They usually respond to 20 – 60 mg of prednisone daily. For recurrent pericarditis, consider a cardiac window for permanent resolution. Other pulmonary and cardiac manifestations are not specifically listed as lupus criteria but may include ILD, pulmonary hemorrhage, arrhythmias, valvular lesions and myocarditis.

Peritonitis is more difficult to evaluate, since there is no specific diagnostic test for it, and abdominal pain can be from appendix, gallbladder, ovarian cysts, PUD, diverticulitis etc. Most ominous is bowel vasculitis, which can be difficult to diagnosis prior to bowel infarction, and post infarction has a high mortality. Bowel vasculitis requires high dose Cytoxan and steroids, if tolerated with the inevitable development of sepsis.

Nephritis

Approximately 50% of lupus patients develop significant renal disease. This can be a presenting manifestation or can occur at any time during the course of lupus. Approximately 10% of patients develop severe renal disease and require aggressive therapy. Many of these patients will go on to dialysis and renal transplantation. Renal disease has been classified by the WHO criteria as follows: I-normal, II-mesangial, III-focal proliferative, IV-diffuse proliferative, V-membranous. Type IV diffuse proliferative requires aggressive therapy due to a high risk of renal failure. Type V -membranous disease will usually be treated with mycophenylate or imuran. The biopsies are also rated according to the amount of active inflammatory changes versus chronic scarring.

Acute renal disease should be treated with high dose steroids and either IV Cytoxan for significant nephritis (monthly x6) or Mycophenolate (cellcept). Studies suggest that a 3 month course of cytoxan followed by prolonged mycophenylate is safer and as efficacious as a longer course of cytoxan. A renal biopsy is useful in patients that have a new onset of nephritis or in established lupus patients with a gradual deterioration of renal function. In these cases, patients with active inflammatory changes can be treated aggressively while those patients with chronic scarring may be treated more conservatively.

All lupus patients should be screened regularly with a creatinine and urine analyses. If there are any abnormalities in these tests, serologic screening with double stranded DNA and complement levels will provide additional useful information. Complements fall and DS-DNA rises with active glomerulonephritis.

CNS

Sixty percent of patients with lupus will experience neuropsychiatric symptoms. The psychiatric manifestations of CNS lupus include psychosis and depression, which may be due to the disease itself or due to the social problems involved with having a chronic disease. Approximately 30% of patients with lupus have cognitive defects with abnormalities on testing of attention and memory. The neurologic manifestations of lupus are protean – seizures, aseptic meningitis, chorea, tremors, HA, psuedotumor cerbri, and peripheral neuropathies. All of these require usual evaluation and treatment. It is generally unclear if further immunosuppression will help these conditions, treatment is individualized.

Transverse myelitis is rare but devastating, emergent IV Cytoxan and bolus steroids are indicated. Strokes in lupus are probably related to an associated antiphospholipid syndrome and generally require anticoagulation.

Lupus patients are commonly taking steroids. At high doses, steroids can cause psychosis which may lead to difficulty in determining whether confusion is due to lupus or the steroid. If initial evaluations are unremarkable, the steroid dose must be empirically raised or lowered and the patient followed closely in a brief clinical trial. Patients taking nonsteroidal anti-inflammatory medications may have CNS side effects. This is particularly true of Ibuprofen which can cause an aseptic meningitis as an idiosyncratic reaction. 80% of patients with psychosis from lupus have an antiribosomal P antibody, but diagnostic value is limited since it is found in 20% of asymptomatic lupus. Anticardiolipin antibody or lupus anticoagulant are associated with a thrombotic disorder in lupus.

Heme

ITP and Coombs positive hemolytic anemia are common, easily diagnosed and can be treated with usual measures – steroids, IVIG, other immunosuppressants. Recurrent cases generally resolve after splenectomy. Leukopenia is common and often doesn’t require treatment. TTP is rare but life threatening, and requires immediate plasma exchange. Suspect is if platelets AND Hct are quickly dropping, diagnostic test is a smear with microangiopathic hemolysis.

General treatment

Lupus patients should use sunscreens and protective clothing to shield them from sunlight. Minor arthralgias will respond well to NSAIDs. Hydroxychloroquine (Plaquenil) has been used since the 1900s to control skin and joint disease. Recently, it has been found to also decrease the number of major flares, so we now try to use it in all patients,. Patients on hydroxychloroquine should have ophthalmologic checks every year to screen for toxicity. Acute or severe flares can be treated with Prednisone. Minor manifestations require 10 or 20 mg a day whereas major flares require 60 mg a day. Severe manifestations as noted above may require bolus IV solumedrol 1 gm daily x3, cellcept or Cytoxan. For patients who require chronic high doses of steroids we may use Imuran as a steroid sparing agent. During pregnancy we can cautiously use steroids, plaquenil or Imuran. Cellcept is considered teratogenic.

TB 2016

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