Systemic Lupus Erythematosus (SLE)
- Does this patient have systemic lupus erythematosus?
- What tests to perform?
- How should patients with systemic lupus erythematosus be managed?
What happens to patients with systemic lupus erythematosus?
How to utilize team care?
Are there clinical practice guidelines to inform decision making?
What is the evidence?
Does this patient have systemic lupus erythematosus?
Systemic lupus erythematosus (SLE) is a systemic disease of unknown etiology in which the normal immune responses are directed against the body’s own healthy tissues. Lupus is a disease whose hallmarks are auto-antibodies. While some auto-antibodies are clearly pathogenic (i.e., anti-platelet antibodies, anti-lymphocyte antibodies), others (i.e, the anti-dsDNA antibodies) form immune complexes that overwhelm the reticulo-endothelial clearance and get deposited in the target organs (i.e., kidney) calling forth an inflammatory response; others may be damaging to structures because of cross-reactivity with other self-antigens.
While some people experience only mild rashes and arthritis, others suffer debilitating fever, fatigue, joint pain, or severe organ and/or life-threatening disease. For the purposes of this review, the terms SLE and lupus will be used interchangeably and refer to the same systemic illness.
For research purposes and for the clinical identification of lupus patients, most rheumatologists agree that the 1982 American College of Rheumatology (ACR) Criteria for diagnosis of SLE are very important. These were revised in 1997. Patients who do not meet the criteria may nevertheless have similar disease manifestations and respond to the therapies noted below. SLE criteria, while not excluding a diagnosis, also allow for patients to be included in research protocols.
The criteria include a set of clinical and laboratory features which are listed in Table 1 with their respective prevalence in lupus.
1. The butterfly rash is characterized by a facial fixed erythema that can be flat or raised and spares the nasolabial folds
2. The discoid rash is defined as raised patches, adherent keratotic scaling, or follicular plugging anywhere on the body. Older discoid lesions can cause hyper- or hypo-pigmented scarring. When scarring occurs in an area with hair, alopecia is irreversible, while alopecia in non-scarring lupus dermatitis is reversible. Discoid lupus (and other types of cutaneous lupus) can be an isolated skin disease and does not have to be a component of SLE.
3. Photosensitivity refers to the skin rashes from sunlight described by the patient history or seen by a physician. Photosensitivity does not mean fair-skinned individuals that sun-burn easily but rather a rash that persists beyond typical sun-burn/erythema.
4. Oral or nasal ulcers are usually painless and must be observed by a physician. SLE ulcers are typically seen on the hard palate and should be differentiated from the commonly occurring aphthous ulcers which are painful and are located on the buccal mucosa.
5. Arthritis in lupus is typically non-erosive, non-deforming, and frequently precedes other manifestations of SLE. It is associated with morning stiffness, can be evanescent or persistent, affects the knees and the small joints of hands, proximal interphalangeal (PIPs), and produces objective evidence of inflammation (tenderness, swelling, effusion). It may result in reducible deformities referred to as Jaccoud’s arthropathy.
6. Serositis may present as painful or painless pleural, pericardial or ascitic fluid collections (i.e., fluid in the chest and abdominal cavities). This indicates inflammation of the lining of lung, heart and abdominal structures. Cardiac manifestations in SLE are common and are present in 25% of patients and comprise of: primary lupus carditis, pericarditis, myocarditis, endocarditis, conduction defects and secondary heart disease (ischemic, hypertensive [systemic or pulmonary] and infective). Pulmonary manifestations in SLE (> 30%) include: pleural effusions, pneumonitis, pulmonary hemorrhage, pulmonary hypertension, pulmonary embolism, and shrinking lung syndrome. However, only pleurisy and pericarditis are classified as criteria.
7. Kidney disease is defined by persistent hematuria (not criteria), proteinuria or cellular casts. This is one of the most common organ-threatening manifestations of SLE occurring in as many as 50% of patients. In order to better understand the severity and prognosis of SLE nephritis, the World Health Organization (WHO) and more recently the International Society of Nephrology (ISN) proposed six classes of renal involvement in SLE, as described below.
Class I (Minimal mesangial lupus nephritis): Mesangial accumulation of immune complexes only seen by immunofluorescence, but normal glomeruli by light microscopy.
Class II (Mesangial lupus nephritis): Mesangial thickening and hypercellularity with immune complexes confined to mesangium. Normal capillary loops and tubules, and absent inflammatory cells.
Class III (Focal proliferative lupus nephritis): Focal and segmental involvement, intra- and extra-capillary proliferative lesions which may obliterate capillary lumina, necrotizing and/or sclerosing lesions of capillary tufts, and immune complexes in mesangium and subendothelial surface of peripheral capillary basement membranes.
Class IV (Diffuse proliferative lupus nephritis): >50% of glomeruli involved (usually most or all), diffuse hypercellularity of glomerular tufts with inflammatory cells, necrosis, sclerosis, and occlusion of capillary lumina (“wire loops’), capsular crescent formation, associated tubular atrophy, andextensive immune complex deposition in mesangium and subendothelial side of capillary basement membranes.
Class V (Membranous lupus nephritis): Diffuse thickening of capillary walls, mesangial thickening due to increased mesangial matrix and mesangial cells, absence of inflammatory infiltrate and hypercellularity of capillary tufts, immune complex deposition confined to intramembranous and subepithelial area of capillary basement membrane (carries a slightly better prognosis but nonetheless needs aggressive therapy in order to prevent kidney damage).
Class VI (Advanced sclerotic lupus nephritis): >90% global glomerulosclerosis without any evidence of active glomerular disease.
Class III and IV form a continuum of disease and carry the worst prognosis. If left untreated, they progress to severe kidney damage, end stage renal disease and the need for dialysis or renal transplantation. Interstitial disease may occur as well, though less common and as such not given a classification of its own.
8. Brain disease in lupus can be manifested in different ways. However, seizures or psychosis (organic mental syndrome), though rare, are the most characteristic central nervous system (CNS) manifestations of the disease and as such have been included as criteria.
Other neuropsychiatric (NP) manifestations in SLE might include common features (such as headache, mood disorders and cognitive dysfunction) to rarer events (such as seizures, psychosis and myelopathy). The reported prevalence of NP disease in patients with SLE has varied from 37% to 95%. Once organic disease has been excluded, functional brain disease requires traditional psychiatric care.
The ACR recognizes 19 NP syndromes which are primary manifestations of the disease. This means that these symptoms are not the result of complications of the disease (e.g., hypertension), or of its therapy (e.g., infection), or of a concurrent non-SLE-related NP event. Current evidence suggests that NPSLE is a consequence of vascular abnormalities, autoantibodies, and the local production of inflammatory mediators. Antiphospholipid (APL) and anti-ribosomal P antibodies have shown the strongest clinical correlation with NP disease, whereas the more recently described anti-NR2 glutamate receptor antibody is novel and of potential interest. NPSLE represents a major challenge for clinicians, in view of the uncertainties surrounding the pathogenesis, diagnosis, and treatment. It is clear that the issue of NP disease in patients with SLE requires further study and there are major efforts underway to better understand it.
9. Low blood cell counts (white, red, platelets)
Hemolytic anemia with reticulocytosis
The following low blood cell counts on 2 or more occasions: Leukopenia (<4,000/mm3), Lymphopenia (<1,500/mm3),
10. Specific autoantibodies (anti-DNA, anti-Sm, APL)
Anti-DNA: diagnostic marker for SLE and possible renal disease
Anti-Sm: diagnostic maker for SLE and possible CNS disease
Positive finding of APL antibodies: associated with thrombosis, stroke, fetal loss, and thrombocytopenia. The APL antibodies can be recorded as follows:
an abnormal serum level of IgG or IgM anticardiolipin (ACL) antibodies,
a positive test result for lupus anticoagulant using a standard method, or
a false-positive test result for at least 6 months confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test.
Other antibodies, often associated with lupus, but not included in the criteria, are as follows:
Anti-RNP, also found in mixed connective tissue disease, progressive systemic sclerosis, and arthritis,
Anti-SSA/Ro and anti-SSB/La, also found in Sjogren’s syndrome with dry eyes and dry mouth, and associated with neonatal lupus.
11. Positive antinuclear antibody (ANA)
A definite diagnosis of lupus requires 4/11 criteria to be present. The presence of 4/11 criteria does not automatically mean the patient has SLE; other diseases that have similar symptoms have to be excluded (i.e., a patient with secondary syphilis may meet ACR criteria but does not have SLE).
Other features supporting the diagnosis of SLE include alopecia, fatigue, fever, Raynaud’s syndrome and low complements.
SLE patients develop premature atherosclerosis; their risk of heart attacks and strokes is 10 times higher than that of their age matched controls, and SLE is now considered an independent risk factor for cardiovascular disease. Since the first report of premature coronary heart disease in lupus patients, an increased rate of myocardial infarction (MI) has been confirmed, especially in young females, where the risk may be 50-fold higher than in age-matched controls. Also, subclinical atherosclerosis, evaluated by the presence of carotid artery plaque or coronary artery calcifications, is detected in 30-40% of lupus patients versus 9-16% of controls.
Clinical and laboratory features with their respective prevalence in SLE.
What tests to perform?
The last three criteria are based on laboratory tests and are discussed in detail above.
Imaging is used to identify or rule out specific organ involvement.
While kidney biopsies are not necessary for diagnosing lupus nephritis, they offer important diagnostic and prognostic information and should always be considered in the work-up of all patients with suspected lupus nephritis.
Overall interpretation of test results should be done in the context of the whole clinical and laboratory picture.
Controversies in diagnostic testing
Occasionally, the first manifestation of auto-immunity can be a false positive test for syphilis.
A positive Venereal Disease Research Laboratory test (VDRL) that is not confirmed by a more specific test, like the fluorescent treponemal agglutination test, FTA-ABS is a marker of the presence of anti-phospholipid antibodies.
How should patients with systemic lupus erythematosus be managed?
Lupus is a disease manifested by flares - periods of increased disease activity. Because of the variable nature of this disorder, activity and severity must be assessed repeatedly over time for the presence of new signs or symptoms and/or worsening signs or symptoms in the involved organs. Rheumatologists will also rely on blood tests to predict and verify the presence of such flares. Typically, blood tests will show anti-dsDNA antibodies rise and the complements (C3 and C4) fall with disease activity. The common inflammatory markers (acute phase reactants such as sedimentation rate and the C-reactive protein) may or may not correlate with disease activity.
Disease flares are classified as either 'mild/moderate' or 'severe' based on the severity of symptoms. These definitions help guide treatments, which will target the dysregulation of the immune system. Management of SLE is complicated by the absence of a single “gold standard” measure of disease activity that can be applied to each individual patient. Pooled indices have been developed that include data from patient history, physical examination, and laboratory tests. The most widely used SLE indices include the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index); SELENA-SLEDAI and BILAG (British Isles Lupus Assessment Group index). These indices that allow for more precise definitions of flares have been widely used in clinical trials and clinical research, but may be too complex and time-consuming for usual clinical care.
Mild to moderate flares present as rashes, oral ulcers, and arthritis. These flares are often confined to skin and joints and at times are also associated with fever and fatigue. Treatment options for mild flares (e.g., malar rash, fatigue, and arthralgia) include antimalarials (such as hydroxychloroquine 200-400mg), non-steroidal anti-inflammatories (NSAIDs) and steroids (often less than 10mg).
For moderate flares (e.g., more severe skin rash, alopecia), antimalarials might be adjusted or prednisone doses greater than 10 mg might be prescribed. Immunosuppressants, such as methotrexate or azathioprine, might be added for a “steroid sparing” effect for those patients who required prednisone greater than 10 mg to control symptoms. Antimalarial adjustment options for moderate flares might include briefly increased hydroxychloroquine to 600mg, addition of quinacrine 50mg Monday through Friday, or a switch to chloroquine. While these medications can help reduce symptoms, improve disease manifestations, and sometimes induce remission, they can also have significant negative side effects. Steroids, in particular, commonly cause insomnia, osteoporosis, muscle weakness, and much more. Belimumab (Benlysta), a monoclonal antibody directed against a soluble B lymphocyte survival factor, has recently been approved for patients in this category.
Severe flares refer to life or organ-threatening disease, such as diffuse ulcerating rashes, significant kidney disease, brain disease, very low platelet or red blood cell count, or bleeding into the lungs. For such severe manifestations of lupus, treatment options include continued hydroxychloroquine 400mg, consideration of pulse steroid (1g per day IV for 3 days), followed by or (the addition of) high dose prednisone 1-2mg/kg per day. More potent immunosuppressants, such as IV cyclophosphamide (Cytoxan), mycophenolate mofetil (CellCept), azathioprine (Imuran) or recently developed biologic therapies like Benlysta and rituximab (RTX) (trade name Rituxan) may be added.
Most medications used to treat SLE are immunosuppressants, increasing the risk of infections and the possible risk of malignancies. Specific steroid toxicity includes avascular necrosis of the bone (hips and/or other sites), osteoporosis, hypertension, diabetes, cataracts, thrush, and Cushingoid features. Patients and physicians should be aware of these risks and minimize the dose and duration of therapy with steroids.
Management of some specific organ manifestation:
The treatment of lupus nephritis (LN) has evolved over the last three decades paralleling an evolution in outcomes. Mycophenolate mofetil (MMF) is the main therapeutic tool for the treatment of LN in addition to high dose steroids.
The first 6 months of therapy are the induction phase. During induction, the goal of therapy is to achieve renal remission which can be attained with the immunosuppressant MMF (2-3 grams daily in 2 divided doses) or the cytotoxic IV cyclophosphamide (CYC) (0.5-1g/m2 monthly or 500 mg every 2 weeks for a total of 6 doses). Most lupus experts agree that the first episode of LN with normal creatinine should be treated with MMF and high dose steroids (1mg/kg). If the first LN episode has abnormal renal function, the patient might receive IV CYC with pulse steroids and high dose oral steroids. If there is no response to MMF or worsening nephritis at 6 months, the patient may then be treated with the National Institute of Health (NIH) IV CYC protocol plus steroids. If there is still no response, RTX might be considered as a last resort. Non-immunomodulatory treatments should also be considered in the treatment plan for LN patients; these includeACE inhibitors, angiotensin receptor blockers (ARBs), and statins.
Following induction, we enter the maintenance phase typically 18 months of therapy aimed at preventing renal flares and deterioration of renal function. During maintenance, the therapeutic option is immunosuppression with MMF or azathioprine. It is unclear whether MMF is more efficacious than AZA (data from ASPREVA, MAINTAIN and Contreras is somewhat discordant). However, in clinical practice most clinicians prefer maintenance with MMF, except when pregnancy is contemplated or the cost is prohibitive. Guidelines for the treatment of SLE Nephritis have recently been published.
Skin disease including alopecia can also be treated with topical and intra-lesional steroids in addition to hydroxychloroquine (HCQ) and other systemic therapies. UV protection is essential in all patients regardless of photosensitivity.
Both pleurisy and pericarditis respond well to non-steroidal anti-inflammatory drugs or glucocorticoids. Large volume effusions need therapy with 1mg/kg of prednisone or equivalent. Occasionally, in addition to steroids massive effusions may benefit from drainage. Patients with cardiac tamponade due to SLE pericardial effusion require pericardiocentesis and drainage, or a pericardial window. Recurrent serositis is managed with immunosuppressants.
Other treatment issues:
Pneumocystis pneumonia prophylaxis
Pneumocystis pneumonia (PCP) prophylaxis in patients on steroids/immunosuppression with reduced lymphocyte counts is controversial and is reserved for patients with very low lymphocyte counts (500 total lymphocytes or lower). Due to the concern for Bactrim drug allergy or SLE flare, some physicians might chose atovaquone (Mepron) or dapsone. Patients with recurrent herpes infections may benefit from a prophylaxis with acyclovir or Valtrex. For those patients who develop thrush, local anti-fungal therapies may be sufficient, while Diflucan needs to be used for esophageal candidiasis.
A large number of lupus patients suffer from sicca symptoms during secondary Sjogren's syndrome in SLE. Moisture replacement therapies such as artificial tears may ease the symptom of dry eyes. Some patients with more severe problems use goggles to increase local humidity or have punctal plugs inserted to help retain tears on the ocular surface for a longer time. Additionally, cyclosporine eye drops (Restasis) are available by prescription to help treat chronic dry eye by suppressing the inflammation that disrupts tear secretion. Prescription drugs are also available that help to stimulate salivary flow, such as cevimeline (Evoxac) and pilocarpine.
Severe Raynaud’s syndrome may require medical therapy with calcium channel blockers, angiotensin receptor antagonists, or, in refractory cases, phosphodiesterase inhibitors, endothelin receptor blockers and PGE2 inhibitors.
SLE patients with coronary events have less risk factors than controls suggesting that SLE is responsible for the additional risk, potentially through endothelial activation. SLE can be viewed as a coronary heart disease (CHD) equivalent condition; the targets for LDL cholesterol should be derived from those used in diabetes mellitus. The LDL goal for lupus patients can be inferred to be less than 100mg/dl, and less than 70mg/dl in very high risk patients. The addition of low-dose aspirin should be reserved for patients with additional risk factors. Preventing cardiovascular disease in SLE should address SLE activity, endothelial activation, and lipid lowering.
Systemic lupus erythematosus emergencies
Acute emergencies in SLE include the following:
Severe neurologic involvement
Profound thrombocytopenia with or without thrombosis, thrombotic thrombocytopenic purpura (TTP)-like syndrome
Rapidly progressive glomerulonephritis
Diffuse alveolar hemorrhage
These may be treated with high-dose intravenous steroids and cytotoxic therapy such as cyclophosphamide. In rare cases, diffuse alveolar hemorrhage or profound steroid-refractory thrombocytopenia and TTP may require plasma exchange or therapy with intravenous immunoglobulin (IVIG), respectively.
Lupus patients are at risk of infections due to the nature of SLE and to the medications used to treat it. A lupus patient presenting with fever should always be considered infected until proven otherwise. Recognizing and treating infections in lupus patients is life saving.
What happens to patients with systemic lupus erythematosus?
Recent data from a large international cohort of lupus patients suggest that the 20-year survival in SLE is 70%, a major improvement over the 50% 5-year survival observed 30 years ago. Another recent study showed that the standardized mortality ratio for people with SLE is 2.4, meaning that a person with lupus is 2.4 times more likely to die of any cause than a demographically matched person without lupus, with the most common cause of death being circulatory disease.
Although the death rate among people with lupus has drastically declined in the past decade, with the help of better and earlier treatment, there is still a high incidence of death in young women early in their disease course, related to the disease itself or treatment for the disease.
How to utilize team care?
The care of all patients with SLE should be managed by a rheumatologist, preferably a lupus expert. A nephrologist should be included in the care of a patient that has evidence of SLE nephritis. Other specialty consultations will depend upon observation of interstitial lung disease, cardiovascular, neurological, severe dermatological manifestations, and functional brain disease.
A special circumstance is the care of a pregnant lupus patient. All lupus pregnancies should be considered high risk and cared for by a high-risk obstetrician and the rheumatologist. The main risks are related to the presence of three classes of antibodies. The APLs put both the mother and fetus at risk of clotting complications. The anti-SSA/SSB convey the risk of neonatal lupus, a passively acquired autoimmunity whereby the maternal antibodies cross the placenta and injure the fetus; the most common manifestations of neonatal lupus are congenital heart block, the irreversible manifestation (2-5% of all SSA/SSB-postive pregnancies) and neonatal lupus rash, the reversible manifestation (5-10% of SSA/SSB positive pregnancies) and will require involvement of an experienced pediatric cardiologist and rheumatologist, respectively. Finally, the other antibodies that can put the mother at risk during pregnancy are the anti-dsDNA antibodies which are associated with an increased risk of nephritis.
Patients with SLE benefit from physical therapy if impaired by musculo-skeletal or neurological disease. At times, a psychologist and/or psychiatrist may be added to the team to help manage depression and anxiety.
Are there clinical practice guidelines to inform decision making?
The European League Against Rheumatism (EULAR) published guidelines for management and monitoring of SLE.
The ACR developed guidelines for lupus nephritis.
Only a few RCTs have been performed to establish optimal management of SLE, and several important issues have not been adequately addressed.
ICD-9 code: 710.0
What is the evidence?
Lahita, RG. "The role of sex hormones in systemic lupus erythematosus". Curr Opin Rheumatol. vol. 11. 1999. pp. 352-356.
Tan, EM. "The 1982 revised criteria for the classification of systemic lupus erythematosus". Arthritis Rheum. vol. 25. 1982. pp. 1271-1277.
Hochberg, MC. "Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus". Arthritis. vol. 40. Rheum 1997. pp. 1725.
Weening, JJ. "The classification of glomerulonephritis in systemic lupus erythematosus revisited". Kidney Int. vol. 65. 2004. pp. 521-530.
Shum, K, Askanase, A. "Treatment of lupus nephritis". Curr Rheumatol Rep. vol. 13. 2011. pp. 283-290.
Hanly, JG. "The neuropsychiatric SLE SLICC inception cohort study". Lupus. vol. 17. 2008. pp. 1059-1063.
"The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes". Arthritis Rheum. vol. 42. 1999. pp. 599-608.
DeGiorgio, LA. "A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus". Nat Med. vol. 7. 2001. pp. 1189-1193.
Hanly, JG. "Neuropsychiatric lupus". Rheum Dis Clin North Am. vol. 31. 2005. pp. 273-298.
Manzi, S. "Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus". Arthritis Rheum. vol. 42. 1999. pp. 51-60.
Urowitz, MB. "The bimodal mortality pattern of systemic lupus erythematosus". Am J Med. vol. 60. 1976. pp. 221-5.
Roman, MJ. "Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus". N Engl J Med. vol. 349. 2003. pp. 2399-406.
Petri, M, Buyon, J, Kim, M. "Classification and definition of major flares in SLE clinical trials". Lupus. vol. 8. 1999. pp. 685-9.
Urowitz, M, Ibanez, D, Gladman, D. "Changing outcomes in SLE over 35 years". ACR/ARHP Annual Scientific Meeting 2005.
Bernatsky, S. "Mortality in systemic lupus erythematosus". Arthritis Rheum. vol. 54. 2006. pp. 2550-2557.
Gordon, D. "First-Time Guidelines for Lupus Nephritis: Biopsy for All. American College of Rheumato (ACR) Annual Meeting 2011".
Wajed, J, Ahmad, Y, Durrington, PN, Bruce, IN. "Prevention of cardiovascular disease in systemic lupus erythematosus - proposed guidelines for risk factor management". Rheumatology. vol. 43. 2004. pp. 7-12.
Bertsias, G. "Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics". Ann Rheum Dis. vol. 67. 2008. pp. 195-205.
Mosca, M. "European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies". Ann Rheum Dis. vol. 69. 2010. pp. 1269-74.
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