Systemic Lupus Erythematosus (SLE)

Does this patient have systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is a systemic disease of unknown etiology in which immune responses are directed against the body’s own tissues.

SLE is a disease whose hallmarks are autoantibodies and complement activation. While some autoantibodies are clearly pathogenic (i.e., anti-platelet antibodies, anti-lymphocyte antibodies), others (i.e., anti-dsDNA antibodies) form immune complexes that overwhelm the reticulo-endothelial clearance. Immune complexes deposit in target organs (i.e., kidney), activating the complement cascade, and inducing an inflammatory response.

We recognise patients with SLE by constellation of clinical and laboratory abnormalities. Patients present with varied manifestations, some people experience only mild rashes and arthritis, others suffer debilitating fever, fatigue, joint pain, or severe organ and/or life-threatening disease. This pleomorphic picture suggests a heterogeneous, rather than a unified, disease process.

Classification criterion for SLE were originally developed by the American College of Rheumatology (ACR) in 1982 and revised in 1997. The ACR criteria contain 11 domains, and a patient needed at least 4 at any point in their lifetime. Concern that not all patients with SLE meet ACR criteria triggered the Systemic Lupus Collaborating Clinics (SLICC) group to revise and validate a second SLE classification criteria in 2012. The SLICC criteria contained 17 domains, and patients needed to fulfill a minimum of four criteria, with at least one clinical criteria AND one immunologic criteria. Presence of biopsy proven lupus nephritis can be used as the sole clinical criteria in the presence of ANA or anti-dsDNA antibodies.

Patients who do not meet the classification criteria may nevertheless have SLE since these criteria are not meant for diagnosis. In the strictest sense, SLE classification criteria standardises how patients can be included in research protocols.

Clinical and laboratory manifestations of SLE

1. Acute cutaneous lupus This includes the characteristic malar rash (or butterfly rash), which is characterized by a facial fixed erythema that can be flat or raised and spares the nasolabial folds. Other lupus skin manifestations include maculo-papular rash, which is usually photosensitive. Sub-acute cutaneous lupus typically manifest with either raised annular rash or psoriasisiform lesions.

2. Chronic cutaneous lupus This includes discoid rash, a localized when over the head, neck, scalp or ears or generalised if it occurs below the neck. Discoid rash presents with keratotic scaly patches, with follicular plugging. Older discoid lesions can cause hyper- or hypopigmented 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. 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.

4. Alopecia patchy hair loss can occur in SLE especially in the setting of discoid disease. However, diffuse and non-scaring alopecia is also very common in patients with SLE.

5. Arthritis in SLE 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. However, only pleurisy and pericarditis are in the classification criteria. Serositis indicates inflammation of the lining of lung, heart and abdominal structures. Clinical features of a pleural/pericardial rub, effusion, or EKG changes are needed satisfy classification criteria. Cardiac manifestations in SLE are common and are present in 25% of patients, comprising of: primary lupus carditis, pericarditis, myocarditis, endocarditis, conduction defects and secondary heart disease (ischemic, hypertensive [systemic or pulmonary] and infective).

7. Kidney disease is defined by persistent hematuria (not in classification criteria), proteinuria, or cellular casts. This is one of the most common organ-threatening manifestations of SLE, clinically apparent 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 based off of histopathologic findings 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): < 50% of glomeruli are involved. Focal and segmental involvement, intra- and extracapillary 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, diffuse hypercellularity of glomerular tufts with inflammatory cells, necrosis, sclerosis, and occlusion of capillary lumina (“wire loops”), capsular crescent formation, associated tubular atrophy, and extensive 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. Neuropsychiatric SLE can be manifest in many different ways. 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 in the classification criteria.

Other neuropsychiatric (NP) manifestations in SLE might include less specific features (such as headache, mood disorders and cognitive dysfunction) to rare 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 as primary manifestations of the disease. This requires that they are not the result of complications of the disease (e.g., hypertension), therapy (e.g., infection), or 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 anti-N-methy-D-aspartate (NMDA) receptor antibodies associated with cognitive dysfunction. 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 investigation and there are major efforts underway to better understand it.

9. Hemolytic anemia has been described in 10% of patients with SLE, this is usually direct Coombs positive. Patients with SLE can have other reasons for anemia including anemia of chronic disease and drug induced anemia.

10. Leucopenia WBC count of < 4,000 meets classification criteria for SLE and occurs in up to 50% of patients with SLE. For many patients, WBC counts drop during periods of active disease. Patients may have neutropenia or lymphopenia (absolute lymphocyte count < 1,500) and is associated with risk of infection.

10. Thrombocytopenia Immune mediated thrombocytopenia (ITP) is fairly common in SLE. Platelet counts < 100,000 is a classification criterion for SLE. ITP may present many years prior to other SLE manifestations. While low platelets are generally common in SLE, symptomatic thrombocytopenia with bleeding is uncommon. Other causes of thrombocytopenia such as microangiopathic hemolytic anemia should also be ruled out.

Autoantibodies

Positive antinuclear antibody (ANA) – this is often used as a screening test for SLE and ANA antibody is thought be positive in nearly 100% of patients with SLE. ANA tests are generally reported with an immunofluorescence pattern and a titre, which may have some bearing on the probability of a SLE diagnosis.

Other autoantibodies of note are:

• Anti-dsDNA: These autoantibodies are considered highly specific and perhaps diagnostic of SLE. Anti-dsDNA antibodies are strongly associated with renal disease and titre of anti-dsDNA antibodies can track with disease activity in some SLE patients. The specificity of this antibody for SLE depends upon the assay used for detection.

• Anti-Sm: are highly specific and used as a 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 IgA or IgM anticardiolipin (ACL) antibodies

  an abnormal serum level of IgG, IgA, or IgM beta 2 glycoprotein 1 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 SLE, 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.

Complement levels

Low complement levels including C3, C4, CH50 levels- are considered markers of disease activity, this is especially true of lupus nephritis. Patients with SLE also may have genetically low levels of C4, this itself confers risk of autoimmune disease. These patients have a low C4 level even in the absence of active disease.

How should patients with systemic lupus erythematosus be managed?

SLE is a disease manifested by flares – periods of increased disease activity. Because of the paroxysmal 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. In some patients, flares are associated with a rise in anti-dsDNA antibodies and a fall in C3, C4 levels, which correlates best in patients with renal disease. Among the common inflammatory markers, ESR correlates better with disease activity than CRP.

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 tool in SLE to measure disease activity is the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index). Several disease activity measures have been derived from the SLEDAI including SELENA-SLEDAI, SLEDAI- 2K, and the SLEDAI-2K Responder Index-50 (this allows measurement of flares and a 50% improvement in disease activity). The BILAG (British Isles Lupus Assessment Group) index was originally described in 2004 and provides more organ specific scoring system based on the physician’s intent to treat. There are 86 questions in the BILAG that the physician assesses as 1-improved, 2-same, 3-worse, and 4-new manifestations. More recently, a new composite disease activity tool called the SLE responder index (SRI) has been used for clinical trials. The SRI is a combination of the SELENA-SLEDAI, BILAG, and Physician Global Assessment (PGA). 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/moderate flares

Mild to moderate flares generally 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 200-400 mg), non-steroidal anti-inflammatories (NSAIDs) and low dose steroids.

For moderate flares (e.g., more severe skin, rash, alopecia), moderate doses of steroids may be used. Immunosuppressants, such as methotrexate or azathioprine, might be added for a “steroid sparing” effect for those patients who required prednisone > 10 mg/day to control symptoms. Antimalarial adjustment options for moderate flares might include maximizing hydroxychloroquine, addition or substitution with quinacrine 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

Severe flares refer to life or organ-threatening disease, such as significant kidney disease, brain disease, very low platelet or red blood cell count, vasculitis. For such severe manifestations of SLE, treatment generally starts with pulse solumedrol (1 gram/day IV for 3 days), followed by high dose prednisone 1-2 mg/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.

Management of some specific organ manifestation:

Renal disease

The treatment of lupus nephritis (LN) has evolved over the last three decades paralleling an evolution in outcomes. Good quality studies have established that mycophenolate mofetil (MMF) is as effective as clyclophosphamide in the treatment of lupus nephritis, perhaps even more so in African American and Hispanic patients.

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) (0.5-1 gram/m² monthly or 500 mg every 2 weeks for a total of 6 doses). Most SLE experts agree that the first episode of LN with normal creatinine should be treated with MMF and high dose steroids (1 mg/kg). This is especially true in younger patients of child bearing age. 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 include ACE inhibitors, angiotensin receptor blockers (ARBs), and statins.

Following induction, a 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

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. IVIG and mycophenolate mofetil may be efficacious for refractory subacute cutaneous disease.

Serositis

Both pleurisy and pericarditis respond well to non-steroidal anti-inflammatory drugs or glucocorticoids. Large volume effusions need therapy with 1 mg/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.

Raynaud's phenomenon

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 Prostaglandin E2 inhibitors.

Sicca symptoms

A large number of patients with SLE suffer from sicca symptoms due to secondary Sjogren’s syndrome in SLE. Moisture replacement therapies such as artificial tears may ease the symptom of dry eyes. Some 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.

Other treatment issues:

Infection prophylaxis

The guidelines for pneumocystis pneumonia (PCP) prophylaxis in patients with SLE are not well defined. PCP prophylaxis should be considered on patients who need >1 month of high dose steroids, or are on stronger immunosuppressive agents like Cytoxan (i.e. induction therapy for lupus nephritis). Patients with SLE may have low lymphocyte counts either due to disease itself or secondary to medications, PCP prophylaxis should be considered in patients with a total lymphocyte count <500. 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 valacyclovir. For those patients who develop thrush, local anti-fungal therapies may be sufficient, while fluconazole needs to be used for esophageal candidiasis.

Cardiovascular risk factor assessment

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 patients with SLE, 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 patients with SLE versus 9-16% of controls. SLE patients with coronary events typically have less traditional 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 patients with SLE can be inferred to be less than 100 mg/dl, and less than 70 mg/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.

Pregnancy in Lupus

A special circumstance is the care of a pregnant patient with SLE. All SLE pregnancies should be considered high-risk and cared for by a high-risk obstetrician and the rheumatologist. Presence of antiphospholipid antibodies especially lupus anticoagulant has adverse effects on pregnancy outcome. Preterm deliveries, low birth weight, preeclampsia and eclampsia are all associated with placental dysfunction due to APS. 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-positive pregnancies) and neonatal lupus rash, the reversible manifestation (5-10% of SSA/SSB positive pregnancies). Finally, anti-dsDNA antibodies, prior history of nephritis, hypertension and uncontrolled disease activity during pregnancy are all associated with poor outcomes. Counselling of patients in child bearing age group for planned pregnancy during periods of disease remission is very important.

Long term medication side effects

Most medications used to treat SLE are immunosuppressants, increasing the risk of infections and the possible risk of malignancies. Many medications can cause bone marrow suppression or long term immunodeficiencies. 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.

Urgent situations in SLE

Acute emergencies in SLE include the following:

• Severe neurologic involvement, like cerebritis, transverse myelitis

• Systemic vasculitis

• 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.

Acute infections also can present as medical emergencies in these patients. It is often difficult to differentiate between SLE flares and infections, indeed infections can often trigger SLE flares. Recognizing and treating infections in patients with SLE is critical.

What happens to patients with systemic lupus erythematosus?

Recent data from a large international cohort of patients with SLE 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 those with SLE is 2.4, meaning that a person with SLE is 2.4 times more likely to die of any cause than a demographically matched person without SLE, with the most common cause of death being cardiovascular 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 SLE expert. A nephrologist should be included in the care of a patient that has evidence of SLE nephritis. Other specialty consultations will depend upon presence of specific organ manifestations. Pregnant patients need follow up with maternal-fetal medicine for high risk care.

Patients with SLE benefit from physical therapy if impaired by musculoskeletal or neurological disease. Depression and anxiety are fairly common in patients with SLE, significantly affecting quality of life. Depression is also associated with disease activity in SLE. Integrated care with a counsellor or psychiatrist is beneficial.

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.

Table I.

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