Systemic lupus erythematosus (SLE) is an inflammatory systemic autoimmune disorder that has a very wide ranging spectrum of clinical manifestations as well as varied clinical course. It is characterized by the presence of autoantibodies, in particular the antinuclear antibodies (ANA) and a relapsing and remitting course. SLE affects mainly women in their childbearing years, although men, the very young, and the elderly are not spared. The disease presents subtly in many patients such as with intermittent mild photosensitive facial rashes ( Fig. 8-1 ), malaise, or incidental findings of mild thrombocytopenia, anemia or elevated erythrocyte sedimentation rate (ESR). On the other hand, the presentation can be very acute as in a medical emergency of sudden dyspnea with or without hemoptysis, a change in mental status or coma, or even an acute abdomen. The Lupus in Minorities: Nature vs. Nurture (LUMINA) cohort study, a longitudinal outcome study, reported that acute disease onset is associated with higher levels of overall disease activity.
The rheumatologist’s first task when consulted is to decide whether the patient indeed has SLE or a nonrheumatologic condition, or not uncommonly, even both disorders concurrently. The next step is the assessment of disease severity, extent of organ involvement and damage, and disease activity. Patients with SLE have a nearly fivefold increased risk of death compared with the general population. Several observational cohorts and case-control studies have identified infections, diabetes mellitus, hypertension, dyslipidemia, atherosclerosis, coronary heart disease, osteoporosis, avascular bone necrosis, and certain types of cancer (non-Hodgkin’s lymphoma, lung cancer, hepatobiliary cancer) as common causes of morbidity and mortality in SLE patients. Attention must be directed toward the presence or absence of these comorbidities when planning the patient’s medical care. Treatment plans should be discussed and formulated with the patient and, when appropriate, with the family. Medical cost is often a concern to the patient faced with a chronic, potentially disabling illness and should be taken into consideration when planning investigations and treatment to encourage patient compliance. Socioeconomic determinants are important in the ultimate outcome of SLE as noted by several investigators, and poverty, not ethnicity, is a predictor of diminished survival in patients with lupus from the LUMINA cohort.
It is increasingly clear that successful management of a patient with lupus requires the rheumatologist to be well versed in internal medicine and practice a holistic approach, working closely with the family physician. Good outcome also often requires the participation of a team of other health care workers including the relevant specialists, nurse counselor, therapist, and social worker. Readers are to refer to the two chapters in this book for details on specific management of the different organ system manifestations. This chapter discusses the broad principles in the approach to the lupus patient and practical considerations in decisions on treatment, monitoring of the disease, and comorbidities.
Assessing patients with lupus requires attention to detail and becomes easier with experience. As in the evaluation of any other disease, the approach starts with a good history and thorough physical examination, followed by well thought out investigations.
History and Physical Examination
It is essential to remember that the American College of Rheumatology (ACR) SLE classification is not a set of diagnostic criteria. In addition, new clinical features and autoantibodies may develop in a patient over time. In the case of a patient who has a prior diagnosis of SLE, it is advisable to go over the patient’s history, investigations, and all available past medical records, to confirm that the diagnosis of SLE is appropriate. Cases of misdiagnosis of SLE based on a positive ANA or weak positive anti-dsDNA antibody (anti-dsDNA Ab) test carried out in a laboratory with less than satisfactory quality assurance occasionally happens. Primary Sjögren’s syndrome may be mistaken for SLE when sicca symptoms are mild and overlooked.
History should include constitutional symptoms and inquiry into all organ systems. The patient is also asked about symptoms that suggest associated connective tissue diseases such as secondary Sjögren’s syndrome and antiphospholipid syndrome (APS). Obtain details of other medical conditions in particular whether there is history of diabetes mellitus, hypertension, hyperlipidemia, cardiovascular and cerebrovascular events, and osteopenia/osteoporosis. In women, obtain menstrual and obstetric history, contraceptive practices and any pregnancy plan. Information on treatment received by the patient already known to have SLE is important and should include both conventional and alternative medications used as well as the disease response and any adverse drug reactions experienced.
In the physical examination, remember to examine the oral mucosa (oral ulcers are painless), feet and fingers for cutaneous vasculitis ( Fig. 8-2 ), pinna for rashes ( Fig. 8-3 ), and scalp for small areas of scarring alopecia that may not be reported by the patient. Fundi are examined for signs of retinal vasculitis. During the physical examination, take note of all organ involvement and any potentially irreversible damage such as scarring alopecia.
Investigations can be grouped into those for diagnosis, monitoring disease activity, monitoring adverse effects of drug therapy; and monitoring comorbidity. Readers are to refer to the other chapters in this book on investigations of specific organ involvement.
There is no necessity to order a whole host of serologic tests for every patient. These tests are best ordered with a clinical question in mind and interpreted accordingly. The anti-dsDNA Ab test should not be used as a screening test for SLE because it is present in only about 60% of patients with lupus even when repeated over time. Neither is its pres-ence alone diagnostic of SLE. Besides reflecting active SLE, it is linked to renal involvement. In clinical practice, the main value of the anti-dsDNA Ab is as an indicator of disease activity and in monitoring the patient’s response to treatment especially in nephritis. There are exceptions to this. Some patients have been reported to have high levels of this antibody without disease activity, and on the other hand, it may be negative during active disease, particularly when organs other than kidneys are affected. Prospective studies have also shown a rise in anti-dsDNA Ab levels well before a major SLE flare and a decrease at the time of or following a flare. A patient with high anti-dsDNA Ab should be observed more closely. The trend of the anti-dsDNA Ab levels in a patient is more relevant in clinical practice than its absolute value.
The Anti-Ro/SSA Ab is ordered when suspecting the rare ANA-negative lupus or when secondary Sjögren’s syndrome is considered. More commonly, it is ordered together with anti-La/SSB Ab and the antiphospholipid antibodies (aPLs) (immunoglobulin G [IgG] and immunoglobulin M [IgM] anticardiolipin antibodies [ACA], lupus anticoagulant [LA], anti-B2 glycoprotein I [anti-B2GP I]) when a patient plans to start a family. Anti-Ro/SSA Ab and anti-La/SSB Ab are associated with neonatal lupus (NNL). The incidence of congenital heart block due to NNL in the offspring of a mother with anti-Ro Ab is about 2%, with a recurrence rate of 16% in subsequent pregnancies. Antiphospholipid antibodies (aPLs) are ordered when secondary APS is suspected and before pregnancy to assess the risks in pregnancy to the fetus and mother and the need for closer monitoring and prophylactic treatment with aspirin.
Complete blood count and white blood cell differential are informative and inexpensive tests for assessing activity in clinical practice. A normochromic and normocytic anemia is consistent with any chronic illness or an acute blood loss such as in pulmonary hemorrhage (note: hemoptysis may be clinically absent during pulmonary hemorrhage). A macrocytic anemia suggests hemolysis, and the reticulocyte count is high in this instance unless there is a vitamin B 12 or folate deficiency. Data from the LUMINA study have shown that anemia/hematocrit is a predictor of not only disease activity but also damage accrual. Leukopenia and lymphopenia indicate active SLE unless patient is already on immunosuppressive drugs such as cyclophosphamide when the possibility of adverse drug reactions has to be entertained. Azathioprine often increases the mean corpuscular volume but rarely causes a pancytopenia. Thrombocytopenia indicates either active SLE or associated secondary APS (when platelets are often only slightly rather than markedly reduced). In a pregnant patient with lupus, thrombocytopenia may be due to active disease or a variety of other causes including secondary APS; pre-eclampsia; and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome associated with pregnancy; heparin therapy; and the gestational state itself.
ESR and complements C3 and C4 are used in conjunction with anti-dsDNA Ab to assess disease activity. A high ESR indicates active disease, although at times, it may remain persistently high without any evidence of lupus activity. In this instance, look for evidence of secondary Sjögren’s syndrome, occult infection, or malignancy. In the presence of a high ESR, C-reactive protein (CRP) may help differentiate active SLE from infection when it is normal or slightly elevated. CRP is moderately raised in patients with SLE with manifestations of serositis and Jaccoud’s arthropathy, and therefore, in these instances, it is not useful in the exclusion of infection.
Complements C3 and C4 are low in active lupus. Rarely, patients may have persistent hypocomplementemia due to inherited complement deficiencies, such as the C4A/C4B null allele that is associated with lupus. During pregnancy, complements C3 and C4 may rise to supranormal levels, and a flare with complement activation may occur despite apparently normal levels of complements C3 and C4. It is more helpful to follow the trend of the complement levels to predict disease flare in pregnancy.
Urine analysis for red and white blood cells, protein, and cellular casts are important tests of renal activity and may reveal clinically silent renal disease. During pregnancy, the patient with history of renal involvement may have a worsening of proteinuria due to physiologic response to pregnancy or pre-eclampsia and not necessarily a flare of lupus nephritis. In this instance, there should not be any feature of active urinary sediments. Blood urea, electrolyte, and serum creatinine should be ordered at baseline. A high creatinine with active urinary sediments indicates active lupus nephritis and warrants prompt initiation of treatment and further investigations such as renal ultrasound and biopsy to avoid delay in instituting appropriate immunosuppressants.
A chest x-ray study is routinely ordered before starting corticosteroids or immunosuppressants. In countries in which the infection is endemic and when individuals are at high risk for hepatitis B, screening for this infection should be ordered because fulminant hepatitis may occur when high-dose corticosteroids or immunosuppressive drugs are used. All patients should have a baseline assessment of fasting lipids and glucose, calcium, phosphate, and bone mineral densitometry (when indicated). When appropriate, electrocardiograms, stress echocardiography, or other cardiac screening measures and duplex scanning of the carotids may be ordered.
FORMULATING TREATMENT PLANS
Based on current knowledge and information, the aims in treatment of SLE should be early control of disease activity, prevention of disease relapse and good control of comorbidities ( Table 8-1 ). The principles in management of SLE are outlined in Table 8-2 , and keys to successful management are provided in Table 8-3 .
In planning treatment, the doctor should take into consideration several issues including comorbidities and concurrent medications, patient’s work and other daily activities, and whether the patient is planning or plans to have a child in the near future. There should be an assessment of the extent of disease damage. Both the doctor and the patient must be realistic in what can be achieved. It is also good to anticipate difficulties that may be encountered such as patient noncompliance with medication, use of alternative therapies, and the frequent defaulters.
Control of diabetes mellitus, hypertension, and hyperlipidemia must be optimized to reduce risk of atherosclerosis and its complications. If patients are taking drugs that predispose them to osteoporosis, bone mineralization should be regularly monitored and appropriate prophylaxis with calcium, vitamin D, bisphosphonate, or hormone replacement therapy (HRT) prescribed. Patients with chronic hepatitis B should be comanaged with a hepatologist because special care is required to avoid fulminant hepatic failure in a patient on corticosteroid or immunosuppressants. Although there are no randomized controlled trials (RCTs) to evaluate the effectiveness of lifestyle modifications, general health advice on adequate rest to relieve fatigue of active disease, exercise, weight reduction, and a healthy diet should be provided. Advise patients on avoidance of known trigger factors. Sun avoidance is encouraged, especially during midday, and sunscreens are recommended. Smoking must be stopped because not only does it worsen Raynaud’s phenomenon but it also interferes with the efficacy of antimalarials and raises pulmonary pressures. Freemer and associates demonstrated that cigarette smoke is an important risk factor for the occurrence of anti-dsDNA Abs in patients affected with SLE.
With regards to oral contraceptives, two RCTs have concluded that oral estrogen contraceptives do not increase the risk for flare in stable disease although estrogen use has been associated with increased risk for developing SLE. HRT results in significantly better change in bone mass density compared with placebo or calcitriol, without increasing the risk for flares. HRT is contraindicated in patients with aPLs or thrombophilia, and the general guidelines for HRT should be taken into account, including the exclusion of hypertension, high cholesterol, obesity and smoking.
SLE is not in itself a contraindication to pregnancy, except when there is severe organ system complications such as pulmonary hypertension or renal failure, when it may be best avoided. Pregnancy loss in patients with SLE is decreased if the patient has been in remission for 6 to 12 months before conception. Thus, pregnancy in SLE should be planned. A management strategy is decided with the patient, before conception ( Table 8-4 ). Preconception counseling includes discussions on medication, a review of obstetric history, and history of hypertension. Drugs that are teratogenic and should be stopped at least 3 months before conception include methotrexate, mycophenolate mofetil, and cyclophosphamide. These drugs should be replaced with an alternative such as azathioprine, because withdrawal may cause a flare during pregnancy. Pregnancy should be postponed for 6 months after withdrawal of bisphosphonates. Patients are also advised about possible exacerbations of SLE in the postpartum period.