Summary

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that mainly affects women of childbearing age. Despite an improvement in the overall survival of patients in the past few decades, morbidities as a result of uncontrolled disease activity and treatment complications are still our major concerns. There are considerable inter-ethnic differences in the clinical presentation, treatment response and prognosis. Extrapolation of the Caucasian data to our local Chinese patients may not be applicable. This article gives an update of the recent insights in the manifestations, diagnosis and treatment of SLE based on our local experience.

摘要

紅班狼瘡是一種臨床多樣化的疾病，常見於懷孕年齡的女性。儘管過去數十年整體的存活率有所改善，但病情未受控制和治療引致的併發症仍然是關注的重點。不同種族紅班狼瘡的臨床表現、治療反應及預後均有一定程度的分別，外國的資料未必適用於本地中國人。本文闡述了本地紅班狼瘡的臨床表徵、診斷和治療反應的最新資料。

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Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that mainly affects the younger population. It is increasingly recognized by family physicians working in both the public and private sectors. With the development of different medical specialties in the past few decades, most SLE patients are nowadays grouped under the care of the rheumatologists and the nephrologists. Knowledge in the clinical presentation, diagnosis, immunopathogenesis, treatment and complications has advanced tremendously in the past decade. However, there have been very few updates on SLE with special reference to the local situation in Hong Kong.^1-3 This article summarizes the recent developments in various clinical aspects of SLE, with emphasis on local data, which are useful for physicians managing these patients.

Demographic characteristics and prevalence

The exact prevalence of SLE in Hong Kong is unknown. An estimation based on data from population census and the actual number of SLE patients followed-up in the New Territories West cluster of the Hospital Authority showed a prevalence of 60/100000 (0.06%).¹ The prevalence among women was 100/100000 (0.1%). This figure may have been slightly underestimated because patients seen in the private sector were not included. Nevertheless, SLE in our Chinese population is about twice as common as the European Caucasians in whom the prevalence were quoted to be 25-45/100000.

SLE mainly affects women of reproductive age. The female preponderance of the disease is consistent among different ethnic groups. An analysis of 1082 adult onset SLE patients being followed-up in three large regional hospitals in Hong Kong showed a female to male ratio of 8.6 to 1.⁴ The mean age was 30.5 13 years and the mode was the age range between 18 and 23 years.

Clinical presentation

The butterfly rash is the hallmark of SLE. The typical description is fixed butterfly-shaped erythema, flat or raised, over the malar eminences, and sparing the nasolabial folds. However, in actual clinical practice, this typical butterfly rash is uncommon. More frequently, patients present with erythematous rash on the face and forehead which adopts different morphologies and may be associated with photosensitivity. A common presentation of SLE to family physicians is fatigue, systemic upset, low grade fever, facial rash, arthritis / arthralgia, and mild alopecia, together with a positive ANA, leucopenia and raised ESR (but normal C-reactive protein). Some patients may present with acute organ dysfunction which necessitates hospitalization. Common major organ manifestations of SLE are renal, haematological and neuropsychiatric diseases.

SLE is a clinically heterogeneous disease. No two patients are exactly alike and the same patient may develop different features at different time points. We recently performed a cluster analysis of the clinical features of 1082 SLE patients who were observed for an average of 8 years.⁴ Three distinct patterns of clinical manifestations were identified - one subset of patients presented with predominantly musculoskeletal and dermatological features, and had the best prognosis; another subset of patients presented predominantly with more serious renal disease which led to a higher mortality, while the remaining group of patients had heterogeneous presentation including multiple organ involvements. Renal disease in this latter subset was less serious and the ultimate prognosis was better than that of the second cluster of patients.

Autoantibodies

A myriad of autoantibodies can be found in patients with SLE, some of which such as anti-nuclear, antiphospholipid and anti-Ro antibodies are present up to 9.4 years before the disease is diagnosed.⁵ The number of autoantibodies may increase just before onset of symptoms, which may be triggered off by multiple but yet unknown intrinsic or environmental factors.⁶ However, the chance of developing SLE in those patients who are found incidentally to have these antibodies is unknown as there are no prospective studies in this regard. In a multicenter prospective study of lupus-like disease (<4 ACR criteria) in Europe, the chance of conversion into SLE after 3 years' follow-up was only 2.5%.⁷

Anti-nuclear antibody (ANA) is present in almost all patients with SLE and is thus a sensitive marker. However, it lacks specificity for SLE. The higher the titer of ANA, the higher is the specificity for an underlying autoimmune disease.

Anti-dsDNA and anti-Sm are specific lupus autoantibodies. However, they have limited sensitivity which may also be affected by the methodology of detection and the cut-off ranges. Interpretation with other clinical features is mandatory during the diagnostic process.

Anti-Ro and anti-La antibodies in SLE are associated with photosensitivity, subacute cutaneous skin lesions and sicca symptoms. The maternal 52kD anti-Ro increases the risk of congenital heart block in the foetus. Anti-nRNP (or anti-U1RNP) is characteristic for undifferentiated connective tissue disease (formerly called mixed connective tissue disease). In SLE patients, isolated presence of the anti-nRNP is associated with Raynaud's phenomenon and less renal involvement.

The antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) are present in up to one-third of our local SLE patients at any time of the disease course. A high titer of the anticardiolipin antibodies and persistent positive test results are often more clinically significant. The presence of an antiphospholipid antibody (at least twice 12 weeks apart) together with either thrombosis or unexplained miscarriages constitutes the antiphospholipid syndrome (Table 1). This set of criteria, also known as the Sapporo criteria, was modified in 2006 to include anti-b2-glycoprotein-I as one of the antiphospholipid antibodies required for the diagnosis.⁸ However, these criteria do not include certain non-thrombotic clinical manifestations of the antiphospholipid syndrome such as livedo reticularis, heart valve lesions, thrombocytopenia and hemolytic anaemia. In the setting of SLE, the fulfillment of these criteria qualifies the diagnosis of the secondary antiphospholipid syndrome.

Finally, anti-ribosomal P antibody (or anti-P antibody) in SLE has been associated with certain neuropsychiatric manifestations such as psychosis and depression. Interpreted with other clinical and serological results, anti-ribosomal P may help to establish the diagnosis of neuropsychiatric lupus, though its usefulness is limited by the low sensitivity.

Mortality and morbidity

The survival of SLE patients has improved tremendously in the past few decades. While the 5-year mortality of SLE in the 1960s' was more than 50%, it was less than 10% in most lupus series around the world. The cumulative 5-year and 10-year survival of our local SLE patients is 92% and 83%, respectively.⁹ These figures are similar to those reported in the Caucasians in the 1990s'.

With the improved survival of patients with the disease, many SLE patients are however living with significant morbidities. This is contributed by irreversible damage of organ functions as results of refractory disease manifestations and complications of treatment. A recent study showed that organ damage, as assessed by the SLE International Collaborating Clinics Damage Index (SDI), was present in 38% of our local SLE patients after 6 years of onset of the disease.¹⁰ Common causes for damage were musculoskeletal complications such as avascular bone necrosis and osteoporotic fractures, uncontrolled renal disease, sequelae after cerebrovascular and cardiovascular events and cyclophosphamide-induced ovarian failure.

Accelerated atherosclerosis and arterial thromboembolism

SLE patients are prone to premature atherosclerosis. Endothelial activation and dysfunction, the earliest stage of atherosclerosis, is more common in SLE patients than age-matched healthy controls. Subclinical atherosclerotic disease of the coronary and carotid vessels is also present in a substantial proportion of apparently asymptomatic SLE patients. The prevalence of coronary calcification as detected by spiral CT scan and carotid plaque as detected by Doppler ultrasonography is between 31% and 37%.¹¹ These figures are alarming because most patients are relatively young.

Compared to age- and gender-matched individuals without SLE, the risk of acute myocardial infarction in SLE patients is 2-50 times higher, whereas the risk of stroke is increased by 2-10 folds.¹² Patients in the 35- to 44-years old age group are particular at risk of acute myocardial infarction. In a comparative study of the incidence of thromboembolism in SLE patients of different ethnic groups, it was demonstrated that arterial thromboembolism such as acute myocardial infarction and cerebrovascular accident occurred in 8.5% of new onset Chinese patients with SLE within the first 5 years of diagnosis.¹³ The incidence was higher than that of the Caucasians.

Traditional vascular risk factors per se are insufficient to account for the observed incidence of arterial thromboembolism in SLE patients. A number of non-traditional but SLE-related factors are likely to be involved.¹¹ These are summarized in Table 2.

Avascular bone necrosis (AVN)

Musculoskeletal damage is the most common treatment-related morbidity in our local SLE patients.¹⁰ An early study showed a 12% point prevalence of AVN in a cohort of local SLE patients.¹⁴ The commonest site was the hip (95% of all cases), with bilateral involvement in 72% of these patients. The main risk factors were high dose corticosteroids and the presence of the lupus anticoagulant. However, whether the route of corticosteroid administration (such as intravenous pulse methylprednisolone) and the antiphospholipid antibodies are associated with AVN in SLE remain controversial.

Premature menopause

Premature menopause may lead to infertility and is an important aetiological factor for the increase in arterial thromboembolism and osteoporotic fractures in patients with SLE. Although autoimmunity itself may cause ovarian inflammation and damage, most cases of premature ovarian failure in SLE are induced by cyclophosphamide treatment. This is a major concern for most patients who are in their reproductive age. The risk of ovarian failure in cyclophosphamide-treated SLE patients is dependent on the age and cumulative doses of cyclophosphamide delivered.^15,16 In selected patients, the use of alternative immunosuppressive agents such as mycophenolate mofetil or concomitant administration of the gonadotropin releasing hormone analogues may reduce the incidence of this untoward treatment complication.

Osteoporosis

Besides long-term corticosteroid treatment, SLE patients are particularly prone to osteoporosis because of renal insufficiency, premature ovarian failure, avoidance of sun exposure, disabling arthritis and myopathy, failure to achieve a peak bone mass and the use of medications such as anticoagulants and anticonvulsants. Studies of Caucasian patients reported that 9.1% to 12.3% of SLE patients suffered from one or more fragility fractures following the diagnosis of SLE. The major risk factors identified were older age, menopause, longer use of corticosteroids and lower bone mineral density as measured by the dual X-ray absorptiometry (DXA) scan. A recent study of our local cases revealed that osteoporosis was a serious problem in older postmenopausal Chinese women with SLE.¹⁷ Seventy- four percent of the studied patients were osteopenic at the hip and 48% were osteoporotic at the lumbar spine. Six percent of patients had multiple thoracic and lumbar vertebral compression fractures.

Adequate calcium intake, weight bearing exercises, cessation of smoking and habitual drinking should be advised. Patients receiving long-term corticosteroids should be routinely prescribed calcium and vitamin D. Bisphosphonates should be considered in those with osteopenia. For patients who have already developed spinal or hip fractures, more aggressive therapies such as the sequential use of parathyroid hormone and the bisphosphonates may be considered. A recent pilot randomized controlled study demonstrated safety and efficacy of raloxifene in maintaining femoral neck and spinal bone mineral density in our local postmenopausal SLE patients receiving long-term corticosteroid therapy.¹⁸

Management strategies

The treatment strategies of SLE depend on a number of factors such as the severity and reversibility of the clinical manifestations, and whether the underlying pathology is inflammatory or non-inflammatory (eg. thrombotic).^2,3 Mild SLE such as joint and skin disease can be managed with topical corticosteroids, sun-screening and the anti-malarial agents. Systemic corticosteroids and other immunosuppressive drugs are mainly indicated for major organ disease. Moreover, an optimal management plan should include primary and secondary prevention of morbidities such as osteoporosis and thrombosis.

Lupus nephritis

Lupus nephritis is the most frequently studied manifestation of SLE because it is fairly common in Chinese. A prospective study of 216 new onset SLE patients showed that 60% of our local patients will develop some degree of renal disease after 5 years of SLE diagnosis.¹⁹ Of the different histological classes of lupus nephritis, diffuse proliferative nephritis carries the worst prognosis, with a 10-year renal survival (survival without dialysis) rate of 80% despite treatment with either intravenous or oral cyclophosphamide.^16,20

Milder form of lupus nephritis (ISN/RPS class I, II, III) is usually manageable with corticosteroids. Azathioprine can be used as a corticosteroid sparing agent and for the treatment of extra-renal manifestations. Mild class V disease can be treated with small doses of corticosteroids and angiotensin converting enzyme (ACE) inhibitors. Class IV disease and severe class V disease require more aggressive induction regimens consisting of corticosteroids and cyclophosphamide, mycophenolate mofetil (MMF), cyclosporin A or tacrolimus.^21,22

The standard treatment of severe proliferative lupus nephritis is corticosteroids combined with intravenous pulse cyclophosphamide²¹ but continuous oral cyclophosphamide has been used with success in our local cases.^16,23 Recent randomized controlled trials have shown that the efficacy of MMF is similar to that of cyclophosphamide in the treatment of lupus nephritis but toxicities such as ovarian failure and major infections are much less frequent.^24,25 Therefore, MMF may be considered as an alternative treatment option in patients with lupus nephritis. However, it should be noted that long term data of MMF beyond 5 years are still unavailable and there is currently no evidence that it works in patients with an initial serum creatinine of more than 200umol/L or those with rapidly progressive crescentic glomerulonephritis.²⁶

The evidence of the calcineurin inhibitors for lupus nephritis is less strong because results from controlled trials are not yet available. They are indicated in patients who are intolerant to other immunosuppressive agents because of cytopenia. Tacrolimus is advantageous over cyclosporine A because of the lower incidence of hypertrichosis, gingivitis, hypertension and dyslipidemia. However, dose-related metabolic complications such as hyperglycaemia and neurological adverse effects such as tremor should be closely monitored.²⁷ Moreover, tapering and discontinuation of the calcineurin inhibitors may be associated with disease flares. This can be minimized by very slow tapering and the sequential use of another immunosuppressive agent.

Neuropsychiatric lupus

Neuropsychiatric lupus is an intriguing manifestation of SLE. Nomenclature and case definitions for 19 neuropsychiatric syndromes in SLE have been provided by the American College of Rheumatology in 1999²⁸ (Table 3). Recent studies have shown that around 23% of our local SLE patients have neuropsychiatric manifestations according to these definitions after a mean of 6.7 years from SLE diagnosis.²⁹ Compared to the Caucasian series, headache and mood disorders are less frequent. Whether this is due to a genuine inter-ethnic difference because of genetic, immunological, socio-cultural and geographic factors warrants further elucidation.

The optimal treatment of neuropsychiatric lupus is unclear because of the general lack of controlled trials. Some manifestations such as seizure, headache, anxiety, depression require symptomatic treatment only. Aggressive immunosuppressive regimens are indicated for certain neuropsychiatric manifestations such as acute confusional state, psychosis, myelitis, optic neuritis, cranial and peripheral / cranial neuropathies, mononeuritis multiplex and myasthenia gravis. A combination of high dose corticosteroid and an extended course of intravenous pulse cyclophosphamide is being adopted by most physicians because its efficacy has been documented in uncontrolled studies.³⁰ Pulse methylprednisolone is indicated for severe or rapidly progressive neurological disease. A recent controlled trial demonstrated that intravenous pulse cyclophosphamide is more effective than pulse methylprednisolone in the treatment of severe neuropsychiatric SLE.³¹ Prednisolone combined with sequential daily oral cyclophophamide and azathioprine has also been used with success in patients with lupus psychosis.³² For patients who are intolerant or refractory to conventional therapies, other regimens such as intravenous immunoglobulin, immunoadsorption, mycophenolate mofetil, cyclosporin A and immunoablative cyclophosphamide may be considered.^33,34

Retinopathy surveillance in patients using antimalarials

Hydroxychloroquine (HCQ) is an effective drug for the treatment of lupus dermatitis and arthritis. Retinopathy is exceedingly rare during the first five years of therapies in patients without risk factors.³⁵ Risk factors for retinopathy include older age (>60 years), obesity, daily dose > 6.5mg/kg/day, use of HCQ for more than 5 years, liver and renal dysfunction and pre-existing eye disease such as macular degeneration. The recent guideline from the American Academy of Ophthalmology recommends baseline ophthalmological examination which includes fundal examination, testing of visual acuity, visual field and color vision for all patients about to receive hydroxychloroquine.³⁵ Low risk patients only require surveillance visits once every 2-5 years, depending on their age. For high risk patients, at least annual ophthalmological examination is mandatory. Patients should be instructed to read Amsler grid at home and report eye symptoms as soon as they develop.

Therapeutic advances in SLE

Novel therapeutic options for SLE should target at achieving a higher efficacy than conventional therapies, reducing treatment-related adverse effects, and ideally inducing a long-lasting disease remission.³⁶ Table 4 summarizes the newer treatment modalities that have been used in patients with SLE and those which are undergoing clinical trials.

Of these newer modalities, B cell depletion, B cell tolerization and anti-cytokine therapies appear to be most promising. Rituximab is a chimeric monoclonal antibody that specifically directs against the CD20 molecule on the surface of pre-B cells and mature B cells. Administration of rituximab leads to profound depletion of these B cell subsets. Stem cells, pro-B cells and plasma cells are not affected. Open-labelled trials have reported that rituximab is effective in various refractory SLE manifestations in adults and in children, including lupus nephritis and neuropsychiatric lupus.³⁷ No major serious infective complications have been reported to date with rituximab treatment per se in patients with SLE. Epratuzumab and belimumab are two other biological agents being tested in SLE. They can achieve B cell depletion similar to that of rituximab.

Special issues in SLE

Pregnancy

Compared with normal pregnancies, maternal and foetal complications such as pre-eclampsia, miscarriages, intra-uterine growth retardation, prematurity, low birth weight and stillbirth are more common in lupus pregnancies.³⁸ This is because of multiple factors that include active SLE, particular nephritis, renal dysfunction, pre-existing hypertension at conception, as well as high dose corticosteroid therapy and the presence of the antiphospholipid antibodies.

Whether pregnancy per se leads to an increase in lupus flares remains controversial but active disease, in particular renal lupus, within 6 months of conception is a major risk factor for disease relapse during pregnancy. Thus, patients who plan to be pregnant must be in clinical remission for at least 6 months. A longer period of disease quiescence is advised if a patient has serious organ manifestations in the past. Couples should be adequately counselled before conception. The presence of the anti-52kD anti-Ro is associated with congenital heart block and the obstetricians should be alerted. For patients with a bad obstetric history as a result of the antiphospholipid syndrome, aspirin with and without subcutaneous heparin, is indicated to improve the outcome of the foetus.

Use of exogenous oestrogens

Whether exogenous oestrogens exacerbate SLE was a controversial issue.³⁹ A recent randomized placebo- controlled trial in the United States demonstrated an increase in mild to moderate flares of SLE with the use of hormonal replacement therapy (HRT).⁴⁰ Coupled with an increased risk of breast cancer and thromboembolism, the use of HRT for osteoporosis per se in SLE is now out of favour, and a short course of HRT should only be considered in those with intractable climacteric symptoms.

On the other hand, two recent randomized controlled trials have confirmed that oral contraceptive pills (OCs) do not increase the risk of lupus flares.^41,42 OCs may be considered in SLE patients with inactive disease, without a history of thromboembolism or the antiphospholipid antibodies, and in the absence of other contraindications.

Primary and secondary prevention of the secondary antiphospholipid syndrome

Patients with SLE should be regularly surveyed for traditional risk factors of atherosclerosis.¹¹ In patients with multiple risk factors, screening investigations for atherosclerosis in major vessels may be considered. General advice such as physical exercise, weight reduction, dietary modification and lifestyle changes should be given. Hyperlipidaemia should be vigorously controlled. An initial target level of LDL-cholesterol of <2.6 mmol/L (100mg/dL) should be contemplated for all SLE patients. The use and the dosage of corticosteroids and the calcineurin inhibitors should be reviewed. Statins should be considered when the LDL level is persistently high despite these measures. The optimal blood pressure in patients with SLE has not been defined. A systolic blood pressure of <130mmHg and a diastolic blood pressure of <85mmHg appears to be a reasonable target. More aggressive control of blood pressure (<120/80 mmHg) should be attempted in patients with multiple cardiovascular risk factors such as renal disease, persistent proteinuria, diabetes mellitus and history of arterial thrombosis. The angiotensin-converting enzyme inhibitors (ACEI) should be considered early.

The role of aspirin in primary prophylaxis of arterial thromboembolism in SLE has not been established. For patients with multiple vascular risk factors such as long-standing SLE, older age, persistent proteinuria, renal insufficiency, strongly positive aPL antibodies, diabetes mellitus, hypertension and dyslipidaemia, aspirin prophylaxis may be considered, but this has to be balanced against the potential risks of long-term aspirin use such as bleeding complications.

For patients without the aPL antibodies who have developed an episode of arterial thromboembolism, the management and secondary prevention strategies are similar to those of non-SLE patients. Appropriate anti-platelet or anticoagulation therapy should be given.

For arterial thrombosis related to the aPL antibodies (secondary antiphospholipid syndrome), there are still no good data in patients with SLE. The choice between anti-platelet and anticoagulation therapy should be individualized. Standard intensity warfarin (targeting an INR to 2.5) is indicated in patients at higher risk for recurrent thromboembolism such as those who have failed aspirin and those with history of venous thrombosis, heart abnormalities (atrial fibrillation, left atrial dilatation, left ventricular dysfunction, valvular heart abnormalities), multiple vascular risk factors, and arterial thrombosis in the absence of angiographic abnormalities. A combination of aspirin and warfarin may be needed.

Conclusion

Our knowledge on the pathogenesis and clinical management of SLE has advanced over the past few decades. There are an increasing number of randomized controlled trials in the management of SLE to determine better therapies with less toxicity. Novel therapeutic agents are now available and are undergoing multicenter trials. Although the survival of SLE patients has improved, much has to be done to improve management further. Primary and secondary prevention of disease and treatment related morbidities are equally important. It is hoped that the outcome of the disease can continue to improve in the next decade.

Key messages

1. Autoantibodies may be found in patients with SLE many years before the onset of symptoms.
2. The anti-b2-glycoprotein I is a newly available antibody that is associated with thrombosis in SLE.
3. SLE patients are prone to accelerated atherosclerosis and arterial thromboembolism, which cannot be fully accounted for by the presence of traditional risk factors.
4. A baseline ophthalmological examination is indicated in SLE patients who are using the antimalarial agents.
5. Mycophenolate mofetil and rituximab are promising novel therapeutic agents for SLE.
6. Pregnancy related complications are more common in SLE patients. Oral contraceptive pills may be considered for those with inactive disease and without a history of thromboembolism or the presence of the antiphospholipid antibodies.
7. The role of aspirin in primary prevention of arterial thromboembolism in SLE warrants further studies.

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References