Summary

Systemic lupus erythematosus (SLE) is a protean disease with variable presentation, clinical course and prognosis. The management of SLE depends on the nature, severity and extent of organ involvement. Patients with mild disease are usually treated more conservatively while those with severe life-threatening manifestations warrant more aggressive immuno-suppressive treatment. An important task of primary care physicians is to follow and monitor patients with mild stable SLE. In this article, the management strategy for patients with mild SLE is discussed.

摘要

系統性紅班狼瘡是種複雜多樣的疾病，其臨床表 現、病情和預後各有不同。治療策略取決於其性質、嚴重程度以及內臟受累的範圍。病情較輕者，易採用 較保守的方法；病情較重危害生命者，須使用較進取的免疫抑制療法。基層醫生的一項重要工作就是對病 情穩定的系統性紅班狼瘡病人進行隨診和監測。本文討論輕症病人的治療策略。

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Introduction

Systemic lupus erythematosus (SLE) is a systemic disorder that affects multiple organ systems. The disease has a predilection for women, with a female to male ratio of about nine to one. The common age of onset is between 20 and 40 years, and onset after the age of 50 is unusual.^1,2 The prevalence of SLE in mainland China is about 0.1% but that in Hong Kong is unknown.³

The primary pathologic findings in SLE are those of inflammation, vasculitis, immune complex deposition and vasculopathy. SLE is associated with a number of autoantibodies directed against various nuclear antigens. The etiology of SLE remains elusive. The concordance of the disease in identical twins suggests that genetic factors play an important role. However, many SLE patients do not have identifiable genetic predisposing factors, suggesting that environmental or other factors also contribute to the pathogenesis.

The management strategy of SLE depends on the nature, severity and the extent of organ system involvement.⁴ A more conservative approach is adopted for non-life-threatening manifestations such as musculoskeletal and dermatological disease. Patients with more serious manifestations such as proliferative nephritis, pulmonary haemorrhage, myelitis and severe thrombocytopenia often require more aggressive treatment.^5,6 One of the important tasks of primary care physicians is to follow and monitor patients with mild stable disease. In this review article, the strategy for the treatment of mild SLE is discussed.

Musculoskeletal manifestations of SLE

Musculoskeletal complaints are the commonest presenting feature. Arthritis or arthralgia occurs in 76 to 100% of patients. Arthritis refers to actual joint swelling, redness, increase in temperature, tenderness and limitation of movement. Lupus arthropathy is usually symmetrical and may involve any joint, but typically the small joints of the hands, wrists and the knees. The arthritis in SLE is mostly non-erosive. The failure of development of bony erosion after a considerable duration of arthritis distinguishes SLE from other erosive arthropathies such as rheumatoid arthritis. However,file:///monster%20HD/job/business/print%20house/2002.01/volume024/ apparent joint deformity can result from recurrent tendinitis and ligamentous laxity. A well-known feature is Jaccoud's "arthropathy" of the hands in which there are flexion deformities and ulnar deviation of the metacar-pophalangeal joints. In contrast to rheumatoid arthritis, Jaccoud's deformity can be reduced passively. Lupus arthropathy often responds well to treatment but 5 to 10% of patients may suffer from persistent arthritis and develop bony erosions. Occasionally, a patient may have overlap of rheumatoid arthritis and SLE in which erosive arthritis prevails.

Avascular bone necrosis (AVN) is another important cause of joint pain in SLE. The prevalence of AVN in SLE patients is between 2.8 and 40%, mostly occurring in the femoral heads.^7-9 The femoral condyles, tibial plateau, talus, metatarsal heads, humeral head, radial head, carpal bones and metatarsal heads may also be affected.^10-12 AVN in SLE is often multiple and bilaterality is the rule.¹³ Although corticosteroid use is the major risk factor for AVN, localised vasculitis and thrombosis of the feeding vessels related to the antiphospholipid antibodies have also been implicated as possible mechanisms.^8,14 Corticosteroid-related AVN appears to be dose-related, with a higher risk in patients who receive a high cumulative dose in the initial few months of treatment.⁸

AVN is suspected in patients with persistent pain localised to a single joint. In the early stage, radiographs are often normal and the diagnosis relies upon more sensitive techniques such as magnetic resonance imaging. As the disease advances, sclerosis is evident on radiographs, which is followed by subchondral collapse and secondary osteoarthritis.

Myalgia is common in SLE. It may be related to disease activity or secondary fibromyalgia. Chronic, poorly localised, diffuse pain beginning from the neck and shoulders with profound fatigue on awakening is characteristic and tender points may be elicited by digital palpation. Polyarthralgia refers to multiple joint complaints without actual arthritis. Patients with persistent polyarthralgia should be evaluated for the possibility of secondary fibromyalgia. Occasionally, patients may also suffer from a withdrawal syndrome of polyarthralgia, polymyalgia, lethargy and general upset when steroid dose was tailed down too rapidly.

Inflammatory myositis occurs in 5-11% of SLE patients.¹⁵ Proximal muscle weakness, elevation of the muscle enzymes and the characteristic electromyographic findings are usually diagnostic. Lupus myositis may be as severe as primary inflammatory myositis and should be treated with equal vigor.¹⁶

Management of musculoskeletal complaints in SLE

Treatment of musculoskeletal complaints in SLE patients should aim at suppression of inflammation, pain relief, maintenance of normal joint function and muscular strength (Table 1). Short-lived arthralgia may not require any medication. Mild persistent joint pain may be relieved by simple analgesics such as acetaminophen. For those with more pronounced arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) may be required. Caution should be taken in patients with a history of gastrointestinal bleeding, peptic ulcer, impaired renal function, or concomitant medications such as diuretics, anticoagulants and other nephrotoxic agents. The newer selective cyclo-oxygenase (COX)-2 inhibitors, celecoxib and rofecoxib, when used in recommended dosage, can reduce the incidence of symptomatic peptic ulcers and their complications in patients with osteoarthritis and rheumatoid arthritis.^17,18 However, they are not superior to the conventional non-selective NSAIDs in terms of efficacy and do not reduce the incidence of fluid retention, heart failure, and renal failure.¹⁹ Thus, at present, the selective COX-2 inhibitors are mainly indicated for patients who are at risk of gastrointestinal toxicity from conventional NSAIDs.

Table 1: Management of musculoskeletal manifestations of SLE

Simple analgesics Non-steroidal anti-inflammatory drugs (NASIDs) Physical modalities for pain relief and muscular training Splintage programs and joint protection Antimalarials (e.g. hydroxychloroquine) Low dose systemic steroids (e.g. prednisolone <10mg/day) Disease modifying agents such as methotrexate, azathioprine and leflunomide in refractory cases Antidepressants for secondary fibromyalgia Core decompression, arthrodesis and joint replacement for avascular bone necrosis Walking aids Referral to rheumatologists and orthopedic surgeons where appropriate

Physiotherapy is an adjunctive treatment for arthritis. Various modalities of pain relief and muscular strengthening exercise can be recommended by the physiotherapist. Patients with persistent arthritis or deformities of the hand may also benefit from splintage programs and education for joint protection by occupational therapists. Assisted devices may occasionally be required for patients with gross joint deformities or persistent joint pain as a result of the disease or avascular bone necrosis.

Besides NSAIDs, antimalarials are also effective in the management of lupus arthropathy. When all the above-mentioned modalities fail, and when the quality of life of the patient is severely affected, a short course of low dose corticosteroid such an prednisolone <10mg/day may be considered as an interim measure. Anti-depressants may be helpful in patients with marked secondary fibromyalgia symptoms.

Steroid-related AVN usually progresses despite treatment. Therefore prevention is important. Judicious use of systemic corticosteroid is mandatory. In the early stages of AVN before the onset of subchondral collapse, conservative measures to alleviate pain, restrict weight bearing, and maintain functional range of the joint are helpful. Core depression with or without bone grafting aiming at relieving intraosseous pressure and promoting revascularisation have been performed with varied success. The results of core decompression correlated with the stage and size of the necrotic lesion and patients treated before femoral head collapse have a significantly better outcome.²⁰ Total joint replacement for the hips, knees or shoulders is the treatment of choice for late-stage AVN with profound secondary degeneration. For smaller bones such as the carpal bones and metatarsal heads, arthrodesis or excision of the necrotic bone is more appropriate.

Dermatological manifestations of SLE

Skin lesions comprise the second most common manifestation of SLE. Cutaneous lesions are variable, ranging from macular rashes to deep skin ulcers. Specific lupus lesions include acute lupus dermatitis, discoid rashes and subacute cutaneous lupus. Non-specific lesions are urticaria, vasculitis, livedo reticularis, bullous pemphigoid and erythema multiforme.

Lupus rashes usually occur on the sun exposed areas of the face, neck, arms and upper torso. The typical malar erythema (butterfly rash) on the maxillary areas of the face and bridge of nose can be flat or raised and usually spares the nasolabial folds. Acute lupus dermatitis may also be generalised to involve the trunk and the limbs and often correlates with systemic disease activity. While most SLE patients demonstrate photosensitivity, cutaneous lesions may appear without antecedent sun exposure.

Discoid lupus lesions are chronic cutaneous lesions, which may occur in the absence of systemic manifestations. Discoid lesions are found in around 5 to 10% of patients at presentation. Fever, increasing arthralgia, systemic upset, and a dropping complement level suggest the possibility of conversion into systemic lupus. Discoid lupus is more common in our local male SLE patients²¹ and appears as discrete erythematous plaques covered by a well-formed adherent scale that plugs into dilated hair follicles. Discoid lesions are commonly found in light-exposed areas of the skin such as the face, ears, V-shaped area of the neck, extensor aspects of the forearms, and may be photosensitive. Scarring with central atrophy and depigmentation is common and is often permanent.

Subacute cutaneous lupus erythematosus (SCLE) is a distinct type of cutaneous lupus. Similar to discoid lupus, SCLE is also found in sun-exposed areas but involvement of the face is less common. SCLE appears as widespread, superficial, erythematous, slightly scaly papules or plaques that may evolve into either psoriasiform/papulosquamous or annular/polycyclic lesions. In contrast to discoid lesions, follicular plugging, dermal atrophy and scarring are not prominent features. Photosensitivity is common. Patients with SCLE are frequently positive for antinuclear and anti-Ro antibodies and approximately half satisfy the criteria for SLE.

Photosensitivity is common in SLE, especially in patients with a positive anti-Ro antibody. Both ultra-violet (UV)A and UVB from sunlight or artificial sources like unshielded fluorescent lighting and photocopiers are reported to exacerbate the lupus rash. Constitutional symptoms such as fever, fatigue, or nausea may also occur after sun exposure. Photosensitive skin rashes are often transient, lasting for no more than a day or two.

Alopecia in SLE can be diffuse or patchy. If associated with disease flares, hair tends to regrow once disease activity is under control. Scarring alopecia may occur with discoid lesions on the scalp and is usually permanent.

Management of dermatological manifestations of SLE (Table 2)

Patients with localised cutaneous lupus and systemic lupus should be advised to avoid direct exposure to the sun by applying physical barriers (including hats, clothing and umbrellas) as well as sunscreens with sun-protection factor (SPF) of at least 15. Sunscreens should be applied at least 30 minutes before sun exposure and reapplied at 2-hour intervals when in contact with water or when in a sweaty environment. UV light-absorbing plastic films can be applied to cars and home windows and UV-ablating diffuser shields can be placed over artificial fluorescent light bulbs.

Topical steroids are the mainstay of treatment for lupus skin lesions. Medium-strength agents should be tried initially. However, more potent ones are often required for chronic discoid lesions. Caution must be taken when prescribing topical steroids for delicate skin areas such as the face and the intertriginous areas. Low potency compounds should be used in these areas to minimise local side effects such as erythema, telangiectasia, and skin atrophy. Systemic side effects may occur when it is applied to a large, inflammed skin area. For chronic discoid lesions, intralesional corticosteroid injection may be needed when topical steroid is ineffective.

Antimalarials are effective in most patients with cutaneous lupus and are particularly useful in patients with widespread DLE, SCLE and lupus panniculitis. Resistant cases necessitate referral to a dermatologist who may try second-line agents such as dapsone, thalidomide, clofazimine and retinoids. Systemic corticosteroids and cytotoxic agents are generally not required for patients with uncomplicated cutaneous lesions. However, they may be employed for brief periods at the beginning of therapy with slow acting agents in the more widespread forms of SCLE, or as a last resort if other agents fail.

Camouflage cosmetics is a remedy when medical treatment is unsuccessful. Surgical interventions such as dermabrasion for chronic disfiguring lesions and hair transplant for scarring alopecia may also be considered for individual patients.

Table 2: Management of dermatological manifestations of SLE

Avoid sun exposure - physical barriers and sunscreens Topical steroids Antimalarials (e.g. hydroxychloroquine) Intralesional steroid injection Combination of antimalarials Second line agents such as dapsone, azathioprine, thalidomide, systemic retinoids Systemic steroids and immunosuppressives for recalcitrant cases Camouflage cosmetics Surgical intervention for disfiguring facial lesions Referral to dermatologists and plastic surgeons where appropriate

Fever in SLE

Fever in SLE is a challenging problem. Most patients develop fever during the course of their disease as a manifestation of active lupus or flares. Conversely, they are prone to infections because of intrinsic immunological aberrations which include impaired cell-mediated immunity, depressed complement level, phagocyte dysfunction, deficient opsonic capacity and functional hyposplenism, as well as immunosuppressive treatment. Intercurrent infections including those caused by viruses may cause fever.

The evaluation of fever requires a detailed history, careful physical examination and appropriate investigations. Any foci of infection should be looked for as hinted by signs and symptoms. Shaking chills, leucocytosis and elevated C-reactive protein (CRP) would suggest infection whereas hair loss, oral ulcers, worsening skin rash or arthritis, leucopenia, increasing anti-dsDNA titre, active urinary sediment together with negative cultures and normal CRP level would favour disease activity. However, infection and disease activity may co-exist.

Fever in SLE patients should be assumed to be caused by infection until proven otherwise and empirical antibiotic treatment should be given where appropriate while waiting for culture results. Lupus fever is amenable to treatment with NSAIDs and low dose steroid, in divided dose, may be needed in certain cases.

Antimalarial therapy: efficacy, toxicity and monitoring guideline

Antimalarial medications are often used to treat lupus. There are a few antimalarials being used in rheumatic diseases but only chloroquine and hydroxychloroquine (HCQ) are currently available in Hong Kong. Antimalarials are rapidly absorbed by the gastrointestinal tract. They are bound by plasma proteins and slowly achieve a dose-dependent steady state (around 4 weeks for chloroquine and 6 months for HCQ). The drugs accumulate at high concentrations in body tissues such as the liver, pituitary, adrenals and the skin. Apart from anti-inflammatory properties, antimalarials also exhibit anti-platelet, lipid lowering, anti-thrombotic and hypoglycemic effects.²²

Antimalarials are effective in treating lupus skin lesions.^23,24 Complete clearing or marked improvement of rash are observed 8 weeks after HCQ treatment in 68% of patients with cutaneous lupus.²⁵ HCQ is also effective in the treatment of lupus arthritis.^26,27 Discontinuation of HCQ is sometimes associated with lupus flares in patients with quiescent disease.²⁸ By reducing the risk of disease flares, the cumulative dosage and long term toxicity of systemic corticosteroids can be diminished.

Antimalarials are generally well tolerated. Adverse effects include skin rash, pigmentation, gastrointestinal upset, headache, dizziness, corneal deposits, cycloplegia, retinopathy, and rarely myopathy and agranulocytosis. Retinopathy is the most common side effect of the antimalarials. Corneal deposits occur in most long term users of chloroquine, which can also cause macular pigmentation that progresses to the typical bull's eye lesion and then widespread pigment epithelial atrophy of the retina. These retinal changes and visual loss are rare in patients treated with HCQ.^29,30

Because of the rarity of HCQ-related retinopathy, routine ophthalmological referral may not be cost-effective. The Royal College of Ophthalmologists published guidelines for eye screening and referrals for patients treated with HCQ.²⁹ A baseline liver and renal function should be obtained. Visual symptoms should be enquired and a baseline test of visual acuity for each eye using test type or a reading chart should also be performed in the clinic. If no abnormality is detected, HCQ can be commenced and annual reassessment of visual acuity and enquiry of visual symptoms should be performed. If visual impairment or eye disease is evident at baseline, or when there are changes in visual acuity or new visual impairment during HCQ treatment, a referral to ophthalmologist is needed.

The American College of Rheumatology guidelines for monitoring drug therapy in rheumatoid arthritis recommend a baseline ophthalmologic evaluation only in patients older than 40 years of age or with family history of eye disease.³² If a patient has had a clinical response to HCQ after 6 months, then a monitoring routine should be instituted. In the absence of risk factors such as renal and liver impairment, age >70 years, cumulative HCQ dose >800 grams or daily HCQ dose >6.5mg/kg/day, it is recommended that an ophthalmologic examination and central field testing be performed every 6-12 months. More frequent ophthalmologic evaluation is required for patients with abnormal renal/liver function or those who have received HCQ for more than 10 years.

Conclusion

Management of SLE is a challenging clinical task. Primary care physicians should be equipped with the knowledge of the disease in order to follow patients with mild stable disease. SLE with predominant joint and skin manifestations can be managed by appropriate analgesics and anti-inflammatory drugs, physical modalities, ultraviolet light protection, topical corticosteroids and antimalarials. Systemic steroid and immunosuppressives may be necessary in recalcitrant cases. Fever in SLE should be evaluated seriously and infection should always be excluded before augmentation of immunosuppression. A baseline evaluation of visual symptoms and testing for visual acuity is mandatory in patients in whom hydroxychloroquine is expected to be used for more than 6 months. More frequent eye assessment is needed for those at risk for retinopathy. Appropriate referrals to various specialists are needed when the dermatological and musculoskeletal symptoms fail to be controlled satisfactorily.

Key messages

1. Musculoskeletal complaints are common in systemic lupus erythematosus (SLE). The main-stay of treatment is non-pharmacological measures, non-steroidal anti-inflammatory drugs and the antimalarials.
2. Persistent pain in a single joint may suggest the possibility of avascular bone necrosis. Secondary fibromylagia should be considered for those patients with polyarthralgia/myalgia without actual signs of inflammation.
3. Acute dermatitis, subacute and chronic cutaneous lesions may accompany SLE. Ultraviolet light protection, topical steroid and the antimalarials are the main treatment modalities.
4. Fever in SLE patients should be evaluated for underlying infection. 5. Because of the rarity of hydroxychloroquine-related retinopathy, routine referral for ophthalmological screening may not be cost-effective.

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References