2008年欧洲抗风湿联盟关于狼疮的治疗建议

2008年欧洲抗风湿联盟关于狼疮的治疗建议

（基于循证医学和专家意见）

        一、一般处理

        1．预后

        系统性红斑狼疮（以下简称为狼疮）患者的临床新征象（皮疹、关节炎、浆膜炎、神经表现和癫痫/精神症状）、常规实验室检查（血象、血清肌酐、蛋白尿和尿沉渣）及免疫学检查（血清C3，抗ds-DNA，抗SSA，抗SSB，心磷脂抗体和抗RNP）可提供总体及主要脏器受累的预后信息，应对这些患者进行评价。在某些病例应考虑行影象学（头颅MRI）和病理学（肾脏活检）检查，这可提供更多的预后信息。

        2．监测

        新的临床表现如皮损类型和数量或关节炎、浆膜炎及神经表现（癫痫/精神症状），实验室检测（血象）、免疫学检查（血清C3/C4， 抗C1q和抗ds-DNA）和总体活动性指数可用于狼疮活动和复发的监测。

        3．合并疾病

        狼疮患者因本病或（和）治疗而患某些疾病的危险性增高，这些疾病包括感染（泌尿系感染，其他感染），动脉粥样硬化、高血压、高血脂、糖尿病、骨质疏松、缺血性坏死、恶性肿瘤（尤其是非霍奇金淋巴瘤）。建议尽可能减少其危险因素，如怀疑存在危险因素时，应毫不延迟地进行评价及密切随诊。

        4．治疗

        无重要脏器受累的狼疮患者可使用抗疟药和（或）糖皮质激素。非甾类抗炎药可短期用于合并症危险性低的患者。激素疗效不好或长期使用而剂量不能减到可接受量时，应考虑用免疫抑制剂如硫唑嘌呤、霉芬酸酯和甲氨蝶呤。

        5．辅助治疗

        皮肤表现的患者行光保护是有益的，应考虑进行。生活方式的调整（如禁止吸烟，控制体重，锻炼）可能对患者预后有好处，应鼓励。根据患者的用药及临床情况不同，应考虑使用其他一些药物（低剂量阿司匹林、钙/维生素D，双膦酸盐、他汀类，抗高血压药（包括血管紧张素转换酶抑制剂）。可应用雌激素（口服避孕药，性激素替代）疗法，但要评估其可能的危险性。

        二、精神神经性狼疮

        1．诊断

        精神神经性狼疮患者的诊断性病情检查（临床，实验室，神经精神和影象学检测）与有神经精神症状的一般人群相似。

        2．治疗

        具有明显精神神经症状（眼神经炎，急性精神错乱状态/昏迷，颅内或外周神经病，精神病和横断性脊髓炎/脊髓病）的狼疮应考虑因炎症所致，使用免疫抑制可获得益处。

        三、狼疮的怀孕

        怀孕以几种方式影响狼疮患者及其后代：（1）母亲：狼疮患者的生育力无明显不同，怀孕可使狼疮病情活动，但复发常较轻微。有抗磷脂抗体的狼疮肾炎患者发生先兆子痫的危险性较高，应密切监测。（2）胎儿：狼疮以几种方式影响胎儿，尤其是如果母亲有狼疮肾炎病史、抗磷脂抗体、抗SSA和（或）抗SSB抗体时，发生流产、死胎、早产、宫内发育迟缓和胎儿先天性心脏传导阻滞的危险性增高。狼疮怀孕可用强的松龙、硫唑嘌呤、羟基氯喹和低剂量阿司匹林。目前，有证据提示霉芬酸酯、环磷酰胺和甲氨蝶呤必须避免使用。

        四、抗磷脂综合症

        低剂量的阿司匹林可用于抗磷脂抗体阳性的狼疮患者预防血栓及流产（初级预防）。需评估患者发生血栓的其他危险因素，如含雌激素的药物可增加血栓的危险。抗磷脂综合症引起血栓形成的非怀孕狼疮患者长期口服抗凝剂可预防血栓再次形成（次级预防）。伴抗磷脂综合症的怀孕狼疮患者联合普通肝素（或低分子肝素）和阿司匹林可降低胎儿流产和血栓形成的发生率，应考虑使用。

        五、狼疮肾炎

        1．监测

        肾活检、尿沉渣分析、蛋白尿和肾功能可独立预测狼疮肾炎患者的预后，但需综合考虑。免疫学指标改变（抗ds-DNA和血清C3）对预测治疗反应的能力有限，仅用作参考。

        2．治疗

        激素联合免疫抑制剂对防止增殖型狼疮肾炎（IV型狼疮肾炎）发展为终末期肾病是有效的，但仅带环磷酰胺的方案显示出长期疗效，不过有较多的不良反应。中短期试验发现，霉芬酸酯至少有与环磷酰胺冲击类似的疗效，且其不良作用谱更可接受，如果使用6个月霉芬酸酯无疗效，则需考虑强化治疗。缓解后的复发不常见，并需密切随访。

        3、终末期肾病

        病程长的狼疮患者中有一定比例的患者行血液透析和移植，其器官存活与非糖尿病非狼疮患者相似，故移植也是可供选择一种方法。

General management

Prognosis

In patients with SLE, new clinical signs (rashes, arthritis, serositis, neurological manifestations and seizures/psychosis), routine laboratory (CBC, serum creatinine, proteinuria and urinary sediment), and immunological tests (serum C3, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, antiphospholipid, anti-RNP), may provide prognostic information for the outcome in general and involvement of major organs, and thus should be considered in the evaluation of these patients. Confirmation by imaging (brain MRI), and pathology (renal biopsy) may add prognostic information and should be considered in selected patients.

Monitoring

New clinical manifestations such as number and type of skin lesions, or arthritis, serositis, and neurological manifestations (seizures/psychosis), laboratory tests (CBC), immunological tests (serum C3/C4, anti-C1q, anti-dsDNA), and validated global activity indices have diagnostic ability for monitoring for lupus activity and flares, and may be used in the monitoring of lupus patients.

Co-morbidities

SLE patients are at increased risk for certain co-morbidities, due to the disease and/or its treatment. These co-morbidities include infections (urinary-tract infections, other infections), atherosclerosis, hypertension, dyslipidaemias, diabetes, osteoporosis, avascular necrosis, malignancies (especially non-Hodgkin’s lymphoma). Minimisation of risk factors together with a high-index of suspicion, prompt evaluation, and diligent follow-up of these patients is recommended.

Treatment

In the treatment of SLE without major organ manifestations, antimalarials and/or glucocorticoids are of benefit and may be used. NSAIDs may be used judiciously for limited periods of time at patients at low risk for their complications. In non-responsive patients or patients not being able to reduce steroids below doses acceptable for chronic use, immunosuppressive agents such as azathioprine, mycophenolate mofetil and methotrexate should also be considered.

Adjunct therapy

 Photo-protection may be beneficial in patients with skin manifestations and should be considered. Lifestyle. modifications (smoking cessation, weight control, exercise) are likely to be beneficial for patient outcomes and should be encouraged. Depending on the individual medication and the clinical situation, other agents (low-dose aspirin, calcium/vitamin D, biphosphonates, statins, antihypertensives (including angiotensin converting enzyme inhibitors)) should be considered. Oestrogens (oral contraceptives, hormone-replacement therapy) may be used, but accompanying risks should be assessed.

Neuropsychiatric lupus

Diagnosis

 In SLE patients, the diagnostic work-up (clinical, laboratory, neuropsychological, and imaging tests) of neuropsychiatric manifestations should be similar to that in the general population presenting with the same neuropsychiatric manifestations.

Treatment

SLE patients with major neuropsychiatric manifestations considered to be of inflammatory origin (optic neuritis, acute confusional state/coma, cranial or peripheral neuropathy, psychosis, and transverse myelitis/myelopathy) may benefit from immunosuppressive therapy.

Pregnancy in lupus

Pregnancy affects mothers with SLE and their offspring in several ways.

  (a) Mother. There is no significant difference in fertility in lupus patients. Pregnancy may increase lupus disease activity, but these flares are usually mild. Patients with lupus nephritis and antiphospholipid antibodies are more at risk of developing pre-eclampsia and should be monitored more closely.

(b) Fetus. SLE may affect the fetus in several ways, especially if the mother has a history of lupus nephritis, antiphospholipid, anti-Ro and/or anti-La antibodies. These conditions are associated with an increase in the risk of miscarriage, stillbirth, premature delivery, intrauterine growth restriction and fetal congenital heart block. Prednisolone, azathioprine, hydroxychloroquine and low-dose aspirin may be used in lupus pregnancies. At present, evidence suggests that mycophenolate mofetil, cyclophosphamide and methotrexate must be avoided.

Antiphospholipid syndrome

In patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss. Other risk factors for thrombosis should also be assessed. Oestrogen-containing drugs increase the risk for thrombosis. In non-pregnant patients with SLE and APS-associated thrombosis, long-term anticoagulation with oral anticoagulants is effective for secondary prevention of thrombosis. In pregnant patients with SLE and antiphospholipid syndrome combined unfractionated or LMW heparin and aspirin reduce pregnancy loss and thrombosis and should be considered.

Lupus nephritis

Monitoring

Renal biopsy, urine sediment analysis, proteinuria, and kidney function may have independent predictive ability for clinical outcome in therapy of lupus nephritis but need to be interpreted in conjunction. Changes in immunological tests (anti-dsDNA, serum C3) have only limited ability to predict the response to treatment and may be used only as supplemental information.

Treatment

In patients with proliferative lupus nephritis, glucocorticoids in combination with immunosuppressive agents are effective against progression to end-stage renal disease. Long-term efficacy has been demonstrated only for cyclophosphamide-based regimens, which are however associated with considerable adverse effects. In short- and medium-term trials, mycophenolate mofetil has demonstrated at least similar efficacy compared with pulse cyclophosphamide and a more favourable toxicity profile: failure to respond by 6 months should evoke discussions for intensification of therapy. Flares following remission are not uncommon and require diligent follow-up.

End-stage renal disease

Dialysis and transplantation in SLE have rates for long-term patient and graft-survival comparable with those observed in non-diabetic non-SLE patients, with transplantation being the method of choice.

(G Bertsias , J P A Ioannidis, J Boletis, et al .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. Annals of the Rheumatic Diseases 2008;67:195-205)