A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan

Purpose. To conduct a national survey of systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Based on current information on the use of MMF, we aimed to evaluate its efficacy and safety for childhood-onset (c-) SLE.

Target. We evaluated 115 patients by questionnaire on MMF use for c-SLE in medical facilities specializing in pediatric rheumatic and renal diseases.

Results. Average age at SLE onset was 10.6 (range, 2–15) years; average age at the time of starting MMF was 12.3 (range, 2–15) years. Average dose per body surface area was 1,059.3 mg/m²/day. Corticosteroid dosing was 20.9 mg/day before treatment but 7.7 mg/day after treatment. Laboratory values before and after MMF treatment were as follows: C3 increased from 67.0 to 84.9 mg/dl (p < 0.001), C4 increased from 10.2 to 15.1 mg/dl (p < 0.001), and anti-DNA antibody decreased from 154.2 to 18.4 IU/ml (p < 0.001). 24 adverse events in 21 cases were reported, but MMF was not discontinued in any.

Conclusions. The amount of MMF for c-SLE in Japan is similar to the standard dose in other countries. Reduction of corticosteroid dose and improvement of laboratory values represent efficacy of MMF. The side effects recorded here indicated tolerability of the drug.     

The effectiveness and safety of mycophenolate mofetil in lupus nephritis

The purpose of this study is to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) for inducing and/or maintaining remission of lupus nephritis (LN). This is a retrospective study of 25 LN patients consecutively treated with MMF. The primary outcome was complete renal remission (CR) defined by urine protein/creatinine ratio ≤0.5 g/g and inactive urine sediment and serum creatinine within <15% above baseline. For induction, 21 episodes of active, moderate to severe LN were treated with MMF. Twelve cases (57%) achieved CR over a median of 8.5 months. Of 13 patients who had LN for <12 months and took ≥2 g/day of MMF, 11 achieved CR, compared to one out of the eight patients who did not meet both criteria (p = 0.0022). For maintenance therapy, 15 patients received MMF for a median of 20 months (range 5–55 months). Two patients (13%) experienced renal flares while taking MMF. Most adverse events were transient and did not require change in therapy. This study suggests that MMF is an effective treatment for both induction and maintenance of remission of moderate to severe LN with a relatively favorable safety profile. Early treatment and a dose ≥2 g/day are essential for optimal outcome. CR may take >6 months.     

Development of systemic lupus erythematosus in a patient with hypoparathyroidism: a case report and review of the literature

Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs undergo damage. Hypoparathyroidism is a rare disease, which presents in two forms: hereditary and acquired. Cases of hypoparathyroidism and SLE rarely co‐exist. Only six cases have been reported; five of them first presented with lupus and then hypoparathyroidism or simultaneously. We present here developing lupus disease in a woman who had idiopathic hypoparathyroidism. According to increasing data about the autoimmune origin of idiopathic hypoparathyroidism, these case reports suggest that there may be an autoimmune process linking these diseases.     

Surveillance for the use of mycophenolate mofetil for adult patients with lupus nephritis in Japan

Objectives. Mycophenolate mofetil (MMF) is used as one of the standard induction/maintenance protocols for lupus nephritis (LN). However, MMF has not been approved for treating LN in any country, resulting in worldwide off-label use of this immunosuppressant. In order to clarify the real-world use of MMF as a treatment for LN in Japan, Japan College of Rheumatology surveyed the use of MMF in daily clinical practice.

Methods. Adult patients with LN who visited enrolled hospitals from October 2008 to September 2013 were surveyed for the initial, maximum, and maintenance doses of MMF. The safety and efficacy of MMF were retrospectively evaluated.

Results. One hundred and thirty-seven LN patients including 116 females were enrolled. The median of initial, maximum, and maintenance doses of MMF were 1.0 g/day, 1.5 g/day, and 1.0 g/day, respectively. Sixty-one adverse events were reported in 39 patients during the follow-up period. Median urine protein level decreased from 1.89 g/gCr to 0.21 g/gCr, meanC3 level increased from 66.4 mg/dl to 80.3 mg/dl, and median anti-DNA antibody titer decreased from 40.6 IU/ml to 10.6 IU/ml.

Conclusion. MMF was commonly used for the treatment of adult LN patients with acceptable efficacy and safety in Japan.     

霉酚酸酯对系统性红斑狼疮患者免疫功能的影响

目的 观察新型免疫抑制剂霉酚酸酯（MMF）对系统性红斑狼疮（SLE）免疫功能的影响。方法 应用ELISA法、间接免疫荧光法和流式细胞术观察MMF、环磷酰胺（CTX）治疗前后SLE患者血清IL－6、IL－8、NTFα、sIL-2R、ANA、A－dsDNA及淋巴细胞亚群的变化以及MMF、CTX对造血系统、肝脏、肾脏功能的影响。结果 SLE患者经MMF治疗3个月后血清IL－6、IL－8、TNF－α、sIL-2R、ANA、A－dsDNA水平显著下降,CD3^ 、CD4^ 、CD4^ 、CD45RA^ 细胞显著增高,CD8^ 、CD4?^ CD45RO^ 、CD86 CD45RA^ 、CD8^ CD45RO^ 细胞显著减少。对造血系统、肝脏、肾脏功能无明显损害。结论 MMF可选择性地抑制T、B淋巴细胞,是一种治疗SLE毒副作用较少的新型免疫抑制剂。     

Efficacy and safety of multi-target therapy using a combination of tacrolimus,mycophenolate mofetil and a steroid in patients with active lupus nephritis

Abstract

Objectives. To examine the efficacy and safety of multi-target therapy using tacrolimus (TAC), mycophenolate mofetil (MMF) and a steroid as initial treatment for active lupus nephritis (LN).

Methods. We conducted a retrospective analysis of the data of 16 consecutive patients who received the multi-target therapy for active Classes III–V LN at our department. We also compared the outcomes of the multi-target therapy with those of TAC therapy (TAC + steroid), a study of which we had conducted previously in 13 patients with active LN (TAC group).

Results. All the patients treated with multi-target therapy achieved complete remission (CR) (mean, 4.6 ± 3.8 months; range, 1–15 months). The clinical profiles of the patients of the multi-target group were similar to those of the TAC group at baseline, except for a significantly higher level of proteinuria (4.6 ± 2.8 vs. 2.5 ± 2.1 g/gCr, p = 0.033) in the former. The CR rate at 6 months was significantly higher in the multi-target group as compared with that in the TAC group (81% vs. 38%, p = 0.018). Two cases of serious adverse events were associated with cytomegalovirus infection in the multi-target group, namely gastric ulcer and pancytopenia, both of which were successfully treated by antiviral therapy.

Conclusions. Multi-target therapy was effective as initial treatment for active LN, with CR achieved early and in a high percentage of patients. Although this therapy was generally well tolerated, it is important to bear in mind the associated risk of cytomegalovirus infection.     

Tumor necrosis factor receptor superfamily 1A-associated periodic syndrome (TRAPS)

PURPOSE: Tumor necrosis factor receptor superfamily 1A associated periodic syndrome (TRAPS) belongs to the group of hereditary fever syndromes, also called hereditary auto-inflammatory syndromes. CURRENT KNOWLEDGE AND KEY POINTS: The diagnosis of TRAPS should be evoked in presence of the following clinical signs, whatever the population of the affected patients. TRAPS acute inflammatory access, of 1 to 3 weeks' duration, is characterised by the presence of fever, abdominal pain, myalgias, various types of skin rash including erysepela-like erythema. Long term inflammatory response can lead to AA amyloidosis. Genetic testing will confirm the diagnosis when showing a mutation in the extracellular part of the TNFRSF1A receptor. Therapeutic management of TRAPS is not definitely established. Daily colchicine does not seem to prevent efficiently inflammatory attacks. Corticosteroids, in contrast can attenuate the intensity and diminish the duration of attacks. FUTURE PROSPECTS AND PROJECTS: The value of biological agents that inhibits TNF action is not yet completely determined in TRAPS. Mechanisms of the disease are not yet elucidated. In some families with specific mutations, a relative soluble TNF receptor deficiency has been found in the plasma. However this mechanism does not account for what is observed in other kindreds.     

吗替麦考酚酯治疗弥漫增生性狼疮性肾炎的多中心临床研究

目的　多中心、前瞻性观察吗替麦考酚酯 (MMF)治疗弥漫增生性狼疮性肾炎的临床疗效和不良反应。方法　全国 9家医院共收集系统性红斑狼疮患者 75例 (男 1 3例 ,女 62例 ) ,均经肾活检确定为活动性弥漫增生性狼疮性肾炎 (LN IV) ,年龄 (31 0± 1 0 1 )岁 ,病程 (38 9± 52 5)个月 ;其中经正规激素联合环磷酰胺治疗无效者 2 6例 ,复发者 2 1例 ,初治患者 2 8例。治疗方案采用激素联合MMF。MMF起始剂量为 0 5～ 2 0g/d ,随访时间≥ 6个月。 38例治疗后行重复肾活检 ,并进行急性指数 (AI)、慢性指数 (CI)、免疫球蛋白 (Ig)及补体沉积半定量评分。结果　MMF平均起始剂量 (1 2 6±0 30 )g/d ,治疗 3、6个月时MMF平均剂量分别为 (1 2 1± 0 30 )g/d、(0 95± 0 33)g/d。治疗 3个月狼疮活动分数 (SLE DAI)由 1 6 9± 6 7降为 8 1± 4 8(P <0 0 1 ) ,血红蛋白由 (92± 2 1 )g/L升至 (1 1 2± 2 8)g/L(P <0 0 5) ,尿蛋白由 (4 2 4± 2 66)g/d降至 (2 1 8± 3 75)g/d(P <0 0 5) ,血清白蛋白升至 (35 3±6 9)g/L(P <0 0 1 ) ,肾功能明显改善 ,无活动性尿沉渣 ;治疗 6个月尿蛋白继续下降至 (1 54± 1 60 )g/d ,血红蛋白、血清白蛋白继续升高。血清A dsDNA抗体阳性及低补体血症患者比例显著降低。     

Diagnosis of lupus anticoagulant in the lupus anticoagulant-hypoprothrombinemia syndrome: report of two cases and review of the literature

We report a severe hemorrhagic disorder in two pediatric patients with lupus anticoagulant (LA) associated to acquired factor II (prothrombin) deficiency. In both patients, hemorrhagic symptoms resolved after corticosteroid therapy. Serial coagulation studies showed that Staclot LA assay was more sensitive than DVVconfirm and Staclot PNP tests to confirm the presence of LA when associated with severe factor II deficiency. Both patients had non-neutralizing anti-prothrombin antibodies and their titers inversely correlated with factor II activity (r = -1.0, P < 0.0001). Associated findings in these patients included positive immunologic tests for systemic lupus erythematosus, a positive anti-cardiolipin antibody, and anti-beta(2) GPI antibodies in one case. Our findings point out the difficulty in diagnosing LA associated with acquired factor II deficiency and suggest that, in confirmation of its phospholipid dependency, the inclusion of a source of normal human plasma in the test sequence to correct for any factor deficiency and a confirmatory step utilizing hexagonal (II) phase phospholipids may be crucial to the diagnosis of LA in some patients with LA-hypoprothrombinemia syndrome.     

Mycophenolate mofetil in the treatment of lupus nephritis: an appraisal of recent data

After nearly two decades of relative requiescence, a plethora of new drugs or biologic agents are currently being studied for their therapeutic potential in lupus nephritis. While corticosteroid remains an indispensable component in induction treatment for severe proliferative lupus nephritis, the advent of mycophenolate mofetil (MMF) offers an alternative to cyclophosphamide (CTX), thereby reducing the occurrence of treatment‐related adverse effects, especially in patients requiring multiple courses of therapy for flares. Data on the high treatment efficacy and favourable tolerability of MMF were first reported in Chinese patients with diffuse proliferative lupus nephritis. The improved safety profile of MMF was subsequently confirmed in patients of Caucasian, Hispanic, or African origin, in whom comparable or even better treatment efficacy compared with CTX was observed. However, the response rates differed between these studies. This review aims to provide a succinct update on the reported experience that compared MMF with other immunosuppressive agents in the treatment of lupus nephritis. Considering potential ethnic differences in the disease course and/or treatment response, it remains to be examined whether the favourable long‐term clinical outcomes observed in Chinese patients with corticosteroid and MMF as continuous treatment from induction to maintenance could be reproduced in patients of other ethnic origins. In addition, the relative merit and cost‐effectiveness of MMF against alternative maintenance immunosuppressive agents in the prevention of disease flares deserve further investigation.     

Treatment of intractable pulmonary hemorrhage in two patients with childhood systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology with multisystem involvement. A number of pulmonary complications including pleuritis, pneumonitis, infectious pneumonia, and pulmonary hemorrhage, have been reported in patients with SLE. Pulmonary hemorrhage is a major life-threatening manifestation in children and adolescents with SLE. Mycophenolate mofetil is an immunosuppressive agent used in solid organ transplantation, and it may play an increasing role in autoimmune disease. In this report, we present two cases of childhood SLE with recurrent pulmonary hemorrhage, which were unresponsive to treatment with high-dose corticosteroids, cytotoxic therapy, IVIG, plasmaphoresis, and supportive therapy, but responded to IV mycophenolate mofetil. A multimodal therapy including mycophenolate mofetil was effective in treatment of these two children.     

Recurrent fever and arthralgia as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a Chinese girl: a case report and review of the literature

Clinical Rheumatology - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by recurrent episodes of inflammation with fever, abdominal pain, chest pain, rash,...     

A case of systemic lupus erythematosus complicated by progressive multifocal leukoencephalopathy: case report and review of the literature

Abstract

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system caused by an opportunistic infection of the JC virus. PML is known to occur in immunocompromised patients. A patient with systemic lupus erythematosus (SLE) who developed PML during i.v. cyclophosphamide and methylprednisolone pulse therapy is described. The pertinent literature relating to complication of SLE by PML is discussed.     

他克莫司治疗难治性狼疮肾炎的疗效和安全性

目的 前瞻性研究环磷酰胺治疗无效的难治性狼疮肾炎患者应用他克莫司(FK506)治疗的临床效果和安全性.方法 收集2009年1月至2010年12月门诊或住院的16～60岁的狼疮肾炎患者.入选患者均符合美国风湿病学会(ACR) 1997年修订的系统性红斑狼疮(SLE)分类标准;尿蛋白定量(24h)≥1.5 g;应用环磷酰胺半年累计剂量超过8 g无效.他克莫司起始剂量2～3 mg/d(体质量≥60 kg,3 mg/d;体质量＜60 kg,2 mg/d),2个月后临床症状无好转,可逐渐调整剂量至4 mg/d,监测血药浓度,观察期为6个月.疗效评价分为完全缓解、部分缓解和无效,达到完全缓解或部分缓解为有效.统计学处理采用单因素方差分析和Pearson相关分析.结果 收集环磷酰胺治疗无效的狼疮肾炎患者14例,其中男性2例,女性12例,平均年龄(30±9)岁,SLE的平均病程(4±3)年;狼疮肾炎的平均病程(2.7±1.9)年.5例患者尿蛋白定量(24 h)1.5～2.9 g,9例患者尿蛋白定量(24 h)≥3.0 g;9例患者有活动性尿沉渣.应用他克莫司的治疗过程中,尿蛋白定量(24h)水平显著下降,从基线(6.2±5.1)g降至6个月(1.1±0.9)g,差异有统计学意义(F=16.21,P＜0.01);血清白蛋白水平呈逐渐上升趋势,从基线(27.9±9.7) g/L升至6个月(37.8±2.2) g/L,差异有统计学意义(F=16.71,P＜0.01).在治疗的第1个月末,8例无效,6例部分缓解;在治疗的第2个月末,3例无效,11例部分缓解;在治疗的第4个月末,2例无效,9例部分缓解,3例完全缓解;在研究6个月时,2例无效,5例完全缓解,7例部分缓解,共12例有效,有效率达86％.他克莫司的起效时间平均(1.7±0.9)个月,其中6例患者1个月内有效,5例患者2个月内有效,1例患者4个月内有效.12例有效患者他克莫司的平均剂量为0.03～0.06 mg/kg,所有他克莫司有效患者的药物浓度均低于3 ng/ml,完全缓解、部分缓解和无效的他克莫司的平均血药浓度分别为(1.6±0.4),(2.0±0.6)和(2.2±1.1)ng/ml,他克莫司的疗效和血药浓度之间无相关性.14例患者仅有1例出现新发高血压,1例出现脱发,观察期间未出现其他不良反应.结论 他克莫司联合糖皮质激素治疗环磷酰胺无效的狼疮肾炎有效,6个月有效率达86％,是一种快速有效的缓解狼疮肾炎的治疗方法,血药浓度3n/ml以下即可有效,其治疗狼疮肾炎的最佳剂量可能为0.03～0.06 mg·kg-1·d-1.     

Serum ferritin level as a marker of disease activity and renal involvement in Egyptian children with juvenile systemic lupus erythematosus

Introduction

Ferritin is an acute-phase reactant that is elevated in several autoimmune disorders. Serum ferritin levels have been correlated with disease activity scores of juvenile systemic lupus erythematosus (JSLE). Furthermore, enhanced levels of ferritin have also been described in lupus nephritis (LN).

Systemic lupus erythematosus: modern strategies for management – a moving target

In the past decade, advances in the area of lupus have led to a significant expansion in our armamentarium of therapeutics, although none is yet approved by the FDA for use in SLE. The use of mycophenolate mofetil has been a substantial advance. Recent clinical trials have shed light on optimizing usages and alternatives of more traditional therapies, such as antimalarials, cyclophosphamide, azathioprine, and mycophenolate mofetil. In addition, targeting components of the immune system has yielded promising new therapies in the arena of biologics, anticytokine therapy, and stem-cell transplantation, which are currently being tested. As data from ongoing trials evolve, our questions involving appropriate patient selection and disease indications will help bridge the gaps in our knowledge and understanding of administration of such potential therapies. Future innovative strategies might include further exploration of: (1) the body's inherent tolerance mechanisms, such as promoting T regulatory cells that help suppress self reactive immune cells; (2) targeting interferon pathways known to be dysregulated in patients with SLE; and (3) exploring interactions between the innate and adaptive immune system, such as studying toll-like receptors and dendritic cell activation.

• A greater understanding of immunopathogenesis has led to the development of biologics targeting individual components of the immune repertoire.

• Future studies are warranted for further investigation of the utility of biologics and promise of stem-cell transplantation in patients with SLE.

Pregnancy outcome in systemic lupus erythematosus (SLE): a review of 54 cases

Aim: To compare the pregnancy outcome, in particular gestational age and birth weight in women with systemic lupus erythematosus (SLE) diagnosed before and after pregnancy, and to review data on presence or absence of the antiphospholipid (aPL) antibody and flares of disease activity. Method: Case histories were reviewed of women with a diagnosis of SLE and an obstetric event attending Monash Medical Centre (MMC) over an eight year period (1988–96). Fifty-four pregnancies in 28 women were studied, with 44 occurring after the diagnosis of SLE (Group 1) and ten prior to the diagnosis of SLE (Group 2). Results: In Group 1 there were 25 live births (63%) with 16 full term and nine premature deliveries, 12 spontaneous abortions, three foetal deaths in utero and four elective terminations. In Group 2 there were seven live births (70%), two spontaneous abortions and one foetal death in utero. The mean gestational age of live births was 35.8 weeks and 39.2 weeks respectively (p<0.001). The mean birth weight of live births was 2448 g and 3030 g respectively (p=0.023). a PL antibodies were positive in eight of 26 women tested with three live births and were negative in 18 of 26 women with 12 live births. Flares of disease activity occurred in 17 of 28 pregnancies. Conclusion: Pregnancy in women with a predisposition to SLE have a high risk of an adverse outcome. Clinical disease confers an additional risk. The mean gestational age and birth weight were significantly less in women with established disease. Mild flares in disease activity resulted in a favourable outcome while renal flares had a worse outcome.