ANCA associated glomerulonephritis in a patient with mixed connective tissue disease

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1 中南大学学报 ( 医学版 ) J Cent South Univ (Med Sci) 2014, 39(2) DOI: /j.issn ANCA associated glomerulonephritis in a patient with mixed connective tissue disease SUN Yining, HE Lan, LÜ Xiaohong, MO Lingfei, ZHANG Jing (Department of Rheumatology, First Affiliated Hospital of the Medical School of Xi an Jiaotong Universtiy, Xi an , China) ABSTRACT KEY WORDS Objective: To investigate the diagnosis and treatment of mixed connective tissue disease (MCTD) and myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis, which is a rare clinical entity in medical practice. Methods: A 35-year-old female of Asian origin was admitted to our hospital due to complaints of Raynaud s phenomenon, myalgia, arthralgia and fatigue. The patient was diagnosed as MCTD in the out-patient department 8 months prior to admission based on Alarcon-Segovia classification criteria of Raynaud s phenomenon, myalgia, arthralgia and a high anti-u1 ribonucleoprotein antibody level. Interstitial lung disease was determined by chest computed tomography. Renal biopsy was performed because of marked proteinuria on 24 h urine collection. Histopathological examination revealed glomerulonephritis with fibrocellular/cellular crescents, in which moderate staining of IgM was shown by direct immunofluorescence. She was tested positive for myeloperoxidase antineutrophil cytoplasmic antibody. Results: High dose of methylprednisolone (500 mg/d for 3 days) was started intravenously when the results of renal biopsy were obtained. Oral prednisone and intravenous cyclophosphamide therapy (0.8 g/month) were continued for 12 months. Daily urinary protein loss decreased dramatically and serum creatinine was maintained at a normal level. Conclusion: Corticosteroids and cyclophosphamide are effective in the treatment of MPO-ANCA associated glomerulonephritis in MCTD. mixed connective tissue disease; myeloperoxidase; antineutrophil cytoplasmic antibody; glomerulonephritis; vasculitis Date of reception: Biography:SUN Yining, Ph.D., vice-chief physician, mainly engaged in research of bone metabolism in rheumatic diseases. Corresponding author:he Lan, xajdljn@126.com

2 210 中南大学学报 ( 医学版 ), 2014, 39(2) 例混合性结缔组织病合并 ANCA 相关肾小球肾炎患者 孙怡宁, 何岚, 吕晓虹, 莫凌菲, 张竞 ( 西安交通大学医学院第一附属医院风湿科, 西安 ) [ 摘要 ] 目的 : 探讨临床上十分罕见的混合性结缔组织病 (mixed connective tissue disease,mctd) 同时合并抗中性粒细胞胞浆抗体 (anti-neutrophil cytoplasmic antibodies,anca) 相关血管炎的诊断和治疗 方法 :1 名 35 岁的亚裔女性, 因双手雷诺现象 肌痛 关节痛和乏力入院 在入院前 8 个月该患者在门诊诊断为 MCTD 患者的雷诺现象 肌痛 关节痛和血清高滴度抗 U1 核糖核蛋白 (U1 ribonucleoprotein,u1rnp) 抗体符合 MCTD 的 Alarcon-Segovia 分类标准 入院后的检查发现患者血清髓过氧化物酶 (myeloperoxidase,mpo) 型抗中性粒细胞胞浆抗体阳性 24 h 尿蛋白定量显著升高 胸部 CT 显示间质性肺病 (interstitial lung disease,ild) 特征 随后的肾穿刺活检提示组织学上表现为纤维细胞 / 细胞新月体型肾小球肾炎, 直接荧光染色显示中度 IgM 阳性 结果 : 获得肾组织病理学检查结果后立即给予患者 500 mg/d 甲泼尼龙静脉冲击治疗 3 d, 随后改为口服泼尼松和每月 0.8 g 环磷酰胺静脉注射, 持续 12 个月 经上述治疗, 患者血清肌酐维持正常, 每日尿蛋白量显著下降 结论 : 糖皮质激素联合环磷酰胺可以有效治疗 MCTD 合并的 MPO-ANCA 相关肾小球肾炎 [ 关键词 ] 混合性结缔组织病 ; 髓过氧化物酶 ; 抗中性粒细胞胞浆抗体 ; 肾小球肾炎 ; 血管炎 Mixed connective tissue disease (MCTD) was first described by Sharp et al [1] in 1972 as a distinct entity of connective tissue disease characterized by overlapping clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and polymyositis/ dermatomyositis (PM/DM) associated with hightiter anti-u1 ribonucleoprotein (U1RNP) antibody. MCTD has a female predominance and the prevalence of MCTD is low. According to Gunnarsson et al [2] the point prevalence of adult MCTD patients in Norway was 3.8 per adults. The most common manifestations of MCTD were Raynaud s phenomenon (Raynaud s phenomenon is characterized by episodes of ischemia commonly involving the digits of the hands and feet and leads to typical dual or tricolor skin changes), swollen fingers, sclerodactyly, arthritis, polymyositis and interstitial lung disease. It is reported that up to 90% of patients who have MCTD sufferred from Raynaud s phenomenon. MCTD was considered to have a low incidence of renal manifestations with approximately 20%-30% cases presenting with relatively mild abnormalities. Studies showed that renal involvement in MCTD could occur as nephritis, nephrotic syndrome and even abrupt onset of malignant hypertension and renal dysfunction which was called scleroderma renal crisis [3-4]. Histopathological examination of kidney biopsy specimens revealed mild membranous glomerulonephritis, diffused proliferative glomerulonephritis, intimal hyperplasia of renal intralobular and arcuate arteries, as well as vasospasm caused by visceral Raynaud s phenomenon [5]. With regards to the lung involvement, it has become evident that interstitial lung diseases (ILD), such as pulmonary fibrosis, as well as pulmonary hypertension (PH) are rather serious complications of MCTD [6-7]. It is estimated that more than half of the MCTD patients had evidence of pulmonary diseases. ILD was detected in approximately 50% of MCTD patients using high-resolution computed tomography (HRCT) [8]. Moreover, a few cases of alveolar hemorrhage have been reported [9]. Antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis are characterized by pauciimmune necrotizing vasculitis of small blood vessels. They comprise three different clinical syndromes: Wegener s granulomatosis, microscopic polyangiitis (MPA) and Churg-Strauss syndrome. These smallvessel vasculitis are characterized by fibrinoid necrosis/ necrotizing inflammation of small vessel walls and the presence of ANCA directing to proteinase 3 (PR3) and myeloperoxidase (MPO). MPO-ANCA is the marker antibody in MPA and Churg-Strauss syndrome, while PR3-ANCA is related to Wegener s granulomatosis. Churg- Strauss syndrome can be distinguished from microscopic polyangiitis by the presence of asthma, eosinophilia, and symptoms of eosinophilic tissue infiltration. Renal and

3 ANCA associated glomerulonephritis in a patient with mixed connective tissue disease SUN Yining, et al. 211 pulmonary symptoms such as proteinuria, hematuria and hemoptysis are characteristic in MPA. Biopsy of the kidney often reveals necrotizing crescentic glomerulonephritis and necrotizing vasculitis of arterioles, capillaries, and venules with few immune complex deposits. The lung disorder in MPA is dominated by interstitial pneumonia and alveolar haemorrhage [10]. We present a case of MCTD associated with MPA. The chest CT scanning and the histopathological findings of the renal biopsy were closely examined. We concluded that MPA associated glomerulonephritis demonstrated in the patient with MCTD was successfully treated with corticosteroids and cyclophosphamide infusion therapy. 1 Case report The case was a 35-year-old Asian female patient. She had bilateral digital cyanosis which started approximately 10 years ago. In she was diagnosed as hashimoto s thyroiditis in our hospital, and was started on levothyroxine 125 μg per day and treated symptomatically since then. Eight months prior to admission to our department, the patient presented to the out-patient department with complaints of fatigue, myalgia, arthralgia mainly at the proximal interphalangeal and metacarpophalangeal joints. Immunological analysis revealed the presence of antibodies to nuclear antigen (ANA) and to U1RNP. She was diagnosed as MCTD according to Alarcon-Segovia classification criteria involving edema of the hands, synovitis, myositis, Raynaud s phenomenon, acrosclerosis and anti-u1 ribonucleoprotein (U1RNP) at a titer of 1:1600 or greater. Then hydroxychloroquine was started at a dose of 0.4 g per day at that time. She was admitted to our hospital in April Physical examination revealed a heart rate of 86 bpm, blood pressure of 100/70 mmhg, respiratory rate of 19/min, enlarged thyroid gland, swollen fingers, Raynaud s phenomenon and slight pedal edema. Crackling sounds were audible from the lower lung. Laboratory findings on admission were as follows: severe anemia (65 g/l), microhematuria, marked proteinuria as well as elevated erythrocyte sedimentation rate (104 mm/h) and high sensitivity C reactive protein (20.76 mg/l). Further examinations showed daily urinary protein loss of 4.10 g. Serum creatinine (85.7 μmol/l), creatine kinase (52.6 U/L) and lactate dehydrogenase (167 U/L) were within normal limits. Thyroid function test showed reduced triiodothyronine (0.50 pmol/l) and thyroxine (3.70 pmol/l), elevated thyroid stimulating hormone (50.8 μiu/ml) and high titers of anti-thyroid peroxidase (TPO) antibody ( IU/mL) and anti-thyroglobulin antibody (44.2%) consistent with hypothyroidism secondary to Hashimoto s thyroiditis. Immunological analysis was positive for antinuclear antibody (ANA), anti-u1rnp antibody and MPO-ANCA (159.8 RU/mL) and negative for anti- Sm and anti-dsdna antibodies. Chest CT obtained on admission showed interstitial lung disease and mild pleural thickening bilaterally. Lung function testing demonstrated a reduced diffusing capacity for carbon monoxide. Cardiac echography revealed mild dilatation of the left ventricle but pulmonary arterial hypertension was not detected. On kidney biopsy, microscopically 30 glomeruli were evaluated on a cut specimen indicating glomerulonephritis with fibrocellular/cellular crescents (Figure 1). Focal nodal glomerulosclerosis was observed in 4 examined glomeruli. In addition, crescents were observed around 26.7% of the examined glomeruli (cellular crescents: 1/30, fibrocellular crescents: 7/30). Direct immunofluorescence staining was positive for IgM and negative for complement. The patient was diagnosed as mixed connective tissue disease, microscopic polyangiitis and hypothyroidism secondary to Hashimoto s thyroiditis. The patient was started on methylprednisolone pulse therapy (500 mg/d for 3 d) after completion of the renal biopsy and followed by monthly high dose of cyclophosphamide infusion therapy (0.8 g per month). Subsequently, oral prednisone at a dose of 50 mg per day was continued and gradually tapered to 15 mg per day in about 4 months. Maintenance dose of 10 mg prednisone has been offered for more than one year. Intravenous cyclophosphamide therapy was continued for 12 months and achieved a total dose of 13.2 g. After treatment, hemoglobin and albumin gradually increased to normal. Erythrocyte sedimentation rate, high sensitivity CRP and daily urinary protein loss reduced dramatically with serum creatinine maintained normal during treatment (Table 1). Unfortunately, interstitial lung disease did not improve after corticosteroids and cyclophosphamide treatment. Chest CT scanning on admission and after treatment for one year are shown in Figure 2.

4 212 中南大学学报 ( 医学版 ), 2014, 39(2) A B Figure 1 Light microscopic appearance of glomerulus (Periodic acid Schiff hematoxylin, 400) A: A glomerulus with fibrocellular crescents; B: A golmerulus with plasma cells infiltration and enlarged Bowman s capsule Table 1 Changes of hemoglobin, albumin, creatinine, ESR, hs-crp and proteinuria In treatment Hemoglobin/(g/L) Albumin/(g/L) Creatinine/(μmol/L) ESR/(mm/h) hs-crp/(mg/l) Proteinuria/(g/24h) A B Figure 2 CT scanning of the chest before and after treatment with corticosteroids and cyclophosphamide A: Chest CT scans from April 2010 show pulmonary fibrosis in both lungs; B: Interstitial lung disease did not improve after treatment on chest CT scans obtained in April 2011

5 ANCA associated glomerulonephritis in a patient with mixed connective tissue disease SUN Yining, et al Discussion MCTD refers to a disease process with combined clinical features of systemic lupus erythematosus, scleroderma and polymyositis/dermatomyositis. The characteristic laboratory abnormality in MCTD patients is the presence of a high titer of anti-u1rnp antibody. To our knowledge, MCTD complicated with MPA is an unusual clinical association, reported only 5 times since All patients were firstly diagnosed as having MCTD because of Raynaud s phenomenon, swollen fingers and a high titer of serum anti- U1RNP antibody. After clinically benign and long-lasting MCTD, the patients developed alveolar hemorrhage and/ or rapidly progressive glomerulonephritis (RPGN) with a positive remark of serum anti-mpo antibodies. All the patients were given methylprednisolone pulse therapy or oral prednisolone and intravenous cyclophosphamide therapy. However, they responded differently to the treatment. Two patients remained in complete clinical remission after prednisolone and cyclophosphamide treatment [11-12]. The other three patients died from respiratory failure secondary to acute exacerbation of interstitial pneumonitis that was unresponsive to steroid pulse therapy [13], diffuse alveolar hemorrhage [14], and sepsis [15]. It has been found that systemic and organ-specific autoimmune diseases can co-associate in the same individual or among related family members, which led to the proposal of the concept of shared autoimmunity [16]. It is well known that Hashimoto s thyroiditis is an organspecific autoimmune disease. Autoimmune thyroiditis has the broadest propensity for autoimmune clustering such as autoimmune hemolytic anemia, SLE, rheumatoid arthritis and autoimmune hepatitis [17]. Apparent clustering of Hashimoto s thyroiditis, MCTD and ANCA-associated vasculitis was demonstrated in this patient. Genetic factors are assumed to be linked to this phenomenon. Inheritance of an at risk genotype comprising female gender [18], major histocompatibility complex (MHC) risk alleles [19] and combinations of mutant alleles of multiple toleranceautoimmunity genes [20] may contribute to the coexistence, overlap and clustering of autoimmune diseases. As we know that it was originally thought that renal involvement was a rare complication of MCTD. However, over the years, it has become clearer that renal involvement can be present in 20%-30% patients of MCTD. Furthermore, immune complex-mediated nephritis is one of the major complications of MCTD. It has been demonstrated that membranous nephropathy (MN) and mesangial proliferative glomerulonephritis were common in MCTD [5]. Intimal hyperplasia of renal intralobular and arcuate arteries resembling sclerodermalike renal damage can also be found in MCTD by kidney biopsy [3]. In this patient marked proteinuria required renal biopsy to determine the feature and extent of damage to the kidney. Histopathological examination of the kidney revealed 26.7% glomeruli presented fibrocellular crescents with moderate IgM staining on direct immnofluorescent microscopy. According to previous observations, crescentic glomerulonephritis is explained to be clinically identical to MPA-associated glomerular lesions. In this case, neither mesangial proliferation nor intimal hyperplasia was observed. After corticosteroids and cyclophosphamide pulse therapy, daily urinary protein loss reduced dramatically and serum creatinine maintained normal. All these findings indicated that renal involvement in this patient may be related to MPA-associated glomerulonephritis. Then this patient should be diagnosed as MCTD combined with MPA. Pulmonary involvement is commonly observed in patients with MCTD. More than half of the MCTD patients can be found pulmonary impairment [21]. Interstitial lung disease (ILD) is a characteristic and serious manifestation of MCTD. The reported frequency of ILD in MCTD is between 21% and 50%. Based on findings of high-resolution computed tomography (HRCT), the prevalence of ILD was suggested to be as high as 67% [7]. Changes characteristic of MCTD seen on HRCT include ground-glass attenuation and non-septal linear opacities with peripheral and lower lobe predominance. Patients frequently present with complaints of dyspnea and nonproductive cough. Severe lung fibrosis and pulmonary arterial hypertension can evolve following ILD. When systemic sclerosis manifestations are present, MCTD-ILD seems to be associated more frequently with pulmonary hypertension and progressive ILD [22]. The prevalence of pulmonary involvement in MPA was high. Interstitial pneumonitis and pulmonary hemorrhage are characteristic pulmonary impairment in MPA [10]. ILD was observed in 7.2% of patients with MPA associated vasculitis. The clinical manifestations were nonspecific, radiographic manifestations included ground glass attenuation, interstitial changes, infiltrates and pleural effusion [23]. In patients with MPA, pathological changes in the lungs usually develop in accordance with rapid development of the renal lesions. In this case interstitial changes were observed in the lower lung fields as demonstrated by chest CT scan. Interstitial lung disease did not change significantly after corticosteroid and cyclophosphamide treatment for almost one year. Therefore, it is probable that in this case lung fibrosis represents scleroderma-like

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