Clinical Features of Microscopic Polyangiitis: A Cohort Study in a Southern Taiwan Medical Center

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1 Acta Nephrologica 26(4): 198-5, 12 DOI: /AN.1128 Original Article Clinical Features of Microscopic Polyangiitis: A Cohort Study in a Southern Taiwan Medical Center Chun-Kai Huang 1, 3, Hua-Chang Fang 1, 3, Kang-Ju Chou 1, 3, Jyh-Seng Wang 2, 3, Po-Tsang Lee 1, 3, Tsu-Yuan Chang 1, 3, Chih-Yang Hsu 1, 3, Wei-Chieh Huang 1, 3, Hsiao-Min Chung 1, 3, and Chien-Liang Chen 1, 3 1 Division of Nephrology 2 Division of Pathology, Kaohsiung Veterans General Hospital, Kaohsiung 3 Department of Medicine, National Yang-Ming University, School of Medicine Taipei, Taiwan, Republic of China Abstract BACKGROUND: To determine the clinical features and outcomes of microscopic polyangiitis (MPA) in Taiwanese patients, we retrospectively reviewed the medical records of patients diagnosed with MPA at a single medical center in Taiwan between January 1, 1996 and June 1, 11. METHODS: A cohort of 21 patients (17 men and 4 women) with a mean age of 67 ± 11 years was investigated. Diagnosis was made according to the Chapel Hill criteria for MPA. All patients had renal histological evidence of microscopic polyarteritis. RESULTS: The main clinical manifestations were renal involvement (1%), lung involvement (67%), gastrointestinal involvement (24%), skin lesion (15%), fever (15%), mononeuritis multiplex (1%), and arthralgia (15%). Antineutrophil cytoplasmic antibodies were present in 18 of the 21 patients (86%). Seventeen patients were treated with steroids and cyclophosphamide. Eleven of these 17 patients had stable or improved courses. Ten of the 21 patients (47.6 %) received dialysis at the time of diagnosis and two of them recovered to achieve a dialysis-independent status. Renal survival rates were 46.1% at 1 year and 36.9% at 3 years. A good renal function at diagnosis, lower chronic kidney biopsy index, and good response to treatment were associated with better renal outcome. Patient survival rates were 73.8% at 1 year and 58.7% at 3 years. CONCLUSION: Taiwanese patients with MPA were older, and had a high rate of lung involvement, all of which are indicators of a poor prognosis. Our study suggests that birmingham vasculitis activity score may be a better prognostic predictor in the evaluation of MPA patients. For patients with renal failure, rapid confirmation with renal biopsy and early treatment may improve outcome. KEY WORDS: antineutrophil cytoplasmic antibody, microscopic polyangiitis, vasculitis Introduction Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) is a multisystem disorder characterized with small-vessel vasculitis and the presence of ANCA. The pathophysiology of AAV is complex involving both the humoral and the cellular immune system. ANCAs promote degranulation of neutrophils and monocytes, thus facilitating endothelial damage (1). The endothelium is also activated and thereby neutrophil adherence is enhanced. The initial damage leads to a cascade of events, resulting Corresponding author: Dr. Chien-Liang Chen, Division of Nephrology, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Rd., Kaohsiung 81362, Taiwan, R.O.C. Tel: ext. 219, Fax: , cclchen@seed.net.tw Received: November 3, 11; Revised: May 15, 12; Accepted: July 3, 12. *This work was supported by grants from Kaohsiung Veterans General Hospital (VGHKS1-3). 198

2 Microscopic Polyangiitis in Taiwan 199 in leukocyte tissue infiltration, T-cell-driven granuloma formation, and further damage (2-4). ANCA-associated vasculitis included Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis (MPA). MPA was initially recognized as a particular type of polyarteritis nodosa with, in most cases, rapidly progressive necrotizing glomerulonephritis and sometimes with lung hemorrhage (5, 6). In 1994, MPA was distinguished from polyarteritis nodosa by the presence of small-vessel involvement (7). MPA, Wegener granulomatosis, and Churg-Strauss syndrome all involve small vessels and hence share similar clinical features, such as alveolar hemorrhage and rapidly progressive glomerulonephritis. However, unlike Wegener granulomatosis and Churg-Strauss syndrome, MPA does not present granuloma formation or eosinophilia (8). While several studies have investigated the prognosis of ANCA-associated vasculitis, few have discussed MPA specifically as a separate entity. Immunosuppressive therapy in MPA is life- and organsaving and its benefits are widely accepted. However, the toxicity of current regimens remains of concern. While several studies addressed the value of clinical and pathological prognostic factors over the renal outcome, others have reported contradictory results and conclusions (8-12). There is evidence that the prevalence of microscopic polyangiitis, rather than Wegner granulomatosis, is higher in patients of Chinese and Japanese descent compared with that in white patients (13-15). Thus, there may be racial differences in the clinical characteristics of this disease. There has been no research on the clinical features and treatment outcomes of MPA in Taiwanese patients. Therefore, in this study, we characterized and analyzed the clinical manifestations, treatments, and outcomes in a cohort of Taiwanese patients diagnosed with MPA. Materials and Methods We retrospectively reviewed the medical records of 21 patients diagnosed with MPA at Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, between January 1, 1996 and June 1, 11. Diagnoses were made according to the Chapel Hill consensus conference definition of MPA (7), which is based on a renal biopsy showing focal or diffuse segmental crescentic glomerulonephritis (Fig. 1) and a paucity of immunofluorescent immune deposits combined with clinical features. Patients with other smallvessel vasculitides, such as Wegener granulomatosis or Churg-Strauss syndrome, were excluded if they had granulomatosis inflammation, a history of asthma, or anti-glomerular basement membrane antibody. We excluded the patients with possible secondary causes Fig. 1. Microscopic polyangiitis. The Hematoxylin and eosin stained section revealed one glomeruli with fibrocellular crescent and segmental sclerosis. There is significant inflammation in the interstitium. of MPA: malignancy, infection (including hepatitis B and C, HIV, and tuberculosis), and drugs (propylthiouracil, allopurinol, and hydralazine). The date of renal biopsy was used as the starting point of entry into the present study. The end-point for renal survival analysis was the start of long-term renal replacement therapy while that for patient survival was death due to any cause. For each patient, the following data were collected: gender, age, clinical manifestations, laboratory, and immunologic data at the time of diagnosis, treatment, duration of follow-up, and cause of death. The clinical manifestations included symptoms, signs, and organ involvement at presentation. Respiratory involvement was diagnosed on the basis of chest X- rays. Patients who presented severe alveolar hemorrhage requiring ventilator support at the time of diagnosis were considered to have respiratory failure. Cardiomyopathy was defined as significant impairment of cardiac function due to poor ventricular wall motion, confirmed by echocardiography. Laboratory data included white blood cell and platelet counts, hemoglobin, C-reactive protein, blood urea nitrogen, serum creatinine, liver enzyme level, and urinalysis. Proteinuria was defined as the presence of 1 g protein or more in 24-h urinary samples. A clinical diagnosis of rapidly progressive glomerulonephritis was defined as serum creatinine exceeding 4.5 mg/dl at presentation or a two-fold increase in serum creatinine concentration within 3 months of disease onset. Immunologic data included the presence of antinuclear antibody, perinuclear (MPO) and cytoplasmic (PR3) ANCA, antinuclear antibody (ANA), rheumatoid factor (RF), complement components of C3 and C4, hepatitis B virus surface antigen (HBsAg), and antihepatitis C virus antibody (anti-hcv).

3 Huang, Fang, Chou, Wang, Lee, Chang, Hsu, Huang, Chung and Chen The extent of glomerular damage for each patient was assessed by one renal pathologist, and expressed as the percentage of cellular crescents, fibrocellular crescents, fibrous crescents, and global sclerosis. Interstitial fibrosis was graded on a scale of -3 (absent, mild, moderate, and severe). Acute glomerular lesions were cellular and fibrocellular crescents, whereas chronic glomerular lesions were fibrous crescents and global sclerosis. To evaluate the association between disease activity at the time of diagnosis and outcome, we retrospectively applied the Five Factor Score (FFS) (12) and Birmingham Vasculitis Activity Score (BVAS) (16). The FFS is a scoring system based on proteinuria (> 1 g/day), renal insufficiency (serum creatinine > 1.58 mg/dl), severe gastrointestinal (GI) tract involvement (defined as bleeding, perforation, infarction, and/or pancreatitis), cardiomyopathy, and/ or central nervous system (CNS) involvement, with the presence of each factor assigned 1 point. The BVAS evaluation form is divided into nine organbased systems (general, cutaneous, mucous membrane/ eye, ear/nose/throat, chest, cardiovascular, abdominal, and nervous system), with each section comprising symptoms/signs that are typical of that particular organ involvement in systemic vasculitis (16, 17). Clinical renal function improvement during first month was defined as renal function improvement or stable compared with the renal function at diagnosis. Estimated glomerular filtration rate was calculated using the MDRD formula (18). End-stage renal disease (ESRD) was defined as a status in need of maintenance dialysis therapy over 3 months during followup period. Most patients were treated with corticosteroid and cyclophosphamide. Treatment response was defined as attenuation or stabilization of clinical manifestations of MPA and improving serum creatinine level as improvement of kidney function after the first pulse therapy for more than 1 month. Causes of death were classified into three subgroups: vasculitis-related, vasculitis-unrelated such as sepsis, and unknown. Long-term survival of patients was determined by follow-up of their outpatient clinic records and contact with the patients themselves, or their first-degree relatives. Statistical Analyses Kaplan-Meier life survival analysis was employed to assess patient and renal survival. FFS, BVAS, age, plasmapheresis and presence of respiratory failure and ESRD were used as independent variables to predict outcomes using the log-rank test. Age, gender, rapidly progressive glomerulonephritis, blood urea nitrogen, serum creatinine, proteinuria, Table 1. The initial presentation of MPA Number (%) General symptoms (95%) Fever 3 (14%) Malaise 4 (19%) Weight loss 2 (1%) Musculoskeletal 3 (14%) Skin rash 3 (14%) Ear, nose and throat 4 (19%) Gastrointestinal 5 (24%) Abnormal liver function 1 (5%) Severe GI involvement 4 (19%) Cardiac (cardiomyopathy or heart failure) (%) Pulmonary 14 (67%) Alveolar hemorrhage 9 (43%) Pleural effusion 3 (14%) Infiltration or nodule 12 (57%) Renal 21 (1%) Azotemia (>1.58 mg/dl) 21 (1%) Hematuria 21 (1%) Proteinuria (>1 g/24 hr) 19 (9%) Neurologic 2 (1%) Peripheral neuropathy 2 (1%) CNS involvement 1 (5%) acute glomerular lesions, chronic glomerular lesions, and interstitial fibrosis were compared between ESRD and non-esrd groups. Continuous data were analyzed using t-test and nominal data were examined using Fisher s exact test. Statistical significance was defined as P <.5. All statistical analyses were performed using SPSS/Windows software (SPSS, Chicago, IL, 12 versions). Clinical Features Results Of the 21 patients, 17 were men and 4 were women with a mean age of 67 ± 11 years (range, 45-88) at the time of diagnosis. The median duration of follow-up was 18 months (range, 1-182). As seen in Table 1, which summarizes the clinical manifestations at the time of diagnosis and during the course of the disease, the most common features of MPA were renal manifestations (n = 21, 1%) and general symptoms (n =, 95%). Lung involvement was seen in 14 patients (67%). Nine patients presented with alveolar hemorrhage, four of whom needed ventilator support. Laboratory Findings At the time of admission for renal biopsy, the

4 Microscopic Polyangiitis in Taiwan 1 Table 2. Immunologic parameters at the time of diagnosis Positive Number (%) MPO antineutrophil cytoplasmic antibody 18 (86%) Antinuclear antibody 3 (14%) Rheumatoid factor 5 (24%) HBsAg 1 (5%) Anti-HCV 2 (1%) C3 (average ± SD, cutoff: 79~152 mg/dl) 82.1 ± 22.3 C4 (average ± SD, cutoff: 16~38 mg/dl).8 ± 5.1 Unless otherwise indicated, values are frequencies (percentages) or means ± SD. Table 3. Comparison of the clinical features and renal pathology between ESRD and non-esrd patients ESRD (n = 12) non-esrd (n = 9) P value Age (years) 69. ± ± 15.2 NS* Gender (M/F) 1/2 7/2 NS Serum BUN (mg/dl) 85. ± ± Serum creatinine (mg/dl) 7.9 ± ± Proteinuria (g/day) 3.5 ± ± 3.9 NS Acute glomerular lesion (%) 37.2 ± ± 3. NS Chronic glomerular lesion (%) 53. ± ± Interstitial fibrosis scores 1.7 ± ±.8 NS Initial treatment response 2/12 9/9 <.1 *NS: not statistically significant. Active glomerular lesion: cellular and fibrocellular crescents. Chronic glomerular lesion: fibrous crescents and global sclerosis. mean white blood cell and platelet counts were 9.5 ± /µl and 256 ± /µl, respectively. The mean level of hemoglobin was 9.2 ± 1.1 g/dl; C- reactive protein, 6. ± 5.2 mg/dl; blood urea nitrogen, 71. ± 25.7 mg/dl; and serum creatinine, 6.7 ± 2.4 mg/dl. All patients (1%) had renal insufficiency (serum creatinine > 1.5 mg/dl) and active urine sediments of hematuria and proteinuria. Nineteen of the 21 patients (9%) had daily urine protein excretion exceeding 1 gram. Eighteen of the 21 patients were found to be positive for MPO-ANCA, while none were found to have PR3-ANCA (Table 2). Treatment, Outcome and Prognostic Factors Of the 21 patients, 17 (81%) were treated with a combination of steroid and cyclophosphamide. Cyclophosphamide was administered intravenously. One of the 21 patients received steroid treatment only, and the remaining 3 patients received conservative treatment owing to fear of poor response to immunosuppressive treatment and risks of infectious complications. Of the 17 patients treated with steroids and cyclophosphamide, 11 (64.7%) showed stabilization of disease or improvement. Of the 21 patients, 1 (47.6%) needed dialysis therapy within one month after renal biopsy. Two of these dialysis patients, who responded well to pulse steroid and cyclophosphamide therapy, became dialysis-independent. Patients who need longterm renal replacement therapy had more chronic glomerular lesions on pathology, poorer presentation of renal function, and poorer treatment response at initial presentation of disease (Table 3). Seven of the 21 patients (33.3%) died (Table 4) during the follow-up period. The overall MPA mortality was 33.3%. Patient survival rates at one and three years were 73.8% and 58.7%, respectively; while mean and median survival times were 27.8 and 18 months, respectively (Fig. 2A). Renal survival rates at one and three years were 46.1% and 36.9%, while mean and median renal survival times were 15.3 and 3 months, respectively (Fig. 2B). The mean FFS at the time of diagnosis was 2.9 (range, 1-3). As seen in Fig. 3, a depiction of patient survival curves analyzed by FFS, BVAS, age, presence of respiratory failure, entering ESRD and plasmapheresis shows that patients who were older (age > 7 years), entered ESRD, presented with initial respiratory failure, and

5 2 Huang, Fang, Chou, Wang, Lee, Chang, Hsu, Huang, Chung and Chen Table 4. Causes of death in patients with microscopic polyangiitis (n = 7) Number (%) Vasculitis-related Alveolar hemorrhage 1 (14%) Uremia (refused renal replacement therapy) 1 (14%) Vasculitis-unrelated Pneumonia 2 (29%) Other comorbidity-cardiac arrhythmia 1 (14%) Unknown (follow-up loss) 2 (29%) A 1 B 1 6 Renal Survival (%) Fig. 2. Kaplan-Meier renal survival (A) and patient survival curve (B) for the 21 patients with microscopic polyangiitis. had BVAS 22 had poorer outcomes. Discussion Since outcome and recommendations regarding the managements of ANCA-related vasculitis were obtained from Wegener granulomatosis and MPA patients (19-21), caution must be taken when applying these findings to Taiwanese patients, especially since most of them are MPA patients. Although the survival of patients with MPA was not significantly different from that of patients with WG after corrected for age and renal function, there have been no studies focusing on clinical features and treatment outcomes of MPA in Taiwan. This study was to analyze the clinical manifestations, outcomes, and treatments in a cohort of Taiwanese patients using the renal biopsy registry data at our hospital. The analysis revealed that, unlike reports from other countries (Table 5), MPA patients in Taiwan were older at age of onset, male predominant, and more likely to have a positive test for MPO-ANCA, 86% versus 5-% (22-24). The male predominance is compatible with that in previous studies (25-26). Taiwanese patients also have a higher rate of lung involvement. Alveolar hemorrhage was noted in nine patients. However, cardiac involvement and neurological manifestations were less common in our patients. Among our patients, 47.6% were in need of dialysis at the time of diagnosis. Neurological impairment with mononeuritis multiplex was noted in only two patients and one with left pons infarction as initial presentation, suggesting that for patients with nephritis in addition to unexplained stroke or peripheral neuropathy, the diagnosis of systemic vasculitis, such as MPA, should be kept in mind. These patients should be encouraged to receive renal biopsy in order to confirm the diagnosis and begin treatment as early as possible. In one study of Caucasians, ANCA was present at the time of diagnosis in 74.5% of patients, with 64.7% having microscopic polyangiitis for MPO- ANCA and 9.8% positive for PR3-ANCA (12). In

6 Microscopic Polyangiitis in Taiwan 3 A 1 FFS < 3 (n = 17) FFS 3 (n = 4) B 1 BVAS < 22 (n = 16) BVAS 22 (n = 5) C 1 Age < 7 yr (n = 1) Age 7 yr (n = 11) D 1 No respiratory failure (n = 17) Respiratory failure (n = 4) E 1 Not entering ESRD (n = 9) Entering ESRD (n = 12) F 1 No plasmapheresis (n = 12) Receive plasmapheresis (n = 9) Fig. 3. Kaplan-Meier patient survival curves for the 21 patients with microscopic polyangiitis analyzed using the variables of (A) FFS (P =.11), (B) BVAS (P =.7), (C) age, (P =.31), (D) presence of respiratory failure (P =.21), (E) entering ESRD (P =.9) and (F) having received plasmapheresis (P =.17). Data were analyzed using log-rank test.

7 4 Huang, Fang, Chou, Wang, Lee, Chang, Hsu, Huang, Chung and Chen Table 5. Comparison of data from the present study with data from previous reports Manifestations Savage (9) D Agati (1) Adu (11) Guillevin (12) Ahn (25) Present Year Number of patients Mean age(range) 5 (14-73) 49.6 (6-) (16-86) (45-88) Male/female ratio General symptoms Fever 41% 5% 56% 55% 58% 14% Musculoskeletal 72% 67.3% 14% Arthralgia 65% 35% 5% 38% Myalgia 5% 25% 41% 47% Skin rash 35% 53% 62% 51% 14% Ear, nose and throat % 19% Gastrointestinal 56% 3% % 24% Cardiac (cardiomyopathy or heart failure) 9% 18% Pulmonary 55% 34% 25% 42% 67% Pulmonary hemorrhage 29% 12% 7% 43% Pleural effusion 15% 6% 13% 14% Renal 1% 1% 1% 79% 75% 1% Neurologic 44% 1% Peripheral neuropathy 18% 15% 14% 58% % 1% CNS involvement 18% % 12% 9% 5% contrast, 86% of our patients were tested positive for MPO-ANCA and none was positive for PR3-ANCA. The difference between Asians and Caucasians may be related to genetic or environmental factors and requires further studies to clarify our understanding of this variation. Two patients who presented with ESRD at the time of diagnosis needed dialysis therapy. They were treated with pulse steroids and cyclophosphamide and recovered to a dialysis-independent status. A better renal function at diagnosis, a lower chronic kidney injury index and a good response to initial treatment were associated with better renal outcome. Accordingly, once suspicion of systemic vasculitis is apparent, a renal biopsy should be promptly performed to confirm the diagnosis and start immunosuppressive therapy as early as possible. Mortality of vasculitis has been shown to be significantly associated with disease activity, as assessed using the FFS and BVAS (17, 25, 27). This study used the FFS, as an assessment of kidney involvement, severe GI tract involvement, cardiomyopathy, and CNS. However, this scale does not include the pulmonary system. We found that kidney and pulmonary system involvement is more prevalent than GI tract, heart and CNS in our patients, suggesting that this scale may not be suitable for evaluating prognosis of MPA in Taiwanese patients. Conversely, the BVAS, which is more complicated but also more detailed, could be a better predictor of the outcomes. In this study, patients with BVAS above 22 had a poorer prognosis. The overall mortality in our study was 33.3%, similar to that reported previously (26, 28). According to our log-rank tests, the older age at diagnosis was a significant prognostic factor. Respiratory failure was also associated with a poor survival, suggesting that severe lung involvement or alveolar hemorrhage can lead to increased risk of death. The efficacy of plasmapheresis for MPA is unproven. Nine patients received plasmapheresis combined with immunosuppressive therapy. Four of nine patients died later. This plasmapheresis may select patients with severe vasculitis. Further large, randomized studies were needed for further evaluation of the benefits of plasmapheresis. The diagnosis of MPA was made according to a renal biopsy showing focal or diffuse segmental crescentic glomerulonephritis and a paucity of immunofluorescent immune deposits combined with other extra-renal clinical manifestations. This approach may lead to an underestimation of the prevalence of MPA, and select patients with severe renal damage and poorer renal survival. However, despite of this limitation, the inclusion and exclusion criteria allowed for a greater degree of diagnostic specificity and increased the validity of our interpretation of the related data. Furthermore, this is a hospital-based cohort study, implying that selection bias may exist. In conclusion, Taiwanese patients with MPA were older, and had a high rate of lung involvement,

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