Antineutrophil Cytoplasmic Antibody-associated Disease Predictors of Treatment Resistance and Relapse in Chinese Patients with

Objective. The prevalence and significance of treatment resistance and relapse in patients from China with antineutrophil cytoplasmic antibody-associated (ANCA) disease are poorly understood. Methods. A total of 98 patients with ANCA vasculitis, diagnosed between January 2003 and December 2009 in the China-Japan Friendship Hospital, were enrolled in this retrospective study. Results. Fifteen patients (15.3%) were categorized as having cytoplasmic and/or proteinase 3 (PR3) ANCA and 83 patients (84.7%) had perinuclear and/or myeloperoxidase (MPO) ANCA. After the induction phase treatment, the disease was resistant to therapy in 24 (25%) of the patients. A response to initial treatment occurred in 74 patients (75%). Of these 74 patients, remission was achieved and sustained with or without maintenance therapy in 41 patients (55%). Multivariable logistic regression models revealed that female sex was a statistically significant predictor of treatment resistance (OR 2.85; 95% CI: 1.06–2.86; p = 0.036). Additionally, elevated serum creatinine level, with each increment of 150 μmol/l, predicted resistance (p = 0.002). Among the 74 patients where remission was achieved, Cox proportional hazards models detected that those with PR3 ANCA were 1.31 times more likely to experience a relapse than were patients with MPO ANCA (95% CI: 1.01–5.35; p = 0.0001). Lung involvement was associated with an increased risk of relapse (HR 1.87; 95% CI: 1.12–4.35; p = 0.014). Although not significant, advanced age tended to be associated with relapse (p = 0.08). Conclusion. Our findings highlight the important effect of female sex and severity of renal disease at presentation as predictors of treatment resistance, and PR3 ANCA and lung involvement as predictors of relapse. (First Release March 15 2014; J Rheumatol 2014;41:916–22; doi:10.3899/ jrheum.130758) Key Indexing Terms: ANTINEUTROPHIL CYTOPLASMIC ANTIBODY TREATMENT RESISTANCE RELAPSE PROTEINASE 3 REMISSION From the Department of Nephrology, Department of Rheumatology, China-Japan Friendship Hospital; Department of Surgery, Beijing LuHe Hospital, Beijing, China. Supported by the National Natural Science Foundation of China (grant number 81200535) and the Scientific Research Foundation for Returned Chinese Scholars, Ministry of Human Resources and Social Security (grant number 2012). Y. Cao, MD, PhD, Department of Nephrology, China-Japan Friendship Hospital; Z. Tian, MD, Department of Surgery, Beijing LuHe Hospital; W. Li, MD, PhD, Department of Nephrology, China-Japan Friendship Hospital; L. Ma, MD, Department of Rheumatology, China-Japan Friendship Hospital; Y. Yu, MD; W. Ren, MD, Department of Nephrology, China-Japan Friendship Hospital. Address correspondence to Dr. W. Li, Professor of Medicine, Department of Nephrology, China-Japan Friendship Hospital, No. 2 Yinghua St., Chaoyang District, Beijing, 100029, P.R. China. E-mail: wenge_lee2002@126.com Accepted for publication December 19, 2013. Antineutrophil cytoplasmic antibody (ANCA) disease is characterized by necrotizing inflammation of small blood vessels. Disorders belonging to the group mainly include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilia granulomatosis with polyangiitis (EGPA)1. Therapy for ANCA disease typically includes induction therapies with corticosteroids and cyclophosphamide and maintenance therapies with azathioprine, mycophenolate mofetil, and cyclosporine2. Rituximab has been given to increasing numbers of patients especially after the publication of 2 randomized-controlled trials, showing that it was as effective as cyclophosphamide at inducing disease remission3,4. The majority of patients respond well to these therapies; remission is achieved in 85%. However, some of those patients who reached remission (about 11% to 57%) experienced a relapse. Some relapses are severe and may result in life-threatening infection and endstage kidney disease (ESKD)3,4,5,6,7. Fear of relapsing has resulted in physicians prescribing prolonged maintenance therapies to the majority of patients. Unfortunately, longterm use of immunosuppressive therapy will often result in unnecessary treatment and therapy-related risks that may outweigh the benefits of preventing relapse. Therefore, it is necessary to find predictors of treatment resistance and relapse to personalize the treatment. Previous studies have demonstrated that female sex, African American ethnicity, older age, and the severity of renal disease at presentation are predictors of therapy Rheumatology The Journal of on June 24, 2015 Published by www.jrheum.org Downloaded from 917 Cao, et al: Treatment response in ANCA resistance, while relapse is associated with proteinase 3 (PR3) ANCA and disease involvement of the lungs and upper respiratory tract8,9. It is not known whether these predictors, which have been demonstrated in US and other Western cohorts, apply to Chinese patients with ANCA disease. Substantial evidence suggests that geographical and genetic factors both play a part in the pathogenesis of ANCA disease. In northern Europe and Germany there are many more patients with GPA than with MPA10,11. But a study from Spain suggested that, in southern Europe, patients with MPA comprised about 2 to 3 times as many patients with GPA12. Assessment of disease by ethnic distributions in US cohorts has suggested GPA is more prevalent in whites than in African Americans13. MPA is more common in Asian countries, such as China and Japan14,15. Therefore, it is of interest to evaluate whether Chinese patients with ANCA disease share similar predictors of outcome with Westerners. MATERIALS AND METHODS Patients. A total of 102 patients with ANCA disease, diagnosed between January 2003 and December 2009 at the China-Japan Friendship Hospital, Beijing, and followed up by specialists in nephrology and rheumatology, were identified in our retrospective study. The end of the followup period was December 2012. Study patients gave informed written consent and participated according to China-Japan Friendship Hospital Institutional Review Board guidelines. Our hospital is affiliated with China’s Ministry of Health and is a teaching hospital of Peking University and Beijing University of Chinese Medicine. We designed a consent form that allows for the files of hospitalized patients to be used for teaching medical students and material for retrospective research. To be included in the study, patients were required to be positive for ANCA, as determined by both immunofluorescence microscopy and ELISA16. Standard indirect immunofluorescence assays were performed according to the manufacturer’s instructions (Euroimmun). Ethanol-fixed human polymorphonuclear leukocytes were used to detect ANCA and monkey liver sections were used to exclude antinuclear antibodies. Cytoplasmic ANCA and perinuclear ANCA were distinguished according to staining patterns by 2 experienced technicians. Antigen-specific PR3 and MPO ELISA were determined by the ELISA kit (Euroimmun). Patients were categorized as having cytoplasmic and/or PR3 ANCA or perinuclear and/or myeloperoxidase ANCA (MPO ANCA). Patients who had perinuclear ANCA alone had to be negative for antinuclear antibodies to be included in the study. Two patients with target antigen specificities to both MPO and PR3 were excluded (Figure 1). All of the patients met the criteria of the Chapel Hill consensus conference definition (for GPA, MPA, and EGPA). Patients with systemic lupus erythematosus, Henoch-Schönlein purpura, and rheumatoid arthritis were excluded. Two patients with EGPA were also excluded because of the small number (Figure 1). Organ involvement was determined by biopsy or by described criteria8,17,18. Methods. The induction therapy included corticosteroids in combination with cyclophosphamide. Prednisone was started at a dose of 1 mg/kg for the first month, and tapered progressively over 12–24 months. Cyclophosphamide was administered monthly either by intravenous (IV) pulse (0.5–1 g/m2) or orally (1–2 mg/kg/day). A 25% dose reduction of cyclophosphamide was made for those participants aged 65 years and those with renal insufficiency. Patients with acute renal failure or pulmonary hemorrhage received 3 pulses of IV methylprednisolone (7–15 mg/kg/day) before standard induction treatment. Some patients with severe pulmonary hemorrhage received plasma exchanges. Azathioprine (2 mg/kg/day with a reduction for those with renal insufficiency) or mycophenolate mofetil (1 g/day) was given in maintenance treatment. Histopathologic renal evaluations included 4 general categories: focal, crescentic, sclerotic, and mixed19. Briefly, the categories labeled focal, crescentic, and sclerotic are based on the predominance of normal glomeruli (≥ 50% normal glomeruli that are not affected by the disease process), cellular crescents (≥ 50% of glomeruli with cellular crescents), and globally sclerotic glomeruli (≥ 50% of glomeruli with global sclerosis), respectively. The mixed category represents a heterogeneous glomerular phenotype wherein no glomerular feature predominates (< 50% normal, < 50% crescentic, < 50% globally sclerotic glomeruli). Treatment categories were based on the first therapy regimen used at diagnosis. Primary outcomes included treatment resistance, remission during or outside therapy, and relapse. Treatment resistance was determined at least 1 month after the start of treatment and defined as a progressive decline in kidney function with persistence of active urine sediment, or unchanged or new appearance of any extra renal manifestations of active vasculitis despite immunosuppressive therapy. Remission was defined as the absence of clinical signs or symptoms or laboratory evidence of vasculitis activity for more than 1 month. Relapse was considered only in patients in whom remission was reached (on and off therapy) and was defined as the return of clinical signs or symptoms or laboratory evide