Shuzo Kaneko, Kunihiro Yamagata, Joichi Usui, Naotake Tsuboi, Hitoshi Sugiyama, Shoichi Maruyama, Ichiei Narita
Epidemiology and temporal changes in the prognosis of rapidly progressive glomerulonephritis in Japan: a nationwide 1989-2015 survey.
Clin Exp Nephrol. 2022 Mar;26(3):234-246. doi: 10.1007/s10157-021-02148-y. Epub 2021 Oct 13.
Abstract/Text
BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) can progress to end-stage kidney disease within a short period. This study is a continuation of the chronological nationwide survey conducted by the Japan-RPGN working group.
METHODS: We examined a total of 2793 RPGN cases registered during four periods (1989-1998, 1999-2001, 2002-2008, 2009-2011) plus 1386 cases in 2012-2015. As potential prognostic determinants, we investigated the onset period, the clinical severity (CS) grade [classified according to age, serum creatinine (sCr) and C-reactive protein levels, and presence/absence of lung lesions], and causative disease.
RESULTS: The cumulative overall RPGN patient survival at 24 months kept improving over the five periods (72.0%, 72.9%, 77.7%, 83.0%, 84.9%, p < 0.001 for trend). The cumulative renal survival also improved in the latest period (68.7%, 75.4%, 76.7%, 73.4%, 78.2%, p < 0.001 for trend). The CS grade was well stratified to predict both life and renal prognoses. Anti-glomerular basement membrane disease (aGBMD)-RPGN had a poorer renal prognosis than other diseases. In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV-RPGN, accounting for > 70% of the overall RPGN), the prognostic results were similar to that for overall RPGN. There was a much better renal prognosis for the latest period under the condition of sCr < 3 mg/dL (the 24-month cumulative renal survival: 97.9%), but not for sCr ≥ 3 mg/dL (61.5%).
CONCLUSIONS: In overall RPGN as well as AAV-RPGN, both life and renal prognoses tended to improve, but the favorable renal result was substantially limited to mild cases. There was no improvement of the renal prognosis in aGBMD-RPGN.
© 2021. Japanese Society of Nephrology.
Kunihiro Yamagata, Joichi Usui, Chie Saito, Naoto Yamaguchi, Kouichi Hirayama, Kaori Mase, Masaki Kobayashi, Akio Koyama, Hitoshi Sugiyama, Kosaku Nitta, Takashi Wada, Eri Muso, Yoshihiro Arimura, Hirofumi Makino, Seiichi Matsuo
ANCA-associated systemic vasculitis in Japan: clinical features and prognostic changes.
Clin Exp Nephrol. 2012 Aug;16(4):580-8. doi: 10.1007/s10157-012-0598-2. Epub 2012 Feb 18.
Abstract/Text
BACKGROUND: This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries.
METHODS: The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive.
RESULTS: Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose <0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C).
CONCLUSIONS: Oral prednisolone dose <0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes.
Shouichi Fujimoto, Shigehiro Uezono, Shuichi Hisanaga, Keiichi Fukudome, Shigeto Kobayashi, Kazuo Suzuki, Hiroshi Hashimoto, Hiroyuki Nakao, Hiroyuki Nunoi
Incidence of ANCA-associated primary renal vasculitis in the Miyazaki Prefecture: the first population-based, retrospective, epidemiologic survey in Japan.
Clin J Am Soc Nephrol. 2006 Sep;1(5):1016-22. doi: 10.2215/CJN.01461005. Epub 2006 Aug 2.
Abstract/Text
Clinicoepidemiological manifestations of the vasculitides differ geographically. According to a nationwide, hospital-based survey in Japan, the prevalence of microscopic polyangiitis (MPA) and/or renal-limited vasculitis (RLV) is much higher than that of Wegener's granulomatosis (WG). However, little is known about the incidence of antineutrophil cytoplasmic autoantibodies (ANCA)-associated primary renal vasculitis (PRV) in Japan. The incidence of PRV was retrospectively determined by a population-based method in Miyazaki Prefecture in Japan between 2000 and 2004. PRV was defined according to the following criteria from the European Systemic Vasculitis Study Group: (1) new patients with WG, MPA, Churg-Strauss syndrome (CSS), or RLV, (2) renal involvement attributable to active vasculitis, and (3) ANCA considered positive if the disease was not histologically confirmed. The numbers of patients with PRV in the years 2000, 2001, 2002, 2003, and 2004 were 9, 9, 9, 16, and 13, respectively. The male to female ratio was 24:32 and the average age was 70.4 +/- 10.9 (mean +/- SD) yr. The estimated annual incidence of PRV was 14.8 (95% confidence interval [CI] 10.8 to 18.9) and 44.8 (95% CI 33.2 to 56.3) per million adults (>15 yr old) and seniors (>65 yr old), respectively. Ninety-one percent of the patients were myeloperoxidase (MPO)-ANCA positive, but none were positive for proteinase 3 (PR3)-ANCA. There were no WG or CSS patients. The incidence of PRV did not differ between Japan and Europe, but WG was not widespread in Japan. Furthermore, the ratio of serum MPO to PR3-ANCA among Japanese with PRV was much higher than that found among European and US patients.
Naoyuki Tsuchiya, Shigeto Kobayashi, Aya Kawasaki, Chieko Kyogoku, Yoshihiro Arimura, Masaharu Yoshida, Katsushi Tokunaga, Hiroshi Hashimoto
Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis.
J Rheumatol. 2003 Jul;30(7):1534-40.
Abstract/Text
OBJECTIVE: To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japanese patients. Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study.
METHODS: Sixty-nine patients, including 50 with microscopic polyangiitis (MPA), were recruited in a multicenter study. Among them, 64 patients were positive for myeloperoxidase (MPO)-ANCA. Associations of HLA-DRB1, tumor necrosis factor-alpha promoter (TNF), TNF receptor 2 (TNFR2), Fcgamma receptor IIa (FCGR2A), IIb (FCGR2B), IIIa (FCGR3A), IIIb (FCGR3B), and CTLA-4 (CTLA4) polymorphisms were examined in a case-control analysis.
RESULTS: A significant association of HLA-DRB1*0901 with MPA (p = 0.0037, OR 2.44, 95% CI 1.33-4.46), as well as with MPO-ANCA positivity (p = 0.0014, OR 2.44, 95% CI 1.41-4.22), was detected. There was no difference in the TNF promoter haplotype frequencies between patients with MPA and controls, excluding the possibility that the association of DRB1*0901 was secondarily caused by linkage disequilibrium with TNF. No association was observed for TNFR2, FCGR, or CTLA4 with MPA, nor with the presence of MPO-ANCA, although the combined genotype FCGR2A-131H/H and 3A-176F/F was increased in patients with MPA (p = 0.025).
CONCLUSION: There was an association of HLA-DRB1*0901 with MPA and MPO-ANCA positive vasculitis in Japanese patients.
N Tsuchiya, S Kobayashi, H Hashimoto, S Ozaki, K Tokunaga
Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese.
Genes Immun. 2006 Jan;7(1):81-4. doi: 10.1038/sj.gene.6364262.
Abstract/Text
Microscopic polyangiitis (MPA) is a rare and severe form of systemic necrotizing vasculitis associated with myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA). We previously reported significant association of HLA-DRB1*0901 with MPA. To define the susceptibility loci within the HLA region, we determined the genotypes of HLA-DQB1, DPB1, B and C in 50 patients with MPA and 77 unrelated Japanese controls. In addition to HLA-DRB1*0901, significant association of DQB1*0303 (allele carrier frequencies 50% in MPA, 29.9% in controls, odds ratio 2.35, P = 0.017) was detected. These alleles were in strong linkage disequilibrium (D' = 0.95, r2 = 0.82). Increased frequency was also observed for DPB1*0201, B*15111 and Cw*0303, which was at least partly accounted for by linkage disequilibrium with DRB1*0901 and DQB1*0303. These results indicate that DRB1*0901-DQB1*0303 haplotype represents the primary genetic risk for MPA within the HLA region in Japanese, and provides the basis that future functional studies on the role of HLA in MPA should target DR9, DQ9 and DR53 proteins encoded by this haplotype.
M Yashiro, E Muso, T Itoh-Ihara, A Oyama, K Hashimoto, T Kawamura, T Ono, S Sasayama
Significantly high regional morbidity of MPO-ANCA-related angitis and/or nephritis with respiratory tract involvement after the 1995 great earthquake in Kobe (Japan).
Am J Kidney Dis. 2000 May;35(5):889-95.
Abstract/Text
Within a 3-year period after the Great Earthquake of Kobe (Japan) resulted in more than 6,000 deaths and complete destruction of the central area of Kobe City, 14 patients (group 1 [G1]) with myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibody (ANCA)-related angitis and/or nephritis presented to Nishi-Kobe Medical Center in western Kobe City. On the other hand, only 15 patients with this disease were encountered between 1990 and 1997 at Kyoto University Hospital in Kyoto City, which is located 80 km from Kobe City and was only minimally affected by the earthquake. These 15 patients and 1 patient who presented to Nishi-Kobe Medical Center before the Great Earthquake were classified as group 2 (G2). Although the average MPO-ANCA titer in G1 was almost the same as that in G2, G1 showed a significantly greater average value for white blood cells than G2 (11,321 +/- 4,369 versus 8,116 +/- 2, 389/microL; P < 0.05). Concerning renal function, a significant elevation in creatinine (Cr) levels at diagnosis (7.4 +/- 3.8 versus 2.1 +/- 1.4 mg/dL; P < 0.01) and rapidly declining rates of reciprocal Cr levels were noted in G1 (0.325 +/- 0.304 versus 0.087 +/- 0.069 dL/mg. wk; P < 0.01). The number of patients who required emergency hemodialysis was significantly greater in G1 than G2 (nine versus three patients; P < 0.02); however, the incidence of renal death and mortality were not significantly different between the groups. The number of patients who reported upper respiratory tract inflammation as an initial symptom was also significantly greater in G1 than G2 (eight versus two patients; P < 0.01). Moreover, patients in G1 experienced a significantly greater rate of severe pulmonary involvement during the hospital course than G2 (pulmonary hemorrhage, five versus no patients; interstitial pneumonitis, four versus two patients, respectively; P < 0.01). The relatively uniform and distinctive clinical features of the disease after the Great Earthquake, in conjunction with a high morbidity, suggest a relationship between disease development and this urban type of earthquake. Severely provoking air pollution caused by massive destruction and reconstruction of the city may have caused high frequencies of upper respiratory tract inflammation as an initial symptom and severe pulmonary involvement.
Ken-Ei Sada, Masayoshi Harigai, Koichi Amano, Tatsuya Atsumi, Shouichi Fujimoto, Yukio Yuzawa, Yoshinari Takasaki, Shogo Banno, Takahiko Sugihara, Masaki Kobayashi, Joichi Usui, Kunihiro Yamagata, Sakae Homma, Hiroaki Dobashi, Naotake Tsuboi, Akihiro Ishizu, Hitoshi Sugiyama, Yasunori Okada, Yoshihiro Arimura, Seiichi Matsuo, Hirofumi Makino, for Research Committee of Intractable Vasculitis Syndrome and Research Committee of Intractable Renal Disease of the Ministry of Health, Labour, and Welfare of Japan
Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study.
Mod Rheumatol. 2016 Sep;26(5):730-7. doi: 10.3109/14397595.2016.1140274. Epub 2016 Mar 11.
Abstract/Text
OBJECTIVE: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
METHODS: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated.
RESULTS: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival.
CONCLUSIONS: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.
Bernhard Hellmich, Oliver Flossmann, Wolfgang L Gross, Paul Bacon, Jan Willem Cohen-Tervaert, Loic Guillevin, David Jayne, Alfred Mahr, Peter A Merkel, Heiner Raspe, David G I Scott, James Witter, Hasan Yazici, Raashid A Luqmani
EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis.
Ann Rheum Dis. 2007 May;66(5):605-17. doi: 10.1136/ard.2006.062711. Epub 2006 Dec 14.
Abstract/Text
OBJECTIVES: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis.
METHODS: An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis.
RESULTS: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research.
CONCLUSIONS: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.
Loïc Guillevin, Christian Pagnoux, Raphaele Seror, Alfred Mahr, Luc Mouthon, Philippe Le Toumelin, French Vasculitis Study Group (FVSG)
The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort.
Medicine (Baltimore). 2011 Jan;90(1):19-27. doi: 10.1097/MD.0b013e318205a4c6.
Abstract/Text
The 1996 Five-Factor Score (FFS) for systemic necrotizing vasculitides (polyarteritis nodosa [PAN], microscopic polyangiitis [MPA], and Churg-Strauss syndrome [CSS]) is used to evaluate prognosis at diagnosis. In the current study we revisited the FFS, this time including Wegener granulomatosis (WG).We analyzed clinical, laboratory, and immunologic manifestations present at diagnosis of systemic necrotizing vasculitides for 1108 consecutive patients registered in the French Vasculitis Study Group database. All patients met the American College of Rheumatology and Chapel Hill nomenclature criteria. Univariable and multivariable analyses yielded the 2009 FFS for the 4 systemic necrotizing vasculitides.Overall mortality was 19.8% (219/1108); mortality for each of the SNV is listed in descending order: MPA (60/218, 27.5%), PAN (86/349, 24.6%), CSS (32/230, 13.9%), and WG (41/311, 13.2%) (p < 0.001). The following factors were significantly associated with higher 5-year mortality: age >65 years, cardiac symptoms, gastrointestinal involvement, and renal insufficiency (stabilized peak creatinine ≥150 μmol/L). All were disease-specific (p < 0.001); the presence of each was accorded +1 point. Ear, nose, and throat (ENT) symptoms, affecting patients with WG and CSS, were associated with a lower relative risk of death, and their absence was scored +1 point (p < 0.001). Only renal insufficiency was retained (not proteinuria or microscopic hematuria) as impinging on outcome. According to the 2009 FFS, 5-year mortality rates for scores of 0, 1, and ≥2 were 9%, 21% (p < 0.005), and 40% (p < 0.0001), respectively.The revised FFS for the 4 systemic necrotizing vasculitides now comprises 4 factors associated with poorer prognosis and 1 with better outcome. The retained items demonstrate that visceral involvement weighs heavily on outcome. The better WG prognosis for patients with ENT manifestations, even for patients with other visceral involvement, compared with the prognosis for those without ENT manifestations, probably reflects WG phenotype heterogeneity.
H Green, M Paul, L Vidal, L Leibovici
Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.
Cochrane Database Syst Rev. 2007 Jul 18;(3):CD005590. doi: 10.1002/14651858.CD005590.pub2. Epub 2007 Jul 18.
Abstract/Text
BACKGROUND: Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.
OBJECTIVES: To assess the effectiveness of PCP prophylaxis among non-HIV immunocompromised patients. To define the type of immunocompromised patients for whom evidence suggests a benefit for PCP prophylaxis.
SEARCH STRATEGY: Electronic searches of The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 1, 2007), PubMed (March 2007), LILACS (March 2007), relevant conference proceedings; references of identified trials; the first author of each included trial was contacted.
SELECTION CRITERIA: RCTs or quasi- RCTs comparing prophylaxis with an antibiotic effective against Pneumocystis versus placebo, no intervention, an antibiotic/s with no activity against Pneumocystis or another antibiotic effective against Pneumocystis for immune-compromised non-HIV patients. Only trials pre-defining Pneumocystis infections as an outcome were included.
DATA COLLECTION AND ANALYSIS: Two authors independently appraised the quality of each trial and extracted data from included trials. Relative risks (RR), with 95% confidence intervals (CI) were estimated and pooled using the random effects model.
MAIN RESULTS: Eleven trials including 1155 patients (520 children), performed between the years 1974 and 1997, were included. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was a 91% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR 0.09 (95% CI 0.02 to 0.32), eight trials, 821 patients. No significant difference was encountered in all cause mortality, RR 0.81 (95% CI 0.27 to 2.37), five trials, 509 patients, while PCP-related mortality was significantly reduced, RR 0.17 (95% CI 0.03 to 0.94), seven trials, 701 patients. Occurrence of leukopenia, neutropenia and their duration were not reported consistently. No significant difference in any adverse event was seen comparing trimethoprim/sulfamethoxazole to no treatment/ placebo (four trials, 470 patients). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients).
AUTHORS' CONCLUSIONS: Given an event rate of 7.5% as in included trials' control group, prophylaxis for PCP using TMP/SMX is highly effective among non-HIV patients, with a number needed to treat of 15 patients (95% CI 13 to 20). Prophylaxis should be considered for the types of patients with hematological malignancies, bone marrow transplantation and solid organ transplantation included in these trials.
Akio Koyama, Kunihiro Yamagata, Hirofumi Makino, Yoshihiro Arimura, Takashi Wada, Kosaku Nitta, Hiroshi Nihei, Eri Muso, Yoshio Taguma, Hidekazu Shigematsu, Hideto Sakai, Yasuhiko Tomino, Seiichi Matsuo, Japan RPGN Registry Group
A nationwide survey of rapidly progressive glomerulonephritis in Japan: etiology, prognosis and treatment diversity.
Clin Exp Nephrol. 2009 Dec;13(6):633-50. doi: 10.1007/s10157-009-0201-7. Epub 2009 Jun 17.
Abstract/Text
BACKGROUND: The etiology, prevalence, and prognosis of rapidly progressive glomerulonephritis (RPGN) including renal vasculitis vary among races and periods.
METHOD: To improve the prognosis of Japanese RPGN patients, we conducted a nationwide survey of RPGN in the nephrology departments of 351 tertiary hospitals, and found 1772 patients with RPGN (Group A: diagnosed between 1989 and 1998, 884 cases; Group B: diagnosed between 1999 and 2001, 321 cases; and Group C: diagnosed between 2002 and 2007, 567 cases). ANCA subclasses, renal biopsy findings, treatment, outcome and cause of death were recorded.
RESULT: The most frequent primary disease was renal-limited vasculitis (RLV) (42.1%); the second was microscopic polyangiitis (MPA) (19.4%); the third was anti-GBM-associated RPGN (6.1%). MPO-ANCA was positive in 88.1% of RLV patients and 91.8% of MPA patients. The proportion of primary renal diseases of RPGN was constant during those periods. The most frequent cause of death was infectious complications. The serum creatinine at presentation and the initial dose of oral prednisolone decreased significantly in Groups B and C compared to Group A. However, both patient and renal survival rates improved significantly in Groups B and C (survival rate after six months in Group A: 79.2%, Group B: 80.1%, and Group C: 86.1%. Six-month renal survival in Group A: 73.3%, Group B: 81.3%, and Group C: 81.8%).
CONCLUSION: Early diagnosis was the most important factor for improving the prognosis of RPGN patients. To avoid early death due to opportunistic infection in older patients, a milder immunosuppressive treatment such as an initial oral prednisolone dose reduction with or without immunosuppressant is recommended.
Jennifer Turnbull, Lorraine Harper
Adverse effects of therapy for ANCA-associated vasculitis.
Best Pract Res Clin Rheumatol. 2009 Jun;23(3):391-401. doi: 10.1016/j.berh.2009.04.002.
Abstract/Text
The introduction of cyclophosphamide- and prednisolone-based treatment regimens has significantly improved outcome in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis. However, these regimens are nonspecific immunosuppressants associated with significant toxicity, including increased risk of infection, leucopenia, diabetes and malignancy. In addition, disease damage, particularly renal failure, increases the risk of toxicity. Improvements in disease management should include the increased awareness of treatment-related toxicity and its prevention.
吉田雅治. 腎機能障害を考慮した免疫抑制薬の使用法、感染症対策. 日腎会誌. 2009;51(2):114-20.
W K Bolton
Goodpasture's syndrome.
Kidney Int. 1996 Nov;50(5):1753-66.
Abstract/Text
Bassam Alchi, Meryl Griffiths, Murugan Sivalingam, David Jayne, Ken Farrington
Predictors of renal and patient outcomes in anti-GBM disease: clinicopathologic analysis of a two-centre cohort.
Nephrol Dial Transplant. 2015 May;30(5):814-21. doi: 10.1093/ndt/gfu399. Epub 2015 Jan 20.
Abstract/Text
BACKGROUND: Patients with anti-glomerular basement membrane (GBM) disease are at increased risk of morbidity and mortality from renal failure, pulmonary haemorrhage or complications of treatment. One-third also have circulating anti-neutrophil cytoplasmic antibodies (ANCA). The aim of this study was to determine the clinicopathologic predictors of patient and renal outcomes in anti-GBM disease with or without ANCA.
METHODS: Retrospective review of 43 patients diagnosed with anti-GBM disease over 20 years in two centres, including nine with dual anti-GBM and ANCA positivity. Renal biopsies from 27 patients were scored for the presence of active and chronic lesions.
RESULTS: Dual-positive patients were almost 20 years older than those with anti-GBM positivity alone (P = 0.003). The overall 1-year patient and renal survivals were 88 and 16%, respectively. Oligoanuria at diagnosis was the strongest predictor of mortality; none of the 16 patients without oligoanuria died. In a Cox regression model excluding oligoanuria, age was the only other independent predictor of survival. Pulmonary haemorrhage and dialysis dependence did not influence mortality. Thirty-five of the forty-three (81%) patients required dialysis at presentation, including all nine dual-positive patients. Of them, only two (5.7%) regained renal function at 1 year. By logistic regression, oligoanuria at diagnosis and percentage of crescents were independent predictors of dialysis independence at 3 months. However, in biopsied patients, the presence of crescents (>75%) added little to the presence of oligoanuria in predicting dialysis independence. Histological activity and chronicity indices did not predict renal outcome. Two of the nine (22%) dual-positive patients relapsed compared with none of the anti-GBM alone patients. Seven patients received kidney transplants without disease recurrence.
CONCLUSIONS: Oligoanuria is the strongest predictor of patient and renal survival while percentage of glomerular crescents is the only pathologic parameter associated with poor renal outcome in anti-GBM disease. Kidney biopsy may not be necessary in oligoanuric patients without pulmonary haemorrhage.
© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
J C Flores, D Taube, C O Savage, J S Cameron, C M Lockwood, D G Williams, C S Ogg
Clinical and immunological evolution of oligoanuric anti-GBM nephritis treated by haemodialysis.
Lancet. 1986 Jan 4;1(8471):5-8.
Abstract/Text
Eight patients with oligoanuric anti-glomerular-basement-membrane (GBM), antibody-mediated glomerulonephritis without lung haemorrhage who were not treated with plasma exchange therapy were reviewed. All had severe crescentic nephritis and required dialysis. Circulating anti-GBM antibodies disappeared gradually and spontaneously in all patients. The autoantibodies became undetectable in five patients after an average of 11 months. No patient recovered renal function. Two patients have been successfully transplanted and anti-GBM nephritis has not recurred. One of these needed a pre-transplant course of plasma exchange and immunosuppression to reduce a slightly raised anti-GBM antibody titre. Of five patients who remain on dialysis, only two cannot be transplanted due to the persistence of circulating autoantibodies. One patient died from causes unrelated to renal disease. Oligoanuric patients with anti-GBM nephritis who need dialysis rarely benefit from aggressive therapy unless lung haemorrhage is present.
C B Wilson, F J Dixon
Anti-glomerular basement membrane antibody-induced glomerulonephritis.
Kidney Int. 1973 Feb;3(2):74-89.
Abstract/Text
J P Johnson, J Moore, H A Austin, J E Balow, T T Antonovych, C B Wilson
Therapy of anti-glomerular basement membrane antibody disease: analysis of prognostic significance of clinical, pathologic and treatment factors.
Medicine (Baltimore). 1985 Jul;64(4):219-27.
Abstract/Text
We have compared the effect of therapy with immunosuppression alone to immunosuppression plus plasma exchange on the clinical course and rate of disappearance of antibody in 17 patients with anti-glomerular basement membrane (anti-GBM) antibody-induced renal disease. Patients receiving immunosuppression (n = 9) and those receiving plasma exchange (n = 8) were similar in terms of entry clinical characteristics, pulmonary manifestations and complications associated with therapy. Rate of disappearance of anti-GBM antibody as estimated from serial estimates of antibody binding was significantly more rapid in patients receiving plasma exchange, and mean serum creatinine in these patients at end of therapy was half that of the patients receiving immunosuppression alone. Analysis of clinical and pathologic values at study entry, however, indicated that the percent of crescents on initial renal biopsy and entry serum creatinine correlated better with outcome than did therapeutic modality. Thus, though plasma exchange may offer some advantage over immunosuppression alone in the treatment of this disease, degree of pathologic involvement appears to be the major factor affecting outcome. Patients with low cresents (less than 30%) and well preserved function did well with either treatment, while patients with severe crescentic involvement and impaired glomerular filtration rate did poorly.
Giusti D, Hayton W. Dosage regimen adjustment. Drug Intel Clin Pharm. 1973;7:382-7.
平田純生. 腎不全と薬の使い方Q&A: じほう; 2005.
C Lapraik, R Watts, P Bacon, D Carruthers, K Chakravarty, D D'Cruz, L Guillevin, L Harper, D Jayne, R Luqmani, J Mooney, D Scott, BSR and BHPR Standards, Guidelines and Audit Working Group
BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis.
Rheumatology (Oxford). 2007 Oct;46(10):1615-6. doi: 10.1093/rheumatology/kem146a. Epub 2007 Sep 5.
Abstract/Text
Kouichi Hirayama, Masaki Kobayashi, Yuko Hashimoto, Joichi Usui, Yoshio Shimizu, Aki Hirayama, Keigyou Yoh, Kunihiro Yamagata, Sohji Nagase, Michio Nagata, Akio Koyama
Treatment with the purine synthesis inhibitor mizoribine for ANCA-associated renal vasculitis.
Am J Kidney Dis. 2004 Jul;44(1):57-63.
Abstract/Text
BACKGROUND: The common treatment for antineutrophil cytoplasmic autoantibody (ANCA)-associated renal vasculitis is oral cyclophosphamide (CYC)-corticosteroid combination therapy. However, there are serious complications associated with long-term use of CYC. In this study, we investigate the efficacy of a purine synthesis inhibitor, mizoribine, for patients at high risk for relapse.
METHODS: Our study included 5 patients, 4 patients with myeloperoxidase (MPO)-ANCA-associated renal vasculitis and 1 patient with proteinase 3 (PR3)-ANCA-associated renal vasculitis, who had achieved remission through treatment with methylprednisolone pulse therapy, corticosteroids, and CYC. When their ANCA titers were found to be greater than normal range after remission status, mizoribine treatment was initiated.
RESULTS: Median time from initial treatment to first administration of mizoribine was 40.0 months (range, 24 to 51 months). Median follow-up was 13.0 months (range, 6 to 16 months). Before initiation of mizoribine treatment, no patient had experienced relapse and ANCA titers were less than the detectable range in all patients at 3 months before mizoribine administration. When mizoribine administration was started, ANCA titers were elevated in all patients (median MPO-ANCA, 101 ELISA units [EU]; range, 65 to 154 EU; PR3-ANCA, 55 EU), but no new symptoms or signs of relapse were noted. After 2 months of mizoribine treatment, only 1 patient had experienced a relapse; however, ANCA titers had decreased in all other patients and normalized in 3 patients. No adverse effects appeared in any patient.
CONCLUSION: Considering the balance between suppression of disease activity and adverse effects of treatment, mizoribine may be useful for preemptive treatment for patients with ANCA-associated renal vasculitis at high risk for relapse.
急速進行性腎炎症候群の診療指針 第二版 日本腎臓学会誌2011；53（4）：509－55.
David Jayne, Niels Rasmussen, Konrad Andrassy, Paul Bacon, Jan Willem Cohen Tervaert, Jolanta Dadoniené, Agneta Ekstrand, Gill Gaskin, Gina Gregorini, Kirsten de Groot, Wolfgang Gross, E Christiaan Hagen, Eduardo Mirapeix, Erna Pettersson, Carl Siegert, Alberto Sinico, Vladimir Tesar, Kerstin Westman, Charles Pusey, European Vasculitis Study Group
A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.
N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286.
Abstract/Text
BACKGROUND: The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission.
METHODS: We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point.
RESULTS: Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03).
CONCLUSIONS: In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.
Copyright 2003 Massachusetts Medical Society
Thomas F Hiemstra, Michael Walsh, Alfred Mahr, Caroline O Savage, Kirsten de Groot, Lorraine Harper, Thomas Hauser, Irmgard Neumann, Vladimir Tesar, Karl-Martin Wissing, Christian Pagnoux, Wilhelm Schmitt, David R W Jayne, European Vasculitis Study Group (EUVAS)
Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.
JAMA. 2010 Dec 1;304(21):2381-8. doi: 10.1001/jama.2010.1658. Epub 2010 Nov 8.
Abstract/Text
CONTEXT: Current remission maintenance therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are limited by partial efficacy and toxicity.
OBJECTIVE: To compare the effects of mycophenolate mofetil with azathioprine on the prevention of relapses in patients with AAV.
DESIGN, SETTING, AND PARTICIPANTS: Open-label randomized controlled trial, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE), to test the hypothesis that mycophenolate mofetil is more effective than azathioprine for preventing relapses in AAV. The trial was conducted at 42 centers in 11 European countries between April 2002 and January 2009 (42-month study). Eligible patients had newly diagnosed AAV (Wegener granulomatosis or microscopic polyangiitis) and were aged 18 to 75 years at diagnosis.
INTERVENTIONS: Patients were randomly assigned to azathioprine (starting at 2 mg/kg/d) or mycophenolate mofetil (starting at 2000 mg/d) after induction of remission with cyclophosphamide and prednisolone.
MAIN OUTCOME MEASURES: The primary end point was relapse-free survival, which was assessed using a Cox proportional hazards model. The secondary end points were Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria.
RESULTS: A total of 156 patients were assigned to azathioprine (n = 80) or mycophenolate mofetil (n = 76) and were followed up for a median of 39 months (interquartile range, 0.66-53.6 months). All patients were retained in the analysis by intention to treat. Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate mofetil of 1.69 (95% confidence interval [CI], 1.06-2.70; P = .03). Severe adverse events did not differ significantly between groups. There were 22 severe adverse events in 13 patients (16%) in the azathioprine group and there were 8 severe adverse events in 8 patients (7.5%) in the mycophenolate mofetil group (HR, 0.53 [95% CI, 0.23-1.18]; P = .12). The secondary outcomes of Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria did not differ significantly between groups.
CONCLUSIONS: Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00307645.
有村義宏, 川嶋聡子, 吉原堅. ANCA関連血管炎とRPGN. 日腎会誌. 2009;51(2):88-93.
Won K Han, Hyon K Choi, Rachel M Roth, Robert T McCluskey, John L Niles
Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis.
Kidney Int. 2003 Mar;63(3):1079-85. doi: 10.1046/j.1523-1755.2003.00821.x.
Abstract/Text
BACKGROUND: The value of measuring serial antineutrophil cytoplasmic autoantibody (ANCA) titers in guiding therapy among patients with ANCA-associated vasculitis is controversial.
METHODS: We measured serial titers of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA by antigen-specific enzyme-linked immunosorbent assays (ELISAs) in 48 patients with ANCA-associated vasculitis who were followed up during remission at the Massachusetts General Hospital from 1990 through 2000 (mean follow-up, 46.2 months). We retrospectively assessed disease activity by Birmingham Vasculitis Activity Score (BVAS).
RESULTS: We found 21 episodes of fourfold or greater ANCA titer rises in 17 patients who were in complete remission (BVAS=0). Among eight patients who had 10 such titer rises and were not given increased immunosuppression, (group I), all suffered relapses after each episode (mean interval, 5.8 months), whereas among 11 patients, each with one titer rise, who received preemptive increased immunosuppression, (group II), only two relapses occurred, at 3 and 6 months. The difference in the cumulative incidence of relapses in a 1-year period between the two groups was 82% (P=0.0002). Changes in ANCA titers were also used to help guide therapy in the other 31 patients in the study; patients with slight titer rises often received incremental increases in immunosuppression, whereas those with falling titers received incremental decreases. The overall outcome in the entire group was favorable; 46 patients were alive at the end of the study; two died of unrelated diseases.
CONCLUSION: Serial measurements of PR3- and MPO-ANCA titers in patients with ANCA-associated vasculitis during remission can help predict relapses, and preemptive increases in immunosuppression following fourfold titer rises reduces the risk of relapses. Moreover, adjustment of immunosuppression based on lesser titer changes appears to result in a favorable outcome.
Gunnar Tomasson, Peter C Grayson, Alfred D Mahr, Michael Lavalley, Peter A Merkel
Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis--a meta-analysis.
Rheumatology (Oxford). 2012 Jan;51(1):100-9. doi: 10.1093/rheumatology/ker280. Epub 2011 Oct 29.
Abstract/Text
OBJECTIVE: The value of repeated ANCA measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) remains controversial. The aim of this study was to explore whether either of the two distinct patterns of ANCA values during remission, a rise in ANCA or persistently positive ANCA, predicted future relapse.
METHODS: MEDLINE and EMBASE searches were performed. Studies with at least 10 subjects with AAV from which both sensitivity and specificity of a rise in ANCA and/or persistent ANCA for future disease relapse could be calculated were included. Likelihood ratios were calculated for each study and pooled to arrive at summary estimates. I(2)-values were calculated as a measure of heterogeneity and meta-regression was used to explore sources of heterogeneity.
RESULTS: Nine articles on a rise in ANCA and nine articles on persistent ANCA were included. The summary estimates for positive likelihood ratio (LR(+)) and negative likelihood ratio (LR(-)) of a rise in ANCA during remission on subsequent relapse of disease were 2.84 (95% CI 1.65, 4.90) and 0.49 (95% CI 0.27, 0.87), respectively. The summary estimates for LR(+) and LR(-) of persistent ANCA during remission for subsequent disease relapse were 1.97 (95% CI 1.43, 2.70) and 0.73 (95% CI 0.50, 1.06), respectively. There was substantial between-study heterogeneity, which was partially explained by the frequency of ANCA measurements.
CONCLUSION: Among patients with AAV, a rise in or persistence of ANCA during remission is only modestly predictive of future disease relapse. There is limited use to serial ANCA measurements during disease remission to guide treatment decisions for individual patients with AAV.
Bahjat Al-Ani, Martin Fitzpatrick, Hamad Al-Nuaimi, Alice M Coughlan, Fionnuala B Hickey, Charles D Pusey, Caroline Savage, Christopher M Benton, Eóin C O'Brien, Declan O'Toole, Ken H Mok, Stephen P Young, Mark A Little
Changes in urinary metabolomic profile during relapsing renal vasculitis.
Sci Rep. 2016 Dec 1;6:38074. doi: 10.1038/srep38074. Epub 2016 Dec 1.
Abstract/Text
Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.
Vincent P O'Reilly, Limy Wong, Claire Kennedy, Louise A Elliot, Shane O'Meachair, Alice Marie Coughlan, Eoin C O'Brien, Michelle M Ryan, Diego Sandoval, Emma Connolly, Gerjan J Dekkema, Jiaying Lau, Wayel H Abdulahad, Jan-Stephan F Sanders, Peter Heeringa, Colm Buckley, Cathal O'Brien, Stephen Finn, Clemens D Cohen, Maja T Lindemeyer, Fionnuala B Hickey, Paul V O'Hara, Conleth Feighery, Sarah M Moran, George Mellotte, Michael R Clarkson, Anthony J Dorman, Patrick T Murray, Mark A Little
Urinary Soluble CD163 in Active Renal Vasculitis.
J Am Soc Nephrol. 2016 Sep;27(9):2906-16. doi: 10.1681/ASN.2015050511. Epub 2016 Mar 3.
Abstract/Text
A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV.
Copyright © 2016 by the American Society of Nephrology.
Rennie L Rhee, John C Davis, Linna Ding, Fernando C Fervenza, Gary S Hoffman, Cees G M Kallenberg, Carol A Langford, W Joseph McCune, Paul A Monach, Philip Seo, Robert Spiera, E William St Clair, Ulrich Specks, John H Stone, Peter A Merkel
The Utility of Urinalysis in Determining the Risk of Renal Relapse in ANCA-Associated Vasculitis.
Clin J Am Soc Nephrol. 2018 Feb 7;13(2):251-257. doi: 10.2215/CJN.04160417. Epub 2018 Jan 25.
Abstract/Text
BACKGROUND AND OBJECTIVES: The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted using participants enrolled in two randomized, placebo-controlled clinical trials who had active GN due to ANCA-associated vasculitis, had positive ANCA, and achieved remission by month 6. Dipstick and microscopic urinalyses were performed at each visit. Persistent hematuria or proteinuria for at least 6 months and the cumulative duration of hematuria were examined. Renal relapse was defined as new or worsening red blood cell casts and/or worsening kidney function according to the Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis.
RESULTS: There were 149 patients included in this study: 42% had persistent hematuria, and 43% had persistent proteinuria beyond 6 months. Persistent hematuria was associated with a significantly higher risk of relapse, even after adjusting for potential confounders (subdistribution hazard ratio, 3.99; 95% confidence interval, 1.20 to 13.25; P=0.02); persistent proteinuria was not associated with renal relapse (subdistribution hazard ratio, 1.44; 95% confidence interval, 0.47 to 4.42; P=0.53). Furthermore, greater cumulative duration of hematuria was significantly associated with a higher risk of renal relapse (adjusted subdistribution hazard ratio, 1.08 per each month; 95% confidence interval, 1.03 to 1.12; P<0.01). The median time to renal relapse was 22 months.
CONCLUSIONS: In patients with ANCA-associated vasculitis and kidney involvement who achieve remission after induction therapy, the presence of persistent hematuria, but not proteinuria, is a significant predictor of future renal relapse.
Copyright © 2018 by the American Society of Nephrology.
Li Lv, Dong-Yuan Chang, Zhi-Ying Li, Min Chen, Zhao Hu, Ming-Hui Zhao
Persistent hematuria in patients with antineutrophil cytoplasmic antibody-associated vasculitis during clinical remission: chronic glomerular lesion or low-grade active renal vasculitis?
BMC Nephrol. 2017 Dec 6;18(1):354. doi: 10.1186/s12882-017-0763-7. Epub 2017 Dec 6.
Abstract/Text
BACKGROUND: Whether persistent hematuria in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during clinical remission reflects active disease or chronic glomerular injury is uncertain. This study aimed to investigate the significance of persistent hematuria during clinical remission in a large cohort of AAV patients.
METHODS: A cohort of 219 AAV patients in complete clinical remission after induction therapy at our center was retrospectively studied, and their clinical and laboratory data as well as long-term outcomes were analyzed.
RESULTS: A total of 80 out of 219 patients had persistent hematuria during clinical remission of AAV. Compared with patients without hematuria during remission, the slope of eGFR decline in patients with persistent hematuria was significantly higher during the long-term follow-up [3.6 (IQR 1.2, 7.2) vs. 1.5 (IQR 0.2, 4.0) mL/min/1.73 m2/year, P < 0.001]. Among the 80 patients with persistent hematuria during remission, there was little difference between those with fast and slow decline of eGFR, as divided by either median or interquartile range of the slope of eGFR decline. We also compared patients without hematuria who had a slope of eGFR decline that was lower than the median level of the slope of eGFR decline with those with persistent hematuria, and found that patients with hematuria had significantly lower levels of CRP and ESR at baseline and higher levels of ANCA at remission.
CONCLUSIONS: Among the AAV patients who achieved clinical remission after immunosuppressive therapy, those with persistent hematuria are not rare and may reflect either chronic renal damage or low-grade active renal disease.
Michael Walsh, Peter A Merkel, Chen-Au Peh, Wladimir M Szpirt, Xavier Puéchal, Shouichi Fujimoto, Carmel M Hawley, Nader Khalidi, Oliver Floßmann, Ron Wald, Louis P Girard, Adeera Levin, Gina Gregorini, Lorraine Harper, William F Clark, Christian Pagnoux, Ulrich Specks, Lucy Smyth, Vladimir Tesar, Toshiko Ito-Ihara, Janak Rashme de Zoysa, Wojciech Szczeklik, Luis Felipe Flores-Suárez, Simon Carette, Loïc Guillevin, Charles D Pusey, Alina L Casian, Biljana Brezina, Andrea Mazzetti, Carol A McAlear, Elizabeth Broadhurst, Donna Reidlinger, Samir Mehta, Natalie Ives, David R W Jayne, PEXIVAS Investigators
Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.
N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/NEJMoa1803537.
Abstract/Text
BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD).
RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups.
CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).
Copyright © 2020 Massachusetts Medical Society.
Levy JB, Pusey CD. Crescentic glomerulonephritis. In: Brady HR, Wilcox CS, editors. Therapy in Nephrology and Hypertension 2nd ed. London: Saunders; 2003. p. 177-88.
Kunihiro Yamagata, Kouichi Hirayama, Kaori Mase, Naoto Yamaguchi, Masaki Kobayashi, Hideto Takahashi, Akio Koyama
Apheresis for MPO-ANCA-associated RPGN-indications and efficacy: lessons learned from Japan nationwide survey of RPGN.
J Clin Apher. 2005 Dec;20(4):244-51. doi: 10.1002/jca.20035.
Abstract/Text
A national survey concerning rapidly progressive glomerulonephritis (RPGN) was conducted in Japan between 1989 and 2000 and resulted in the registration of 715 patients with RPGN. Among the documented patients, the most frequent primary disease was primary pauci-immune crescentic glomerulonephritis (n = 283), and the second most frequent was microscopic polyangitis (n = 127). Overall, 370 patients had MPO-ANCA, and 23 patients had PR3-ANCA. We found that both renal and patient survivals were significantly worse in patients with MPO-ANCA-associated RPGN than patients with PR3-ANCA. Fifty-three patients received apheresis therapy with various combinations of immunosuppressive regimens. They had higher serum creatinine, higher CRP, and a higher frequency of complicated pulmonary involvements as compared to the controls without apheresis therapy. In dialysis-dependent patients, no additional benefit from apheresis therapy was observed. Only pulmonary renal syndrome patients with CRP > 6 mg/dl at presentation showed a slightly better prognosis (patient survival with apheresis; 66.7%, without apheresis; 56.7%). Furthermore, a rapid MPO-ANCA titer reduction was observed in patients treated with apheresis. Patients with MPO-ANCA-associated RPGN were older, and had more chronic and sclerotic lesions than patients with PR3-ANCA-associated RPGN. Based on these findings, we suggest that a lower dose of immunosuppressant should be considered in order to avoid opportunistic infection. In this situation, cytapheresis is the treatment of choice. Nevertheless, in patients with an aggressive form of RPGN with rapid deterioration of renal function like the PR3-ANCA-associated RPGN, or pulmonary renal syndrome complicated severe inflammation, or relapses with high MPO-ANCA titer, we conclude that apheresis therapy should be considered.
(c) 2005 Wiley-Liss, Inc.
David R W Jayne, Gill Gaskin, Niels Rasmussen, Daniel Abramowicz, Franco Ferrario, Loic Guillevin, Eduardo Mirapeix, Caroline O S Savage, Renato A Sinico, Coen A Stegeman, Kerstin W Westman, Fokko J van der Woude, Robert A F de Lind van Wijngaarden, Charles D Pusey, European Vasculitis Study Group
Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.
J Am Soc Nephrol. 2007 Jul;18(7):2180-8. doi: 10.1681/ASN.2007010090. Epub 2007 Jun 20.
Abstract/Text
Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.
J B Levy, C G Winearls
Rapidly progressive glomerulonephritis: what should be first-line therapy?
Nephron. 1994;67(4):402-7.
Abstract/Text
Frank B Cortazar, John L Niles, David R W Jayne, Peter A Merkel, Annette Bruchfeld, Huibin Yue, Thomas J Schall, Pirow Bekker, ADVOCATE Study Group
Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan.
Kidney Int Rep. 2023 Apr;8(4):860-870. doi: 10.1016/j.ekir.2023.01.039. Epub 2023 Feb 3.
Abstract/Text
INTRODUCTION: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m2 in the avacopan group and 4.1 ml/min per 1.73 m2 in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m2.
METHODS: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups.
RESULTS: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m2. At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m2 in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m2, respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group.
CONCLUSION: Among patients with baseline eGFR ≤20 ml/min per 1.73 m2 in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.
© 2023 International Society of Nephrology. Published by Elsevier Inc.
Frank B Cortazar, Saif A Muhsin, William F Pendergraft, Zachary S Wallace, Colleen Dunbar, Karen Laliberte, John L Niles
Combination Therapy With Rituximab and Cyclophosphamide for Remission Induction in ANCA Vasculitis.
Kidney Int Rep. 2018 Mar;3(2):394-402. doi: 10.1016/j.ekir.2017.11.004. Epub 2017 Nov 14.
Abstract/Text
INTRODUCTION: Remission induction in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis may be complicated by slow response to treatment and toxicity from glucocorticoids. We describe outcomes with a novel remission induction regimen combining rituximab with a short course of low-dose, oral cyclophosphamide and an accelerated prednisone taper.
METHODS: Patients were included in this retrospective study if they had newly diagnosed or relapsing ANCA vasculitis with a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS-WG) ≥3 and received a standardized remission induction regimen. The primary outcome was complete remission, defined as a BVAS-WG of 0 and a prednisone dose of ≤7.5 mg/d.
RESULTS: We identified 129 patients who met the inclusion criteria, 31% of whom also received plasma exchange (PLEX) for rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage. Seventy percent of patients had myeloperoxidase (MPO)-ANCA and 9% had relapsing disease. Median time to complete remission was 4 months (interquartile range [IQR] 3.9-4.4), and by 5 months 84% of patients were in complete remission. Prednisone was tapered to discontinuation as tolerated, such that the median prednisone dose at 8 months was 0 mg/d (IQR 0-2.5). In patients with RPGN, proteinase 3-ANCA was associated with a greater increase in eGFR at 6 months compared with MPO-ANCA (16 vs. 5.6 ml/min per 1.73m2; P = 0.028). During the year following remission, 1 major relapse occurred over 122 patient-years. Serious infections occurred more frequently in patients receiving PLEX and were associated with increasing age and diffuse alveolar hemorrhage. Four deaths occurred, 3 of which were associated with serious infections.
CONCLUSION: Combination therapy was efficacious, allowed for rapid tapering of high-dose glucocorticoids and was well tolerated.
John H Stone, Peter A Merkel, Robert Spiera, Philip Seo, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Anthony Turkiewicz, Nadia K Tchao, Lisa Webber, Linna Ding, Lourdes P Sejismundo, Kathleen Mieras, David Weitzenkamp, David Ikle, Vicki Seyfert-Margolis, Mark Mueller, Paul Brunetta, Nancy B Allen, Fernando C Fervenza, Duvuru Geetha, Karina A Keogh, Eugene Y Kissin, Paul A Monach, Tobias Peikert, Coen Stegeman, Steven R Ytterberg, Ulrich Specks, RAVE-ITN Research Group
Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.
Abstract/Text
BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.
CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)
2010 Massachusetts Medical Society
Rachel B Jones, Jan Willem Cohen Tervaert, Thomas Hauser, Raashid Luqmani, Matthew D Morgan, Chen Au Peh, Caroline O Savage, Mårten Segelmark, Vladimir Tesar, Pieter van Paassen, Dorothy Walsh, Michael Walsh, Kerstin Westman, David R W Jayne, European Vasculitis Study Group
Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.
N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169.
Abstract/Text
BACKGROUND: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens.
METHODS: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.
RESULTS: The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14).
CONCLUSIONS: A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)
2010 Massachusetts Medical Society
尾崎承一, 槇野博史、松尾清一：ANCA関連血管炎の診療ガイドライン. 2011.
D R Jayne, H Chapel, D Adu, S Misbah, D O'Donoghue, D Scott, C M Lockwood
Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity.
QJM. 2000 Jul;93(7):433-9.
Abstract/Text
Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.
Toshiko Ito-Ihara, Takahiko Ono, Fumiaki Nogaki, Katsuo Suyama, Mari Tanaka, Satomi Yonemoto, Atsushi Fukatsu, Toru Kita, Kazuo Suzuki, Eri Muso
Clinical efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis.
Nephron Clin Pract. 2006;102(1):c35-42. doi: 10.1159/000088313. Epub 2005 Sep 19.
Abstract/Text
BACKGROUND: To determine whether intravenous immunoglobulin (IVIg) can control disease activity in patients with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated rapidly progressive glomerulonephritis (RPGN).
METHODS: Twelve patients with serologically and histologically confirmed MPO-ANCA-associated RPGN (7 men, 5 women; mean age 71 +/- 3 years) received IVIg (400 mg/kg/day) alone for 5 days. The effects of IVIg were evaluated by white blood cell counts, serum C-reactive protein levels, Birmingham Vasculitis Activity Score, rate of change in reciprocal creatinine (1/Cre), and plasma tumor necrosis factor-alpha levels after IVIg administration. Corticosteroids with or without cyclophosphamide were commenced after IVIg.
RESULTS: After IVIg treatment, a significant decrease was observed in white blood cell count (p < 0.05), C-reactive protein values (p < 0.001), and Birmingham Vasculitis Activity Score (p < 0.001) concomitant with the amelioration of systemic symptoms. The rate of change in 1/Cre significantly improved (p < 0.05). Plasma tumor necrosis factor-alpha levels that were significantly elevated in patients before IVIg compared with normal controls (p < 0.0001), rapidly declined after IVIg with a significant reduction (p < 0.05). Three months post-treatment with IVIg, all patients showed improvement of disease without serious infectious complications.
CONCLUSION: IVIg is a potential component of remission induction therapy for patients with MPO-ANCA-associated RPGN.
2006 S. Karger AG, Basel
Valérie Martinez, Pascal Cohen, Christian Pagnoux, Stéphane Vinzio, Alfred Mahr, Luc Mouthon, Laurent Sailler, Claire Delaunay, Alain Sadoun, Loïc Guillevin, French Vasculitis Study Group
Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients.
Arthritis Rheum. 2008 Jan;58(1):308-17. doi: 10.1002/art.23147.
Abstract/Text
OBJECTIVE: To evaluate at 9 months and 24 months the safety and efficacy of intravenous immunoglobulins (IVIGs) administered for 6 months to treat relapses of Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) occurring either under treatment or during the year following discontinuation of corticosteroids and/or immunosuppressants.
METHODS: Patients received IVIGs (0.5 gm/kg/day for 4 days) as additional therapy administered monthly for 6 months and were assessed every 3-6 months. Corticosteroids could be maintained or reintroduced at the time of relapse; immunosuppressants could be continued but could not be reintroduced. At months 9 (end point) and 24 (followup), the following information was collected: complete or partial remission, relapse as assessed with the Birmingham Vasculitis Activity Score (BVAS) 2005, and tolerance and safety of IVIG therapy.
RESULTS: Twenty-two Caucasian patients (7 men and 15 women) were studied: 19 had WG, and 3 had MPA. Their median age was 53 years (range 19-75 years), and their median duration of systemic vasculitis was 27 months (range 7-109 months). Their median BVAS 2005 score was 11 (range 3-25). At study entry, 21 patients were ANCA positive, and 21 patients were taking steroids and/or immunosuppressants. All patients experiencing relapse were treated with the same drug(s) plus IVIGs. All patients initially responded to IVIG therapy. By month 9, 13 patients had complete remission, 1 had partial remission, 7 had relapse, and 1 had treatment failure. In 8 of the 14 patients who had remission, the response persisted at month 24. Seven patients experienced minor side effects.
CONCLUSION: IVIGs induced complete remissions of relapsed ANCA-associated vasculitides in 13 of 22 patients at month 9. Because of the good safety and tolerance profiles of IVIGs, these agents can be included in a therapeutic strategy with other drugs used to treat relapses of WG or MPA.
Midori Hasegawa, Asako Watanabe, Hiroki Takahashi, Kazuo Takahashi, Masami Kasugai, Nahoko Kawamura, Hiroko Kushimoto, Kazutaka Murakami, Makoto Tomita, Kunihiro Nabeshima, Atsushi Oohashi, Fumiko Kondou, Hisaji Ooshima, Yoshiyuki Hiki, Satoshi Sugiyama
Treatment with cytapheresis for antineutrophil cytoplasmic antibody-associated renal vasculitis and its effect on anti-inflammatory factors.
Ther Apher Dial. 2005 Aug;9(4):297-302. doi: 10.1111/j.1744-9987.2005.00285.x.
Abstract/Text
To evaluate the efficacy of cytapheresis for the treatment of rapidly progressive glomerulonephritis (RPGN) caused by myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis, the renal prognosis and the mortality rate at 1 year after treatment were compared between a Cytapheresis Group and a Steroid Pulse Group. The Cytapheresis Group included 10 patients who were treated with cytapheresis and oral corticosteroids. Five had granulocytapheresis with the Adacolumn (Japan Immuno Research Laboratories Co. Ltd, Takasaki, Japan) and the remaining five had leukocytapheresis with the leukocyte removal filter, Cellsorba (Asahi Medical Co. Ltd, Tokyo, Japan). The Steroid Pulse Group was comprised of 12 patients who were treated with methylprednisolone pulse therapy and oral corticosteroids. In the Cytapheresis Group, renal function recovered in 70% of the patients and the mortality rate was 10%. In the Steroid Pulse Group, renal function recovered in 66.7% and the mortality rate was 33.3%, with infection as the cause of death. Total doses of corticosteroids converted to prednisolone dose during a 1 month period, ranged from 280 mg to 1226 mg in the Cytapheresis Group. On the other hand, these dosages ranged from 2375 mg to 8380 mg in the Steroid Pulse Group. These results indicated that the mortality rate by infection could be reduced by adding cytapheresis therapy. Concerning the mechanism of cytapheresis, anti-inflammatory factors such as soluble tumor necrosis factor receptor, and interleukin-10 reduced after cytapheresis. These changes might be responsible for the efficacy of cytapheresis. In conclusion, cytapheresis is thought to be one of the effective treatments for RPGN caused by MPO-ANCA-associated vasculitis, reducing the levels of anti-inflammatory factors.
Midori Hasegawa, Atsushi Ohashi, Nao Kabutan, Saori Hiramatsu, Masao Kato, Kazutaka Murakami, Makoto Tomita, Kunihiro Nabeshima, Yoshiyuki Hiki, Satoshi Sugiyama
Cytapheresis for the treatment of myeloperoxidase antineutrophil cytoplasmic autoantibody-associated vasculitis: a pilot study of 21 patients.
Ther Apher Dial. 2006 Oct;10(5):412-8. doi: 10.1111/j.1744-9987.2006.00404.x.
Abstract/Text
Twenty-one patients with myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis were treated using cytapheresis. Of these, 17 were treated for glomerulonephritis and four were treated for pulmonary hemorrhage. The overall survival rate was 85.7% with a follow-up duration of 24.0 +/- 13.8 months. In the 17 patients with MPO-ANCA-associated glomerulonephritis, pretreatment creatinine was 3.2 +/- 1.6 mg/dL, and renal function recovered in 76.5%. Pulmonary hemorrhage was ameliorated in all four patients. Abdominal pain occurred in three of the 21 patients but symptoms resolved soon after the cytapheresis procedure was completed. No other adverse effects occurred during cytapheresis. From these results, cytapheresis can be considered a safe and effective treatment for MPO-ANCA-associated vasculitis. As for the mechanism of its action, soluble tumor necrosis factor receptor 1 (sTNFR), sTNFR2 and interleukin 1 receptor antagonist were elevated soon after cytapheresis and those levels 2 h after the cytapheresis procedure were higher than before the procedure in some cases. These elevations might be related to the efficacy of cytapheresis.
Alexandre Karras, Christian Pagnoux, Marion Haubitz, Kirsten de Groot, Xavier Puechal, Jan Willem Cohen Tervaert, Mårten Segelmark, Loic Guillevin, David Jayne, European Vasculitis Society
Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.
Ann Rheum Dis. 2017 Oct;76(10):1662-1668. doi: 10.1136/annrheumdis-2017-211123. Epub 2017 May 25.
Abstract/Text
OBJECTIVES: A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).
METHODS: Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis.
RESULTS: One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 μmol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p<0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival.
CONCLUSIONS: Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.
TRIAL REGISTRATION NUMBER: ISRCTN13739474.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Jan-Stephan F Sanders, Anoek A E de Joode, Ruud G DeSevaux, Jan Broekroelofs, Alexandre E Voskuyl, Pieter van Paassen, Cees G M Kallenberg, Jan Willem Cohen Tervaert, Coen A Stegeman
Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial.
Nephrol Dial Transplant. 2016 Sep;31(9):1453-9. doi: 10.1093/ndt/gfw211. Epub 2016 May 30.
Abstract/Text
BACKGROUND: Cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) positivity at remission has been associated with an increased relapse rate in patients with proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis (PR3-AAV) after a switch to azathioprine maintenance therapy. We therefore hypothesized that extended azathioprine maintenance therapy could reduce the incidence of relapse in this setting.
METHODS: Patients newly diagnosed with PR3-AAV at 12 centres in The Netherlands during 2003-11 who received a standardized induction regimen consisting of oral cyclophosphamide and corticosteroids were enrolled (n = 131). Patients were randomized to standard or extended azathioprine maintenance therapy when C-ANCA was positive at the time of stable remission. Standard maintenance treatment consisted of azathioprine (1.5-2.0 mg/kg) until 1 year after diagnosis and subsequent tapering to 25 mg every 3 months. Extended azathioprine maintenance therapy (1.5-2.0 mg/kg) was continued until 4 years after diagnosis and tapered thereafter. The primary endpoint was relapse-free survival at 4 years after diagnosis.
RESULTS: In patients with PR3-AAV who were C-ANCA positive at the time of stable remission, relapse-free survival at 4 years after diagnosis did not differ significantly between standard azathioprine (n = 24) and extended azathioprine (n = 21) maintenance therapy (P = 0.40). There was also no significant difference in relapse-free survival between patients receiving standard azathioprine (n = 106) versus extended azathioprine maintenance therapy (n = 21; P = 0.94). In addition, there was no difference in the relapse rate between patients with PR3-AAV who were C-ANCA positive (n = 45) at the time of remission versus patients who became C-ANCA negative at the time of remission (n = 82; P = 0.62).
CONCLUSIONS: This randomized trial suggests that extended azathioprine maintenance therapy has only a limited effect on the prevention of relapse in patients with PR3-AAV at 4 years after diagnosis. Moreover, positive C-ANCA status at stable remission was not associated with an increased rate of relapse.
TRIAL REGISTRATION: ClinicalTrials.gov NCT 00128895.
© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
