Treatment of Anca Positive Vasculitis Essay

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Anca positive vasculitis refers to the group of vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). Common features like focal necrotizing or pauci-immune glomerulonephritis are found in renal histology leading to similar outcomes for the group; some differences exist (1). The illnesses included under ANCA positive vasculitis are Wegener’s granulomatosis and microscopic polyangiitis. Immunosuppressive therapy induces remission first and then maintains the immunosuppression for a longer period to prevent a relapse. The Birmingham Vasculitis Activity Score is used to define the symptoms including arthralgia, arthritis and fever and any involvement of eight organs (1). Persistent symptoms are given one point while worse symptoms are marked with two points. The worse manifestations which threaten the life of the patient include gangrene, alveolar hemorrhage, respiratory failure, sensory deafness, retinal exudates and hemorrhage and an increase of serum creatinine. With the possibility of multiple organ involvement and renal involvement in particular, the therapy is difficult and absolute remission is the aim of therapy which is the stage of no active disease (1). Cyclophosphamide is the regular treatment for remission, either as a daily dosage regimen (1.5-2 mg/kg) or a pulse dosage intravenously. Relapse is prevented by the continuation of the cyclophosphamide or institution of maintenance therapy with methotrexate or azathioprine. Glucocorticoids are given right from the start of treatment. These concepts have been researched and various new ideas have been suggested. Leukopenia must be ruled out frequently through blood counts for leucocytes. Cyclophosphamide resistance is one problem that accompanies therapy and must be watched out for. Contraindication is another where a patient cannot tolerate the drug (1). Methotrexate is believed to be useful in a milder disease form and some patients are known to respond if combined with plasma exchange. Many questions still bother researchers and clinicians about the best therapy for ANCA-positive vasculitis. This paper is critically reviewing the many concepts of the therapy of ANCA positive vasculitis.

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The treatment regimens for ANCA-associated vasculitis are effective to a great extent. However toxicity remains to be a problem by and large (2). New therapeutic drugs specific for the illness have now been identified “with better potential specificity for both the inflammation and immunologic causes of vasculitis: new immunosuppressive drugs (mycophenolate), monoclonal antibody modulators of lymphocyte function (rituximab), and cytokine-directed therapies (infliximab and etanercept)” (2). Research has indicated that duration of treatment with cyclophosphamide is short usually for 3 months. Long term maintenance therapy helps to avoid relapse; azathioprine or methotrexate is used (2)

The prospective study by Hoffman et al (1992) investigated the clinical features, pathophysiology, treatment and prognosis of 158 patients of Wegener’s granulomatosis who were referred to the National Institute of Allergy and Infectious Diseases in the past 24 years (3). Follow-up lasted from 6 months to 24 years. The data was collected from a computer-based information retrieval system. The setting was given as the Warren Magnuson Clinical Centre (3). The sample included equal number of men and women. Most were whites (97%) and above 19 years of age (85%). Follow-up was for 8 years on an average. 84 % were given low dose cyclophosphamide daily with glucocorticoids. 8 % did not have glucocorticoids. 4% were treated with other cytotoxic agents and glucocorticoids while 10% were given only glucocorticoids (3). Details of the treatment and outcomes or prognosis have been indicated but the clinical features and pathophysiology have not been discussed in the paper. The conclusion also mentions treatment mainly. That low cyclophosphamide therapy is the best cannot be understood from the findings as it is not mentioned which treatment group constituted the 91 % who showed marked improvement. Future research needs to look into toxicity of prolonged cyclophosphamide therapy (3).

The efficacy and adverse effects of cyclophosphamide in the oral dosage and the pulse dosage has been compared in a study by De Groot et al (4). 14 studies were taken for the meta-analysis and review. 3 prospective randomised control trials were selected to compare the outcomes of the “remission, relapses, infection, leucopenia, death and renal failure” (4). 11 randomised control studies had 202 participants. It was found that the pulse dose treatment had lesser toxicity and it was equally effective in producing remission. This study had limitations in that the times to remission and relapse were not available. The elements of irreversible damage or quality of life were also not addressed (4). Future research needed to address these issues for a more complete picture.

Birmingham Vasculitis Activity Score (BVAS) which is a specific activity index for Wegener’s granulomatosis has been validated and refined by 16 members of the International Network for the Study of the Systemic vasculitides (INSSYS). The paper addresses the research question (5). Some of the unnecessary items in the index were removed so that the instrument became more valuable for future research. The features which helped to specify the manifestations of Wegener’s granulomatosis were highlighted. The instrument was streamlined for diagnosing the illness more accurately. 38 items from the instrument were removed, 9 were revised and 7 new items were added (5). Data collection was made as written questionnaires from 117 patients with Wegener’s granulomatosis. from 2 simulation exercises and a clinical case series using the revised instrument BVAS. Methodology was quantitative (5). Sample was selected for a diagnosis of Wegener’s granulomatosis and patients in remission were not selected. The setting has not been mentioned. The scores on the BVAS correlated with the physician’s global assessment of disease activity. The Spearman’s correlation coefficient between the BVAS and the PGA was r=0.81 (95% confidence interval). For the exercises, interobserver reliability was r=0.93 for the BVAS and 0. 88 for the PGA the first time and r=0.91 and r=0.88 the second time (5). Observer effect did not show in the results. It is not clear how the themes and concept were derived from the data. The analysis had more than one researcher. Cases of Wegener’s which were in remission were not selected. No verification was done but a repeat of the simulation exercise gave an impression that the method and results were similar. The primary finding is that BVAS correlates well with PGA and BVAS is sensitive to change and has good inter-observer and intra observer reliability (5). The findings are verifiable as the BVAS and PGA have same results. The revised instrument can reliably be used in future evaluations of Wegener’s granulomatosis. The instrument can be used to evaluate the response of illness to treatment using drugs like etanercept in the search for a cure. The research was performed in Wegener’s granulomatosis specifically and could be representative as the purpose was to conduct outcomes or responses to trial drugs (5).

Another prospective randomised study by Haubitz et al in 1998 compared the efficacy of intravenous pulse dosage with oral continuous treatment (6). This study concluded similarly that the intravenous dosage was effective in ANCA positive vasculitis and renal involvement. Low toxicity is also reported (6).

Treatment of Wegener’s granulomatosis, an antineutrophil cytoplasmic antibody, is the focus of study by Hogan et al. Predictors of treatment resistance and relapse have not been yet determined and this study hopes to provide some information (7). The ambitious objective is to identify clinical, pathological and serological predictors. The results show that a few predictors have been identified for resistance to initial treatment for Wegener’s granulomatosis: females, blacks and those with severe renal disease (7). Risk for relapse has been recognised in lung disease or upper airway disease and serologically in anti-PR3 antibody seropositivity (7). Method of data collection has not been mentioned. Patients were initially divided into two groups according to whether they had antiproteinase 3 antibodies or anti-myeloperoxidase antibodies. Being a quasi-experimental, prospective, cohort design study, the ethics of treatment maintains that patients should not have side-effects and lack of randomisation causes the external validity to be lower than the clinical trial. A community-based cohort of 350 patients who were newly identified for Wegener’s granulomatosis through a biopsy was selected; these patients were diagnosed between 1985 and 2003 for ANCA associated vasculitis and could be followed up for 49 months (7). A biopsy or a well-defined clinical picture confirmed involvement of an organ. Clinical manifestations or the finding of sediment in the urine indicates the renal dysfunction which occurs due to resistance to therapy. The time of relapse is the period during which symptoms of disease activity reappear. The setting was the Glomerular Disease Collaborative Network. Data analysis and interpretation were done but the method was not obvious or mentioned. The themes are clear however. The results show that 23% of the 334 in the study were females, blacks and had severe kidney disease. The severity of renal disease was marked by odds ratio per serum creatinine of 100micromol/Litre. Confidence interval was 95%. 77% patients who had relapse soon had remission.

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This was associated “with a seropositivity for anti PR3 antibodies, hazard ratio of 1.71 for disease of lung and a hazard ratio of 1.73 for upper respiratory tract” (7). 26% of patients who had no risks and 73 % who showed 3 risk factors had relapses (7). 143 patients reached remission and stopped all immunotherapy. These patients had similar relapse rates to the patients who had 6 months or less of cyclophosphamide therapy and patients who had more of therapy with risk factors adjusted. The study had limitations in that uniform treatment was not provided and the course of the illness before the biopsy was unknown (7). Feedback by participants was not studied. The findings are applicable in that more information is obtained and future studies could be done.

The study by Adu et al (1997) investigated the difference in the outcomes of treatment of systemic vasculitis in a randomised controlled trial of 54 patients (8). The objective was to compare the treatment outcomes in 24 patients (A group) with pulse cyclophosphamide and prednisolone to outcomes in 30 patients (B group) who continued their treatment with azathioprine within 1.5 to 10 months and come a step closer to finding the right treatment for vasculitis (8). Of the sample of 54 patients between 15 and 70 years of age, 8 had classical polyarteritis, 17 had microscopic polyarteritis and 29 had Wegener’s granulomatosis. It was found that the number of deaths were the same (5 in A group and 4 in B). Relapses were 7 in A and 8 in B. Treatment failures were 4 each in A and B. The improvement in renal functions was similar. Toxicity was found in 71% of A and 87% of the B. However the obvious difference between the two was in the three-year survival: it was 77 % in A and 90 % in B (8). The findings may not be applicable unless the types of vasculitis selected are in the same proportion. It is not clear whether the diagnosis of vasculitis has any bearing on the response to treatment. Moreover since the findings of ill effects are mostly similar in the two groups, it does not determine which treatment is better.

A randomised control study has been done by de Groot et al in relation to therapy (2009). As most treatment for (ANCA)-associated vasculitis is limited by toxicity, a comparison is being made here between pulse cyclophosphamide and daily oral cyclophosphamide for inducing remission (9). Assignment was randomised by computer generation of allocations. Patients, investigators or assessors were not blinded. 42 centres in 12 European countries were taken as the setting. Participants were patients who had been recently diagnosed with ANCA-associated vasculitis and had renal disease in addition but were safe from life-threatening problems: they were 149 in number. The dosage of intravenous cyclophosphamide was 15 mg/kg every two or three weeks and given to 76 patients. 73 patients had the daily oral dose at 2mg./kg. All had prednisolone (9). The primary outcome was the remission and the time take to reach it was measured. The secondary outcomes were also measured: renal function tests were done to measure if any renal dysfunction had set in. Other secondary outcomes include adverse events which could be life-threatening too. The cumulative dose of cyclophosphamide determines the toxicity of the drug again a secondary outcome (9). Remission time and percentage of patients who went into remission were the same for both groups. The pulse group showed more remissions within nine months. Higher cumulative dosage was seen in the daily dosage group (9). The pulse group therefore had lesser cases of leukopenia. The difference in relapse rates of both groups could not be determined. The pulse cyclophosphamide acted just like the daily dosage of cyclophosphamide in inducing remission but was better off in that the accumulative dosage was less and lesser cases of leukopenia resulted (9).

This study by De Groot has been done to find an alternative to the treatment of ANCA associated vasculitis (10). An unblended, randomised controlled prospective trial was conducted in 100 patients to determine whether methotrexate could replace cyclophosphamide and glucocorticoid combination for inducing remission in the early stage. The sample included newly diagnosed vasculitis patients with serum creatinine below 150mumols/liter with no critical organ dysfunction (10). One group of 51(A) received daily oral cyclophosphamide at 2mg/kg. The other of 49 (B) received Methotrexate 20-25 mg/week. Both received prednisolone. Treatment lasted for 12 months and was tapered off. Follow-up was for 18 months. It was found that the remission rate in B was 89.8% and almost similar to the other at 93.5 % (10). The relapse rate was more in the B group at 69.5% when compared to group A at 46.5%. Leukopenia was less in B group. Methotrexate can replace cyclophosphamide as treatment of ANCA associated vasculitis. Immunosuppressive treatment must be continued for more than 12 months to prevent relapses (10).

A retrospective study was conducted by Villa-Forte et al (11) with same objective as the study above of DeGroot et al in 2005 (11). However this study used outcomes for comparison. Patients were treated with Cyclophosphamide and methotrexate for mild to moderate disease and Methotrexate was continued for severe disease. Patients of Wegener’s granulomatosis supervised by the Cleveland Clinic Center for Vasculitis Care and Research were selected for the study sample (11). The disease activity was evaluated at each visit and then converted to the BVAS score modified for Wegener’s granulomatosis. 253 patients were participants (11). The results of this study were given in some detail. They appeared to be similar to the findings with cyclophosphamide in earlier research.

EULAR recommendations were developed in a study by Mukhtyar et al, 2009 where treatment for small and medium vessel vasculitis was investigated (12). “10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and USA, a clinical epidemiologist and a representative of a drug regulating agency discovered 10 topics using a modified Delphi technique” (12). 15 recommendations were drawn up for use in daily life (12).

Safe and effective treatment has not been found for remissions in Wegener’s granulomatosis (13). The maintenance of remission was studied in 2 groups of patients of Wegener’s granulomatosis who were having the usual treatment: one had etanercept and the other had placebos. Sustained remission was the expected outcome for at least six months (13). The BVAS was used to record a score of 0 for the remission (higher score would indicate more active disease). When remission was reached, the standard therapy was tapered. Follow-up was for 27 months. 72.4% reached remission but only 49.4% remained in remission. The rates of sustained remission were the same in both groups. Disease flares were common in both but more in the control group (13). One severe or life threatening incident occurred with similar frequency in both groups (56.2 against 57.1). The etanercept group had solid cancers while the control group did not. The etanercept was found not effective to maintain remissions. Moreover the chances of treatment related complications were high (13). The finding of solid cancers in the etanercept group is significant and may lead to a study if etanercept has other good uses.

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Jayne et al studied maintenance therapy for ANCA-associated vasculitis in a randomised trial (14). This automatically refers to Wegener’s granulomatosis and microscopic polyangitis. The objective was to find out whether azathioprine following cyclophosphamide at the time of remission could reduce the toxicity of cyclophosphamide. The sample was 155 patients with a newly diagnosed generalised vasculitis and with a maximum serum creatinine of 500 micromols / litre. Cyclophosphamide and glucocorticoids were given to the patients for the regular 3 months. 71 patients had azathioprine while 73 continued with cyclophosphamide on attaining remission (14). Both groups had glucocorticoids. 11 relapses in the azathioprine group and 10 in the other group were noted. Severe adverse effects were seen in the induction and remission phases in both groups. Relapses were lesser in microscopic polyangitis. Data collection was not described in detail. As the incidence of relapses was seen in both groups, it could not be concluded that azathioprine worsened the condition of the patient. So substitution may be done to reduce the toxicity of cyclophosphamide. No hint on future research has been given.

The efficacy of low dose intravenous methotrexate has been compared with daily dosage of trimethoprim/sulfamethoxazole in the treatment of remission in patients of Wegener’s granulomatosis by De Groot (15). 65 patients were the participants who had attained remission with cyclophosphamide and prednisolone. Clinical, radiographic and sero-immunological data were evaluated. Possible predictive factors were discovered. It was found that low dose methotrexate was superior for the maintenance of remission (15).

The usual dosage regimen of Wegener’s granulomatosis includes cyclophosphamide and prednisolone followed by azathioprine or methotrexate as maintenance therapy. A study has been done to compare the azathioprine with methotrexate for efficacy and toxicity by Pagnoux et al (16). A prospective open label multicentre trial was done. The 159 patients were randomly assigned for therapies. One group had azathioprine at dosage of 2mg/kg per day. The other group had methotrexate at the dosage 0.3 mg/kg per week which was increased to 25mg per week in steps (16). The end point was any effect which caused stoppage of drug or death; 29 azathioprine and 35 methotrexate patients had adverse events. This study did not prove that methotrexate was less toxic. The two appear to be of similar safety where maintenance therapy is concerned (16).

The relapse rate and outcome of patients with Wegener’s granulomatosis who were treated with cyclophosphamide and prednisolone for remission and then maintained on methotrexate were studied by Langford et al (17). Clinical features, pathological findings, laboratory results and radiographic pictures were used to assess outcomes. All the patients were in remission by three months. It was found that the drug combination was effective in allowing patients to reach remission and maintain it well (17).

Hoffman has said that Wegener’s granulomatosis has a relapsing tendency with the usual regimen of cyclophosphamide and prednisolone (18). He has indicated that conventional therapy has produced remission but 50% of patients may have relapses. Efforts to find more effective but less toxic therapies has resulted in the methotrexate and azathioprine maintenance therapies (18). The role of the antiproteinase-3 antibodies may provide a path to better therapy.

Conclusion

The illnesses included under ANCA positive vasculitis are Wegener’s granulomatosis and microscopic polyangitis. Immunosuppressive therapy induces remission first and then maintains the immunosuppression for a longer period to prevent a relapse. Arthralgia, arthritis and fever are some main symptoms of Wegener’s granulomatosis. Involvement of one or more of eight organs could further complicate matters. All these are included in the Birmingham Vasculitis Activity Score (1). With the possibility of multiple organ involvement and renal involvement almost surely, the therapy is difficult and absolute remission is the aim of therapy which is the stage of no active disease (1). Cyclophosphamide is the regular treatment for remission, either as daily dosage regimen (1.5-2 mg/kg) or a pulse dosage intravenously. Relapse is prevented by the continuation of the cyclophosphamide or institution of maintenance therapy with methotrexate or azathioprine. New therapeutic drugs specific for the illness have now been identified “with better potential specificity for both the inflammation and immunologic causes of vasculitis: new immunosuppressive drugs (mycophenolate), monoclonal antibody modulators of lymphocyte function (rituximab), and cytokine-directed therapies (infliximab and etanercept) (2). Future research needs to look into toxicity of prolonged cyclophosphamide therapy as it can complicate matters (3) The issues of irreversible damage or quality of life with the cyclophosphamide therapy have not been addressed in studies yet (3). The Birmingham Vasculitis Activity Score (BVAS) is a specific activity index for Wegener’s granulomatosis (5). Of the two types of cyclophosphamide therapies, the intravenous dosage was effective in ANCA positive vasculitis and renal involvement and showed low toxicity (6). Predictors of Wegener’s granulomatosis have been found to be females, blacks and those with severe renal disease (7). The intravenous pulse form of cyclophosphamide is equal in effectiveness to the oral form and it is actually less toxic because its accumulative dosage is less. Methotrexate can replace cyclophosphamide as treatment of ANCA associated vasculitis (10). Etanercept was found not effective to maintain remissions (13). It was found that low dose methotrexate was superior for the maintenance of remission than the trimethoprim/ sulfamethoxazole (15). The role of the antiproteinase-3 antibodies may provide a path to better therapy (18)

References

Stone, J.H., Kaplan, A.A. and Falk, R.J. (2009). Initial Immunosuppressive therapy in Wegener’s granulomatosis and microscopic polyangitis. (Journal not named)

Buhaescu I; Covic A; Levy J., Systemic vasculitis: still a challenging disease. Am J Kidney Dis 2005;46(2):173-85 Dialysis and Renal Transplantation Center, Parhon University Hospital, Iasi, Romani.

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Hoffman GS; Kerr GS; Leavitt RY; Hallahan CW; Lebovics RS; Travis WD; Rottem M; Fauci AS., Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116(6):488-98 National Institutes of Health, Bethesda, Maryland.

De Groot L., Adu D. and Savage, C.O. (2001). The value of pulse cyclophosphamide in ANCA associated vasculitis: meta-analysis and critical review. Nephrology Dialysis Transplant, Vol. 10, p. 2018-2027

Stone JH; Hoffman GS; Merkel PA; Min YI; Uhlfelder ML; Hellmann DB; Specks U; Allen NB; Davis JC; Spiera RF; Calabrese LH; Wigley FM; Maiden N; Valente RM; Niles JL; Fye KH; McCune JW; St Clair EW; Luqmani RA. A disease-specific activity index for Wegener’s granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum. 2001;44(4):912-20 Johns Hopkins University, Baltimore, Maryland, USA

Haubitz M; Schellong S; Gobel U; Schurek HJ; Schaumann D; Koch KM; Brunkhorst R. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study. Arthritis Rheum 1998;41(10):1835-44.

Hogan SL; Falk RJ; Chin H; Cai J; Jennette CE; Jennette JC; Nachman PH. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 2005;143(9):621-31 Division of Nephrology and Hypertension, Department of Medicine, UNC Kidney Center, University of North Carolina, Chapel Hill, North Carolina.

Adu D; Pall A; Luqmani RA; Richards NT; Howie AJ; Emery P; Michael J; Savage CO; Bacon PA. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM 1997;90(6):401-9. Department of Nephrology, Quenn Elizabeth Medical Cnetre, Birmingham, UK

de Groot K; Harper L; Jayne DR; Flores Suarez LF; Gregorini G; Gross WL et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670-80 Klinikum Offenbach, Offenbach, Germany.

De Groot K; Rasmussen N; Bacon PA; Tervaert JW; Feighery C; Gregorini G; Gross WL; Luqmani R; Jayne DR. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52(8):2461-9. Medical School Hannover, Germany.

Villa-Forte A; Clark TM; Gomes M; Carey J; Mascha E; Karafa MT; Roberson G; Langford CA; Hoffman GS. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience. Medicine (Baltimore). 2007; 86(5):269-77. Department of Rheumatic and Immunologic Diseases,Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA

Mukhtyar C; Guillevin L; Cid MC; Dasgupta B; de Groot K; Gross W; et al, EULAR recommendations for the management of primary small and medium vessel vasculitis Ann Rheum Dis. 2009;68(3):310-7. Epub 2008 University of Oxford, Oxford, UK.

Etanercept plus standard therapy for Wegener’s granulomatosis, New England Journal of Medicine, 2005, Vol. 352, No. 4, p. 351-361.

Jayne D; Rasmussen N; Andrassy K; Bacon P; Tervaert JW and Dadoniene J. et al (2003). A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med;349(1):36-44. Department of Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom.

De Groot, K., Reinhold-Keller, E., Tatsis, E., Paulsen, J., Heller, M. and Noelle, B. et al. (1996) Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’s granulomatosis. Methotrexate versus trimethoprim /sulfamethoxazole Arthritis Rheum; 39(12):2052-61

Pagnoux C; Mahr A; Hamidou MA; Boffa JJ; Ruivard M; Ducroix JP et al, (2008) Azathioprine or methotrexate maintenance for ANCA-associated vasculitis N Engl J Med;359(26):2790-2803 Universite Paris Descartes, Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France

Langford CA; Talar-Williams C; Barron KS; Sneller MC. (2003). Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener’s granulomatosis: extended follow-up and rate of relapse. Am J Med;114(6):463-9.

Hoffman, G.S. (1993). Wegener’s granulomatosis, Current opinion Rheumatology, Vol. 5, No. 1, p. 11-7

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