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The Importance of Demographic and Geographical Factors on the Incidence and Outcome of Systemic Small Vessel Vasculitis Associated with Anti-Neutrophil Cytoplasmic Antibodies
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) comprise microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Two serotypes are recognized: myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA. Renal involvement is a common and severe manifestation associated with increased mortality. The incidence varies geographically, but studies are difficult to compare due to heterogeneous methodology and inclusion criteria. AAV is commonly found in the elderly, but there are little data on outcome and optimal treatment in the highest age groups. This thesis focuses on the epidemiology of AAV: incidence, geographical distribution, and outcome.

In Paper I annual incidence rates and outcome were compared between nephritis in AAV and nephritis in systemic lupus erythematosus (SLE) in two geographically defined populations in Sweden. Even though SLE is twice as common as AAV, ANCA-associated nephritis outnumbered lupus nephritis by three to one, and was significantly more severe in terms of mortality and development of end stage renal disease.

In Paper II associations between ANCA serotype and geographical and demographic factors were investigated in a large multi-centre study of 1408 patients with renal biopsy-proven AAV. PR3-ANCA was associated with male gender, younger age and higher glomerular filtration rate. PR3-ANCA was also associated with higher latitude and lower ultraviolet radiation levels, but analyses of subgroups suggested that genetic rather than environmental explanations might be more important for this geographical gradient.

In Paper III a consecutive cohort of 151 elderly patients with MPA and GPA was studied with a focus on treatment, mortality and renal survival. Patients who had received immunosuppressive treatment with cyclophosphamide or rituximab had better survival rates compared to less intensively treated or untreated patients. Severely impaired renal function at diagnosis was associated with worse outcome in terms of both patient and renal survival.

In Paper IV the elderly cohort was extended to 202 patients. In this study we found that treatment with cyclophosphamide or rituximab was associated with the development of less permanent organ damage, and not with higher utilization of in-hospital care. However, high doses of glucocorticoids were associated with fatal infections and treatment-related damage.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 82
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1701
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:liu:diva-161582DOI: 10.3384/diss.diva-161582ISBN: 9789176850008 (print)OAI: oai:DiVA.org:liu-161582DiVA, id: diva2:1367628
Public defence
2019-11-22, Berzeliussalen, Hus 463, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-11-04 Created: 2019-11-04 Last updated: 2019-11-05Bibliographically approved
List of papers
1. Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden.
Open this publication in new window or tab >>Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden.
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2015 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 30, p. i23-i30Article in journal (Refereed) Published
Abstract [en]

Objectives :The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden.

METHODS: In the health care districts surrounding the Skåne University Hospital in Lund [mean population ≥18 years (1997-2008), 188 400] and the University Hospital in Linköping [mean population ≥18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period.

RESULTS: Eighty-two patients (Lund 44 + Linköping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linköping 14). The annual incidence rate per million inhabitants aged ≥18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020.

CONCLUSIONS: In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage.

Place, publisher, year, edition, pages
Oxford University Press, 2015
National Category
Basic Medicine Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-113101 (URN)10.1093/ndt/gfu396 (DOI)000353500300005 ()25540097 (PubMedID)
Available from: 2015-01-09 Created: 2015-01-09 Last updated: 2019-11-04
2. Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis
Open this publication in new window or tab >>Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis
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2019 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 34, no 2, p. 301-308Article in journal (Refereed) Published
Abstract [en]

Background. In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods. Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results. A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); Pamp;lt;0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO: PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions. The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2019
Keywords
ANCA-associated vasculitis; glomerulonephritis; latitude; MPO-ANCA; PR3-ANCA
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:liu:diva-155008 (URN)10.1093/ndt/gfy106 (DOI)000459322000015 ()29718465 (PubMedID)
Note

Funding Agencies|Ingrid Asp Foundation; Swedish Renal Foundation; Swedish Society of Medicine (Svenska Lakaresallskapet); Swedish Rheumatism Association (Reumatikerforbundet); National Institute for Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, MD, USA [P01-DK5-30834]

Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-11-04
3. Outcome and Treatment of Elderly Patients with ANCA-Associated Vasculitis
Open this publication in new window or tab >>Outcome and Treatment of Elderly Patients with ANCA-Associated Vasculitis
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2015 (English)In: Clinical journal of the American Society of Nephrology : CJASN, ISSN 1555-905X, Vol. 10, no 7, p. 1128-1135Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND OBJECTIVES: ANCA-associated vasculitis is commonly found in elderly patients, but there are few data concerning outcome and treatment in the highest age groups.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Consecutive patients (N=151) presenting between 1997 and 2009 were retrospectively included from local registries in six centers in Sweden, the United Kingdom, and the Czech Republic if diagnosed with microscopic polyangiitis or granulomatosis with polyangiitis at age ≥75 years during the study period. Patients were followed until 2 years from diagnosis or death. Data on survival and renal function were analyzed with respect to age, sex, ANCA specificity, renal function, C-reactive protein, comorbidities, and Birmingham Vasculitis Activity Score at diagnosis as well as treatment during the first month.

RESULTS: Median follow-up was 730 days (interquartile range, 244-730). Overall 1-year survival was 71.5% and 2-year survival was 64.6%. Older age, higher creatinine, and lower Birmingham Vasculitis Activity Score were associated with higher mortality in multivariable analysis. Patients who were not treated with standard immunosuppressive therapy had significantly worse survival. Renal survival was 74.8% at 1 year. No new cases of ESRD occurred during the second year. High creatinine at diagnosis was the only significant predictor of renal survival in multivariable analysis.

CONCLUSIONS: ANCA-associated vasculitis is a disease with substantial mortality and morbidity among elderly patients. This study showed a better prognosis for those who received immunosuppressive treatment and those who were diagnosed before having developed advanced renal insufficiency.

Place, publisher, year, edition, pages
American Society of Nephrology, 2015
Keywords
ANCA, glomerulonephritis, survival, vasculitis
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:liu:diva-119904 (URN)10.2215/CJN.00480115 (DOI)000357754200006 ()26100457 (PubMedID)
Available from: 2015-06-30 Created: 2015-06-30 Last updated: 2019-11-04
4. Impact of treatment on damage and hospitalization in elderly patients with microscopic polyangiitis and granulomatosis with polyangiitis
Open this publication in new window or tab >>Impact of treatment on damage and hospitalization in elderly patients with microscopic polyangiitis and granulomatosis with polyangiitis
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2019 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, article id jrheum.190019Article in journal (Refereed) Epub ahead of print
Abstract [en]

OBJECTIVE: Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown.

METHODS: Consecutive patients from Sweden, England, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide, rituximab, and corticosteroids the first three months was registered. Outcomes up to two years from diagnosis included vasculitis damage index (VDI), hospitalization, and cause of death.

RESULTS: Treatment data was available for 167 of 202 patients. At two years, 4% had no items of damage. There was a positive association between VDI score at two years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using cyclophosphamide or rituximab. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. MPO-ANCA positivity and lower creatinine levels decreased the odds for readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose.

CONCLUSION: Immunosuppressive treatment with cyclophosphamide or rituximab in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first three months was associated with treatment-related damage and fatal infections.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:liu:diva-161581 (URN)10.3899/jrheum.190019 (DOI)31308208 (PubMedID)
Available from: 2019-11-04 Created: 2019-11-04 Last updated: 2019-11-04

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