Clinical and molecular studies in ANCA associated vasculitis
Author: Wendt, Mårten
Date: 2015-01-16
Location: Föreläsningssal Medicin, A6:04, Karolinska Universitetssjukhuset Solna
Time: 09.00
Department: Inst för klinisk vetenskap, intervention och teknik / Dept of Clinical Science, Intervention and Technology
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Thesis (2.323Mb)
Abstract
ANCA associated vasculitis (AAV) is a heterogeneous group of diseases characterised by sterile pauci-immune systemic small vessel inflammation and closely associated with the presence of anti-neutrophil cytoplasmatic antibodies (ANCA). Although AAV can affect any organ, the kidney, skin, lungs and upper and lower airways are most commonly involved. In some patients there is granuloma formation and in some asthma and eosinophilia, and based on this patients can be further classified as microscopic polyangiitis (MPA) (no granuloma), granulomatosis with polyangiitis (GPA) or eosinophil granulomatosis with polyangiitis (EGPA). Induction treatment of AAV consists of a cytotoxic agent in combination with glucocorticoids and is usually effective, although relapse, infections and drug toxicity remain a problem.
The aim of this thesis was to investigate the role of novel proinflammatory molecules in the pathogenesis of AAV and as markers of disease. We also wanted to investigate the outcome of new therapies.
In paper I we investigated the pro-inflammatory mediator high-mobility group box-1 protein (HMGB1) in patients with active AAV and in remission. Elevated levels of circulating HMGB1 were found in active disease compared to inactive disease. We found increased expression of HMGB1 in renal tissue of patients with active renal AAV compared to inactive AAV, indicating a role for HMGB1 in AAV.
In paper II we carried out a long time follow-up on patients treated with rituximab as a second line treatment in patients with refractory or relapsing disease. We found that a high proportion of patients achieved remission but there were several adverse events including two cases of hepatitis B reactivation. Patients with a negative conventional ANCA but positive capture ANCA seemed to be at risk of relapse after rituximab treatment.
In paper III macrophage inhibitory factor and thyroid hormones were investigated prospectively in 30 patients with active AAV. We found that levels of MIF were elevated in active disease compared to remission and that MIF levels correlated with disease activity. There were thyroid hormone alterations with lower triiodothyronine in active disease, similar to what has previously been described in critically ill patients. In addition there was an indication of an interaction between MIF and thyroxine similar to what has previously been described in sepsis.
In paper IV we investigated pentraxin – 3 (PTX3) and soluable Tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in 40 patients with active AAV and found that PTX3 was elevated in active disease compared to remission and correlated with disease severity. sTWEAK levels in active disease did not significantly change compared to remission, but seemed to vary with disease phenotype. Patients with high sTWEAK and low PTX3 were less likely to achieve remission.
In conclusion several proinflammatory molecules may be implicated in the pathogenesis and exacerbation of AAV and are possible targets of therapy. There seems to be thyroid hormone alterations in active AAV and there may be an interaction between MIF and thyroxine in AAV. PTX3 may be a useful marker of disease. Rituximab may be a useful treatment in refractory or relapsing disease but it is important to assess hepatitis status and adverse events are a concern.
The aim of this thesis was to investigate the role of novel proinflammatory molecules in the pathogenesis of AAV and as markers of disease. We also wanted to investigate the outcome of new therapies.
In paper I we investigated the pro-inflammatory mediator high-mobility group box-1 protein (HMGB1) in patients with active AAV and in remission. Elevated levels of circulating HMGB1 were found in active disease compared to inactive disease. We found increased expression of HMGB1 in renal tissue of patients with active renal AAV compared to inactive AAV, indicating a role for HMGB1 in AAV.
In paper II we carried out a long time follow-up on patients treated with rituximab as a second line treatment in patients with refractory or relapsing disease. We found that a high proportion of patients achieved remission but there were several adverse events including two cases of hepatitis B reactivation. Patients with a negative conventional ANCA but positive capture ANCA seemed to be at risk of relapse after rituximab treatment.
In paper III macrophage inhibitory factor and thyroid hormones were investigated prospectively in 30 patients with active AAV. We found that levels of MIF were elevated in active disease compared to remission and that MIF levels correlated with disease activity. There were thyroid hormone alterations with lower triiodothyronine in active disease, similar to what has previously been described in critically ill patients. In addition there was an indication of an interaction between MIF and thyroxine similar to what has previously been described in sepsis.
In paper IV we investigated pentraxin – 3 (PTX3) and soluable Tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in 40 patients with active AAV and found that PTX3 was elevated in active disease compared to remission and correlated with disease severity. sTWEAK levels in active disease did not significantly change compared to remission, but seemed to vary with disease phenotype. Patients with high sTWEAK and low PTX3 were less likely to achieve remission.
In conclusion several proinflammatory molecules may be implicated in the pathogenesis and exacerbation of AAV and are possible targets of therapy. There seems to be thyroid hormone alterations in active AAV and there may be an interaction between MIF and thyroxine in AAV. PTX3 may be a useful marker of disease. Rituximab may be a useful treatment in refractory or relapsing disease but it is important to assess hepatitis status and adverse events are a concern.
List of papers:
I. Bruchfeld A, Wendt M, Bratt J, Qureshi AR, Chavan S, Tracey KJ, Palmblad K and Gunnarsson I. High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol Med. 2011 17: 29-35.
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II. Wendt M, Gunnarsson I, Bratt J and Bruchfeld A. Rituximab in relapsing or refractory ANCA-associated vasculitis: a case series of 16 patients. Scand J Rheumatol. 2012 41:116-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Wendt M, Börjesson O, Avik A, Bratt J, Anderstam B, Qureshi AR, Miller EJ, Gunnarsson I and Bruchfeld A. Macrophage Migration Inhibitory Factor (MIF) and Thyroid Hormone Alterations in Antineutrophil Cytoplasmatic Antibody (ANCA)-Associated Vasculitis (AAV). Mol Med. 2013 20:109-14.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. M Wendt, O Börjesson, A Avik, J Bratt, AR Qureshi, I Gunnarsson and A Bruchfeld. PTX3 and soluble TWEAK levels in active ANCA associated vasculitis (AAV) patients undergoing treatment – correlation to disease activity and relapse. [Manuscript]
I. Bruchfeld A, Wendt M, Bratt J, Qureshi AR, Chavan S, Tracey KJ, Palmblad K and Gunnarsson I. High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol Med. 2011 17: 29-35.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Wendt M, Gunnarsson I, Bratt J and Bruchfeld A. Rituximab in relapsing or refractory ANCA-associated vasculitis: a case series of 16 patients. Scand J Rheumatol. 2012 41:116-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Wendt M, Börjesson O, Avik A, Bratt J, Anderstam B, Qureshi AR, Miller EJ, Gunnarsson I and Bruchfeld A. Macrophage Migration Inhibitory Factor (MIF) and Thyroid Hormone Alterations in Antineutrophil Cytoplasmatic Antibody (ANCA)-Associated Vasculitis (AAV). Mol Med. 2013 20:109-14.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. M Wendt, O Börjesson, A Avik, J Bratt, AR Qureshi, I Gunnarsson and A Bruchfeld. PTX3 and soluble TWEAK levels in active ANCA associated vasculitis (AAV) patients undergoing treatment – correlation to disease activity and relapse. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Bruchfeld, Annette
Issue date: 2014-12-19
Rights:
Publication year: 2014
ISBN: 978-91-7549-762-4
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