Mikkel Faurschou

Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis

OBJECTIVE Experimental studies indicate that patients with Wegeners granulomatosis (WG) experience accelerated atherosclerosis. The purpose of this study was to investigate whether the occurrence of overt ischemic heart disease (IHD) is increased in WG. METHODS A total of 293 WG patients were included in the study. Information on all hospitalizations for IHD in Denmark from 1977 to 2006 was obtained from the Danish National Hospital Register. The WG patients were compared with the Danish background population with respect to rates of hospitalization for clinical manifestations of IHD after the date of vasculitis diagnosis by calculating standardized ratios of observed to expected (O:E) events. RESULTS Sixty-three first IHD events were registered in the WG group during the 2,482 patient-years of followup, corresponding to a significantly increased O:E ratio for IHD of 1.9 (95% confidence interval [95% CI] 1.4-2.4). A significantly increased risk was found for acute myocardial infarction (MI) (O:E ratio 2.5 [95% CI 1.6-3.7]), but not for angina pectoris (O:E ratio 1.3 [95% CI 0.7-2.1]). In analyses stratified according to the time between the diagnosis of vasculitis and the cardiovascular event, increased O:E ratios were found for IHD and acute MI occurring <5.0 years after WG diagnosis (2.1 [95% CI 1.4-3.0] for IHD and 3.6 [95% CI 2.0-5.9] for acute MI) and for IHD occurring > or =10.0 years after WG diagnosis (2.2 [95% CI 1.3-3.4]). Significantly increased O:E ratios for IHD and acute MI were found in patients who were > or =50.0 years of age at the time of diagnosis of WG, in male patients, and in patients who received high cumulative doses of cyclophosphamide. CONCLUSION Compared with the background population, WG patients seem to experience an increased number of both early and late cardiovascular events due to IHD.

Long-Term Mortality and Renal Outcome in a Cohort of 100 Patients With Lupus Nephritis

To evaluate the long‐term mortality and renal outcome in a cohort of Danish patients with lupus nephritis (LN) and to identify outcome predictors among findings registered at the time of the first renal biopsy.

Defensin-rich granules of human neutrophils: characterization of secretory properties

The various granule subtypes of the human neutrophil differ in propensity for exocytosis. As a rule, granules formed at late stages of myelopoiesis have a higher secretory potential than granules formed in more immature myeloid cells. Neutrophils contain four closely related alpha-defensins, which are stored in a subset of azurophil granules. These defensin-rich azurophil granules (DRG) are formed later than defensin-poor azurophil granules, near the promyelocyte/myelocyte transition. In order to characterize the secretory properties of DRG, we developed a sensitive and accurate ELISA for detection of the neutrophil alpha-defensins HNP 1-3. This allowed us to quantify the exocytosis of alpha-defensins and markers of azurophil (myeloperoxidase), specific (lactoferrin) and gelatinase (gelatinase) granules from neutrophils stimulated with different secretagogues. The release pattern of alpha-defensins correlated perfectly with the release of myeloperoxidase and showed no resemblance to the exocytosis of lactoferrin or gelatinase. This finding was substantiated through subcellular fractionation experiments. In conclusion, despite a distinct profile of biosynthesis, DRG are indistinguishable from defensin-poor azurophil granules with respect to exocytosis. Thus, in contrast to peroxidase-negative granules, azurophil granules display homogeneity in their availability for extracellular release.

Brief Report: Long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody–associated vasculitis

OBJECTIVE The NORAM (Nonrenal Wegeners Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Duration of relapse-free survival was longer among CYC-treated patients than among MTX-treated patients during short-term followup. The aim of the present study was to describe the long-term outcome in patients enrolled in the randomized clinical trial. METHODS Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC-treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse-free survival, mortality, and occurrence of other clinical events. RESULTS The median duration of followup was 6 years (range 0.1-10.8 years). One patient developed end-stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse-free survival tended to be lower in the MTX group (P = 0.056). CONCLUSION In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long-term followup. However, first-line treatment with MTX was associated with less effective disease control than CYC-based induction therapy.

High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: A long-term followup study in a Danish cohort

OBJECTIVE Patients with systemic lupus erythematosus (SLE) seem to experience an increased prevalence of oncogenic virus infections. The aim of the present study was to investigate whether SLE patients have an increased risk of virus-associated malignancies, defined as malignancies potentially caused by virus infection. METHODS A hospital-based cohort of 576 SLE patients was linked to the Danish Cancer Registry. The cohort was followed up for malignancies from the date of SLE diagnosis, and standardized incidence ratios (SIRs) were calculated for various forms of cancer. RESULTS The median duration of followup was 13.2 years. Compared to the general population, the patients experienced an increased overall risk of cancer (SIR 1.6 [95% confidence interval (95% CI)] 1.2-2.0). We observed an increased risk of virus-associated cancers combined (SIR 2.9 [95% CI 2.0-4.1]). Among human papillomavirus (HPV)-associated malignant and premalignant conditions, high risk was found for anal cancer (SIR 26.9 [95% CI 8.7-83.4]), vaginal/vulvar cancer (SIR 9.1 [95% CI 2.3-36.5]), epithelial dysplasia/carcinoma in situ of the uterine cervix (SIR 1.8 [95% CI 1.2-2.7]), and nonmelanoma skin cancer (SIR 2.0 [95% CI 1.2-3.6]). Increased SIRs were also found for other potentially virus-induced cancer types (liver cancer SIR 9.9 [95% CI 2.5-39.8], bladder cancer SIR 3.6 [95% CI 1.4-9.7], and non-Hodgkins lymphoma SIR 5.0 [95% CI 1.9-13.3]). CONCLUSION The patients in this SLE cohort experienced an increased risk of HPV-associated tumors and other potentially virus-induced cancers during long-term followup. Our findings call for clinical alertness to oncogenic virus infections in SLE patients.

Prodefensins are matrix proteins of specific granules in human neutrophils

Defensins are potent antimicrobial and proinflammatory peptides. The human neutrophil defensins human neutrophil peptide (HNP)‐1–3 are synthesized as 94 amino acide (aa) preproHNPs, which are converted to 75 aa proHNPs by cotranslational removal of a 19 aa endoplasmic reticulum signal peptide. At the promyelocytic stage of myelopoiesis, proHNPs are further proteolytically modified and accumulate in azurophil granules as 29–30 aa HNPs. In contrast, proHNPs produced by more mature myeloid cells are not subjected to proteolytic cleavage and undergo a high degree of constitutive exocytosis. The proHNPs are devoid of antimicrobial potential, and the significance of their secretion is unknown. To investigate whether mature neutrophils contain proHNPs, we developed antibodies against proHNP‐1 by DNA immunization of rabbits. In addition, antibodies against the 45 aa proHNP pro‐piece were raised by conventional immunization procedures. These antibodies allowed detection of proHNPs in homogenates of peripheral blood neutrophils. The proHNPs were isolated by affinity chromatography, and their identity was confirmed by mass spectrometry and N‐terminal aa sequence analysis. Finally, the neutrophil proHNPs were identified as novel matrix proteins of specific granules by subcellular fractionation experiments, release studies, and immunoelectron microscopy. Thus, human neutrophils not only store large amounts of mature defensins in azurophil granules but also contain a more easily mobilized reservoir of unprocessed prodefensins in specific granules.

Long-Term Follow-Up of Cyclophosphamide Compared with Azathioprine for Initial Maintenance Therapy in ANCA-Associated Vasculitis.

BACKGROUND AND OBJECTIVES Treatment with azathioprine within 3 months of remission induction with cyclophosphamide is a common treatment strategy for patients with ANCA-associated vasculitis. This study comprised patients undergoing long-term follow-up who were randomly allocated to azathioprine after 3-6 months or after 12 months of cyclophosphamide treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients from 39 European centers between 1995 and 1997 with a new diagnosis of ANCA-associated vasculitis that involved the kidneys or another vital organ were eligible. At the time of diagnosis, participants were randomly allocated to convert to azathioprine after 3-6 months (the azathioprine group) or after 12 months of cyclophosphamide (the cyclophosphamide group). Patients who did not achieve a remission within 6 months were excluded. This study assessed relapses, ESRD, and death during long-term follow-up. RESULTS Patients were allocated to the azathioprine group (n=71) and the cyclophosphamide group (n=73). Of these patients, 63 (43.8%) developed a relapse, 35 (24.3%) developed a renal relapse, 13 (9.0%) developed ESRD, and 21 (14.6%) died. Although there were worse outcomes in the azathioprine group, none were statistically significant. The subdistribution hazard ratio [sHR] for relapse was 1.63 (95% confidence interval [95% CI], 0.99 to 2.71), the composite of relapse or death hazard ratio [HR] was 1.59 (95% CI, 1.00 to 2.54), the ESRD sHR was 1.71 (95% CI, 0.56 to 5.19), and the death HR was 0.75 (95% CI, 0.32 to 1.79). CONCLUSIONS It remains uncertain whether converting to azathioprine after 3-6 months of induction cyclophosphamide therapy is as effective as converting after 12 months. Outcomes are still poor for this group of patients and further research is required to determine the optimal timing of maintenance therapy.

Mortality in patients with giant cell arteritis

OBJECTIVE The aim of this study was to examine whether GCA is associated with increased mortality. METHODS We conducted a nationwide population-based cohort study including all individuals who between 1993 and 2011 were registered in the Danish National Hospital Register and the Danish Pathology Register with a biopsy-proven diagnosis of GCA (n = 1787). Through the Danish Civil Registration System we identified a comparison cohort of 33 953 persons from the background population, individually matched on age and sex. Data on causes of death were obtained from the Danish Registry of Causes of Death. We used Poisson regression to determine mortality rate ratios as estimates of relative risk of death and specific causes of death. RESULTS Compared with the general population, the relative risk (RR) of death in patients diagnosed with GCA was 1.17 (95% CI 1.01, 1.36) and 1.22 (95% CI 1.05, 1.41) 0-2 years and >10 years after diagnosis, respectively, whereas we observed no increased mortality during the follow-up period of 2-10 years [RR 0.96 (95% CI 0.88, 1.05)]. The increased mortality during the first 2 years of follow-up was mainly due to diseases of the circulatory system, including aortic aneurisms. CONCLUSION GCA is associated with slightly increased early and late mortality.

Anti-B cell antibody therapies for inflammatory rheumatic diseases.

Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjögrens syndrome. For some anti-B cell agents, clinical benefits have been convincingly demonstrated, while other B cell-targeted therapies failed to improve outcomes when added to standard-of-care treatment or were associated with increased rates of adverse events. Although the risk-benefit balance seems to be acceptable for currently licensed anti-B cell agents, additional studies are required to fully assess the safety of treatment regimens involving prolonged interference with B cell counts and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies.

High Risk of Pulmonary Embolism and Deep Venous Thrombosis but Not of Stroke in Granulomatosis With Polyangiitis (Wegener's)

To assess the incidence of stroke, pulmonary embolism (PE), and deep venous thrombosis (DVT) in granulomatosis with polyangiitis (Wegeners) (GPA).