Annelies E. Berden

Histopathologic Classification of ANCA-Associated Glomerulonephritis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is the most common cause of rapidly progressive glomerulonephritis worldwide, and the renal biopsy is the gold standard for establishing the diagnosis. Although the prognostic value of the renal biopsy in ANCA-associated glomerulonephritis is widely recognized, there is no consensus regarding its pathologic classification. We present here such a pathologic classification developed by an international working group of renal pathologists. Our classification proposes four general categories of lesions: Focal, crescentic, mixed, and sclerotic. To determine whether these lesions have predictive value for renal outcome, we performed a validation study on 100 biopsies from patients with clinically and histologically confirmed ANCA-associated glomerulonephritis. Two independent pathologists, blinded to patient data, scored all biopsies according to a standardized protocol. Results show that the proposed classification system is of prognostic value for 1- and 5-year renal outcomes. We believe this pathologic classification will aid in the prognostication of patients at the time of diagnosis and facilitate uniform reporting between centers. This classification at some point might also provide means to guide therapy.

Long-term patient survival in ANCA-associated vasculitis

Background Wegeners granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of patients with ANCA associated vasculitis treated with current regimens is uncertain. Objective To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease. Methods Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models. Results The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate <15 ml/min, advancing age, higher Birmingham Vasculitis Activity Score, lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival. Conclusion Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.

Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis

OBJECTIVE To determine the association between characteristics at diagnosis and the time to first relapse in a large cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS We studied long-term followup data from 4 clinical trials that included newly diagnosed patients with a broad spectrum of AAV severity and manifestations. Patient and disease characteristics at baseline were used in competing risk regression models with relapse as the event of interest and death as the competing event. RESULTS We assessed 535 patients with 1,804 patient-years at risk of relapse. At diagnosis, the median age was 60.7 years (interquartile range [IQR] 48.8-69.1 years), 284 patients (53%) had granulomatosis with polyangiitis (Wegeners), and the median creatinine level was 203 μmoles/liter (IQR 97-498). A total of 201 patients (38%) experienced a relapse and 133 patients (25%) died, 96 of whom had not had prior relapse. Anti-proteinase 3 antibodies (subhazard ratio [sHR] 1.62 [95% confidence interval 1.39-1.89]) and cardiovascular involvement (sHR 1.59 [95% confidence interval 1.07-2.37]) were independently associated with a higher risk of relapse. Compared with patients with a creatinine level ≤100 μmoles/liter, patients with higher creatinine levels had a lower risk of relapse (sHR 0.81 [95% confidence interval 0.77-0.85] for a creatinine level of 101-200 μmoles/liter; sHR 0.39 [95% confidence interval 0.22-0.69] for a creatinine level >200 μmoles/liter). CONCLUSION Relapse of disease is common for patients with AAV. A creatinine level >200 μmoles/liter at the time of diagnosis is strongly associated with a reduced risk of relapse and may help guide monitoring and treatment of patients with AAV.

Tubular Lesions Predict Renal Outcome in Antineutrophil Cytoplasmic Antibody–Associated Glomerulonephritis after Rituximab Therapy

Histopathological features in renal biopsies of patients with antineutrophil cytoplasmic antibody-associated vasculitis have predictive value for renal outcome in patients who receive standard treatment with cyclophosphamide and corticosteroids; however, whether the same holds true for rituximab-treated patients is unknown. We describe associations between renal histopathology and outcomes among patients treated with a rituximab-based regimen in the Randomized Trial of Rituximab versus Cyclophosphamide in ANCA-Associated Vasculitis trial. Two pathologists, blinded to clinical data, reviewed biopsies from 30 patients according to a standardized protocol that included assessment of T cell, B cell, and plasma cell infiltration, as well as scoring for tubulitis, interstitial inflammation, and glomerulitis. We did not observe associations between immunohistology scores and age, sex, estimated GFR at entry, or requirement for dialysis. However, tubulointerstitial inflammation was more severe among patients who had a positive test for the myeloperoxidase antineutrophil cytoplasmic antibody. In a multiple linear regression model, both CD3(+) T cell tubulitis and tubular atrophy independently associated with estimated GFR at 12 months. Tubular atrophy remained an independent predictor at 24 months (P<0.01). These results suggest that in addition to anti-B cell therapy, therapy directed at T cells may improve renal outcomes in antineutrophil cytoplasmic antibody-associated vasculitis.

Diagnosis and management of ANCA associated vasculitis.

#### Summary points Vasculitides associated with antineutrophil cytoplasmic antibodies (ANCAs) are systemic autoimmune diseases of unknown cause that affect small to medium sized blood vessels. They include granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). This review mainly focuses on granulomatosis with polyangiitis and microscopic polyangiitis. Although they are relatively rare, they must be diagnosed and treated early because untreated disease may rapidly develop into multiple organ failure and death. With modern treatment, these diseases are no longer fatal but chronic. Early diagnosis and treatment may prevent progression to end organ damage and lengthen healthier life. A recent large survey of patients with ANCA associated vasculitis found a lag of three to 12 months between disease onset and diagnosis, suggesting that diagnostic delay is a problem.1 We review the diagnosis and management of ANCA associated vasculitides for the generalist reader, drawing on the findings of observational studies, randomised controlled trials, and meta-analyses. #### Sources and selection criteria We searched PubMed (original search performed in August 2011, updated in December 2011) for relevant articles on epidemiology, diagnosis, and management of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis. Where possible, we sought data from …

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.

Renal function and ear, nose, throat involvement in anti-neutrophil cytoplasmic antibody-associated vasculitis: prospective data from the European Vasculitis Society clinical trials

OBJECTIVE We investigated whether ENT involvement is associated with renal biopsy findings and renal function in patients with ANCA-associated vasculitis (AAV). METHODS Newly diagnosed AAV patients derived from three international, multicentre trials were included. To investigate an association between ENT involvement and estimated glomerular filtration rate (eGFR) at diagnosis and 5-year follow-up, we performed multivariable regression analyses including clinical and histopathological parameters. To investigate whether our findings are specific to ENT involvement, we performed comparable analyses between eGFR and other early disease manifestations (arthralgia/arthritis, cutaneous and lung involvement). RESULTS One hundred and eighty-five of the 414 patients had ENT involvement. The mean presenting eGFR of patients with and without ENT involvement was 39.16 and 23.88 ml/min/1.73 m(2), respectively (P < 0.001). Mean eGFR increased by 6.76 ml/min/1.73 m(2) with each added ENT symptom (P = 0.007). Patients with ENT involvement had less interstitial fibrosis and tubular atrophy and a prognostically more favourable histopathological class on renal biopsy examination. Multivariable regression analyses correcting for clinical and histopathological parameters showed that ENT involvement is associated with both baseline and 5-year follow-up eGFR. There were no associations between baseline and 5-year follow-up eGFR and arthralgia/arthritis, cutaneous or lung involvement, suggesting that our findings are specific to ENT involvement. CONCLUSION The presence of ENT involvement in AAV patients is associated with prognostically favourable renal biopsy findings and better renal function. These results indicate that there may be different phenotypes of AAV defined by ENT involvement.

Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Diagnosed Between 1991 and 2013

To investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients.

Repeat protocol renal biopsy in ANCA-associated renal vasculitis

BACKGROUND Histopathological lesions in renal biopsy (RB) at presentation of ANCA-associated vasculitis (AAV) have been described in depth but repeat protocolized renal biopsies are seldomly performed in AAV. In this study, we present a group of AAV patients with repeat protocolized biopsies, and we evaluate their clinical significance. METHODS A total of 17 consecutive patients diagnosed between 1991 and 1995 with AAV and renal involvement confirmed by biopsy at presentation in a single center underwent a protocol planned rebiopsy in remission after a median of 13 months (range 11-28) from diagnosis. Biopsies were assessed by two independent pathologists, blinded to patient data. Clinical data were collected retrospectively. RESULTS Patients were followed-up for a median of 189 months from diagnosis. Renal relapse was observed in eight patients (47.1%), seven patients died, three patients reached end-stage renal failure. There was a significant decrease in the percentage of acute lesions (cellular crescents, fibrinoid necrosis, P < 0.001) and a significant increase in chronic lesions (glomerulosclerosis, interstitial fibrosis, P ≤ 0.01) in the repeat RB compared with the first RB. This resulted in a class change over the biopsies within most patients. The percentage of normal glomeruli in the first biopsy positively correlated with estimated GFR at the end of follow-up (rs = 0.509, P = 0.05). CONCLUSIONS This is the first study on protocolized repeat biopsies in AAV, giving insight into disease activity under immunosuppressive treatment. Apparently, many AAV patients have grumbling disease with ongoing activity, eventually leading to an increased amount of chronic lesions.

Incidence of malignancies in patients diagnosed with ANCA‐associated vasculitis between 1991 and 2013

To investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients.