Factors associated with major infections in patients with granulomatosis with polyangiitis and systemic lupus erythematosus treated for deep organ involvement

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Abstract

This study is an audit and a comparison of major infective complications in patients with granulomatosis with polyangiitis (GPA) and systemic lupus erythematosis (SLE). Data were collected on consecutive patients attending a single treatment approach, multidisciplinary vasculitis centre who met diagnostic criteria for GPA and SLE from 01/01/2006 to 30/06/2006. Immunosuppressive treatment is used in this clinic with guidelines targeting avoidance of neutropenia. For each patient, documentation was made of disease presentation, organ involvement and therapy used. A history of major infections requiring hospital admission and intravenous antimicrobials pre- and post-diagnosis was recorded. Patients with GPA received a higher cumulative dose of cyclophosphamide, had a higher median age, shorter period of follow-up and had lower mean and nadir absolute lymphocyte counts and nadir neutrophil counts. GPA patients had more major infections per patient years (P = 0.0027) and respiratory tract infections (P = 0.0031) per patient years. Relative risk (RR) of major infection was significantly increased with methylprednisolone, RR 11.1 (P = <0.0001), cyclophosphamide, RR 2.0 (P = 0.0246) and the intensive phase of treatment, RR 13.3 (P = <0.0001). Marked lymphopenia was common in both groups during follow-up and was associated with an increased risk of major infection (P = 0.0020). Major infections, in particular respiratory tract infections, are more common in those treated for GPA than SLE. This may be due to a combination of factors including greater doses and duration of methyprednisolone and cyclophosphamide. We recommend treatment strategies that aim not only to avoid neutropenia but that also identify lymphopenia as a risk factor for major infection.

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Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.

Frédéric A. Houssiau, Carlos Silva Vasconcelos, David D'Cruz … (2002)

Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.

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Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.

David Jayne, Gill Gaskin, Niels Rasmussen … (2007)

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

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Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.

MARVIN STEINBERG, J Klippel, Robert Austin … (1986)

We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.