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Severe infections occurred in 25% of patients with anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV) who were treated with rituximab, according to results of an observational study conducted in the United Kingdom (U.K.) and Austria. Trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis, however, reduced the risk of severe infections, the investigators reported in Annals of the Rheumatic Diseases.1
Andreas Kronbichler, MD, PhD, at the Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge, U.K., says the risk of severe infections with rituximab therapy “is sevenfold higher than in rheumatoid arthritis in patients with ANCA-associated vasculitis. Antibiotic prophylaxis with TMP/SMX helps reduce the risk by 70%, at least in our investigation.”
Patients with preexisting or ongoing lung damage or involvement are at “particular risk to develop severe infections,” Dr. Kronbichler says.
The aim of the study was to assess the frequency of severe, life-threatening infection and identify the risk factors for development of severe infection, classified as [Common Terminology Criteria for Adverse Events] CTCAE grade ≥3, in patients with AAV who received rituximab. One hundred ninety-two patients with AAV who had been referred for rituximab to two tertiary care specialist centers in Cambridge and Innsbruck, Austria, between 2004 and 2014 were included in the study. Among the 192 patients, 134 were diagnosed with granulomatosis with polyangiitis (GPA), 28 with microscopic polyangiitis (MPA), and 30 with eosinophilic granulomatosis with polyangiitis (EGPA).
“The risk of severe infections was higher than I expected before starting collection of data,” Dr. Kronbichler says.
Follow-up, which began when rituximab therapy was initiated, ended two years later or when a patient died or was lost to follow-up. Mean follow-up was 22.67 months. The researchers found that respiratory tract infections were the leading cause of severe infections. Additionally, they found an association of endobronchial involvement, bronchiectasis and rituximab use for major relapses with severe respiratory tract infections.
Risk Factors for Severe Infection
Forty-nine patients experienced a total of 95 severe infections, according to the study, an event rate of 26.06 per 100 person-years. Although respiratory tract infections (n=63) were the most common infectious complications among this population, other types included urinary tract (n=12), gastrointestinal tract (n=8), mastoiditis/otitis externa (n=4), skin (n=3), sepsis/septicaemia with unidentified site of infection (n=1) and others.
Twenty-five percent of observed infections occurred in the first four months of follow-up, 50% after 12 months and 80% after 18 months.
For those cases with a positive microbial result, opportunistic pathogens identified included Pseudomonas aeruginosa (n=4), Staphylococcus aureas including methicillin-resistant strains (n=4), Escherichia coli (n=3), Clostridium difficile (n=2), Pneumocystis jirovecii (n=1), Legionella pneumophila (n=1) and invasive aspergillosis (n=1). Campylobacter jejuni gastroenteritis was observed in one case.
The investigators also analyzed the specific risk factors associated with development of severe infectious complications among patients with AAV who received rituximab. Baseline predictors of severe infections included higher erythrocyte sedimentation rate (ESR), white blood cell count, higher steroid doses and an IgG decline ≥30%. Concomitant comorbidities, including chronic obstructive pulmonary disease, diabetes and reduced left ventricular ejection fraction/previous myocardial infarction, were identified as risk factors.
The research found that older age, endobronchial involvement, chronic obstructive pulmonary disease and treatment with alemtuzumab before rituximab were independent risk factors for the development of severe infections following rituximab therapy.
Antibiotic prophylaxis with TMP/SMX at different dosages was used in 73 of 192 patients. Its use was associated with reduced risk of infections, according to the investigators. A multivariate logistic regression analysis showed that its use as a prophylactic antibiotic measure had a positive impact on reducing severe infections. Its use significantly reduced time to first significant infection, according to the published data.
In this study, most patients received a 480 mg dose of TMP/SMX on alternate days; other doses included 960 mg on alternate days and 960 mg twice daily. The prophylaxis was stopped in five patients due to hematopoietic complications in three patients, sore mouth in one patient and abnormal liver function test in the remainder, the researchers reported. In general, its use was maintained for 14.67 months.
Dr. Kronbichler says that in his practice patients receive TMP/SMX “until steroids are stopped. TMP/SMX will be discussed with each patient and those who are keen to stop medication are stopping antibiotic prophylaxis, but I recommend staying on TMP/SMX thrice weekly.”
Antibiotic prophylaxis with TMP/SMX was used in 73 of 192 patients. Its use was associated with reduced risk of infections, according to the investigators.
Current Recommendations
European recommendations (European League Against Rheumatism/European Renal Association–European Dialysis and Transplant Association [EULAR/ERA-EDTA]) encourage the use of P. jirovecci prophylaxis to manage patients with AAV who are receiving cyclophosphamide. No firm recommendations exist concerning its use in patients receiving rituximab, although the updated European Medicines Agency label does recommend prophylaxis during and following rituximab, as appropriate, according to Dr. Kronbichler and colleagues’ report. Dr. Kronbichler anticipates changes will be made in a future update of the EULAR/ERA-EDTA recommendations.
The investigators noted uncertainty exists regarding whether patients with AAV who receive rituximab benefit from P. jirovecii prophylaxis, because “little is known about infections in patients with AAV treated with rituximab.” Two studies published in 2010, the RAVE and RITUXVAS trials, found rituximab to be noninferior to cyclophosphamide as first-line treatment for AAV.2,3 Both trials found similar rates of serious side effects between treatment groups. The RITUXVAS trial reported an 18% rate of severe infections in both arms of the trial, but the number of patients presenting with non-severe infections was 18% in the rituximab group vs. 9% in the cyclophosphamide group.
Dr. Kronbichler and colleagues say their study confirms “a protective effect of prophylactic trimethoprim-sulfamethoxazole use on the risk to develop severe infections. Thus it may be appropriate to conclude that trimethoprim-sulfamethoxazole may reduce P. jirovecii pneumonia and also reduces overall infective risk and prophylaxis should be initiated when patients with AAV receive rituximab. … While these results require confirmation, they support routine use of trimethoprim-sulfamethoxazole in rituximab-treated patients,” they say.
Dr. Kronbichler notes an overall reduction of severe infections of 70% was seen among those who received trimethoprim-sulfamethoxazole compared with those who did not receive prophylaxis in the study. “In general, antibiotic prophylaxis is not capable of reducing infections to zero, as we have learned in the cyclophosphamide era, because infectious complications—including severe cases—have been reported frequently.”
Additional research is underway to understand the occurrence of infections in patients with AAV who are treated with rituximab. Dr. Kronbichler explains, “We will learn about the influence of steroids from the ADVOCATE study, which is comparing Avacopan without steroids against steroids, alongside rituximab or cyclophosphamide. Specific associations, especially lung involvement, may influence infectious risk. There is clearly a need to have more reports on this issue, and international collaborations to highlight the importance of lung involvement are on their way.”
Kathy Holliman, MEd, has been a medical writer and editor since 1997.
References
- Kronbichler A, Kerschbaum J, Gopaluni S, et al. Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2018 Jun 27. pii: annrheumdis-2017-212861.
- Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221–232.
- Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211–220.
