How Do Reduced-Dose Glucocorticoids Plus Rituximab Affect ANCA-Associated Vasculitis?

Rheumatologists typically treat patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis with an induction dose of glucocorticoids (i.e., 1 mg/kg daily of prednisone) and rituximab.

However, a recent clinical trial evaluated the benefits of reduced glucocorticoid dosing during remission induction for patients with ANCA-associated vasculitis. Shunsuke Furuta, MD, PhD, of Chiba University Hospital, Japan, and colleagues examined patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage to determine if induction of disease remission could be achieved at six months with a reduced dose (0.5 mg/kg/day) of prednisolone. They found a regimen of reduced-dose glucocorticoids plus rituximab was noninferior to a regimen of high-dose (1 mg/kg/day) glucocorticoids plus rituximab and published the results on June 1 in JAMA.¹

Other studies have also assessed whether patients with ANCA-associated vasculitis can be effectively treated with lower glucocorticoid doses than are commonly used. Examples:

1. The ADVOCATE clinical trial evaluated the efficacy of avocapan, a C5a receptor inhibitor, for its ability to induce remission as defined by a Birmingham Vasculitis Activity Score of 0 and no receipt of glucocorticoids for four weeks before week 26, and sustained remission, defined as remission at week 26 and at week 52 and no receipt of glucocorticoids for four weeks before week 52. That trial found avocapan was noninferior at week 26 to high-dose prednisone (cyclophosphamide given intravenously at a dose of 15 mg per kilogram of body weight up to 1.2 g on day 1 and at weeks 2, 4, 7, 10 and 13 or cyclophosphamide orally at a dose of 2 mg per kilogram up to 200 mg per day for 14 weeks) in inducing remission and superior to high-dose prednisone at week 52 in sustaining remission.²
2. RITAZAREM evaluated patients with relapsing ANCA-associated vasculitis and found that, when combined with rituximab, a reduced-dose prednisone regimen, with a starting dose of 0.5/mg/kg/day, had a similar remission rate as a high-dose regimen of 1 mg/kg/day;³ and
3. The PEXIVAS clinical trial evaluated whether patients with the most severe ANCA-associated vasculitis had better outcomes with reduced dose or standard glucocorticoid tapering. All patients received oral prednisone or prednisolone at the same dose for the first week. At the start of the second week, the dose in the reduced-dose group was reduced by approximately 50%. The dose in the standard-dose group was tapered more gradually, starting in week 3. At six months, the cumulative dose of oral glucocorticoids in the reduced-dose group was less than 60% of that in the standard-dose group. The study revealed that reduced dose tapering was noninferior to standard tapering with respect to death or end-stage kidney disease.⁴

New Data Reinforce Message

“Generally speaking, when we, as physicians, deal with a serious life-threatening disease or condition, such as vasculitis, to save our patients lives—and based on our medical training—we usually believe a more aggressive approach or treatment, including using a higher dose of steroids, is the better option for our patients and will give them a higher chance for favorable outcomes,” says Mehrnaz Hojjati, MD, medical director of the Vasculitis Clinic at Loma Linda University Health, California.

The new study does not support this approach. Dr. Hojjati was not affiliated with the new study by Furuta et al., but she is familiar with the urge to prescribe higher dosages of steroids. This impulse can occur even when physicians know higher dosages don’t necessarily lead to better outcomes. This lingering inclination is one of the reasons researchers continue to document the noninferiority of lower doses of steroids.

Study Details

Furuta et al. conducted this randomized, clinical trial in multiple centers in Japan between November 2014 and June 2019. The investigators designed the study to be open label in acknowledgement of the difficulty in blinding physicians to the effects of high-dose glucocorticoids on patients’ appearances and blood tests.

The study enrolled only newly diagnosed patients without comorbidities who required glucocorticoids. The researchers randomized the 140 patients (57.8% women) to receive reduced-dose prednisolone (0.5 mg/kg per day) plus rituximab (375 mg/m² per week, four doses) or high-dose prednisolone (1 mg/kg per day) plus rituximab (375 mg/m² per week).

The study did have some prescribing flexibility. It allowed physicians to postpone the initiation of the prednisolone discontinuation step in the reduced-dose group if the predefined conditions were met and an investigator suspected persistent low disease activity. These predefined conditions include a Birmingham Vasculitis Activity Score (version 3) that did not reach 0 or C-reactive protein (CRP) and ANCA values that were not normalized. Even with this flexibility, at the end of the study, the median cumulative dose of prednisolone over the six-month period was 1,318 mg in the low-dose group and 4,151.25 mg in the high-dose group.

At six months, approximately 70% of patients in each group achieved remission. When the researchers performed adjusted analyses that accounted for ANCA subtype, age and kidney function, they also found no differences between the treatment groups. A post hoc analysis also revealed no differences in the Vasculitis Damage Index scores between the two groups at six months.

The researchers used the Medical Outcomes Study 36-Item Short Form to measure quality of life at six months and saw no differences between the groups in either the physical or mental component summary scores. At six months, the Birmingham Vasculitis Activity Scores also did not significantly differ between the two groups, and the investigators saw no differences in median serum CRP levels or estimated glomerular filtration rate (eGFR) levels between the two groups.

In addition to the conventional end points, the researchers also used patient Visual Analog Scales (VAS) to assess patient-reported outcomes. At six months, they saw no difference in patient VAS scores for disease activity, but they did see a difference in treatment toxicity, with patients in the reduced-dose group reporting significantly less treatment toxicity than patients in the high-dose prednisolone group.

Decreased Side Effects

The reduced-dose prednisolone group had significantly fewer objective serious adverse events, including serious infections and predefined glucocorticoid-related adverse effects, such as diabetes, insomnia and all infections, than the high-dose prednisolone group.

The investigators documented two deaths in the reduced-dose group and three deaths in the high-dose group, a difference that was not statistically different. Two patients in the study developed cancer—one developed colon cancer in the reduced-dose group and one developed lung cancer in the high-dose group. The investigators documented 21 serious adverse events in 13 patients in the reduced-dose group and 41 serious adverse events in 24 patients in the high-dose group. Seven serious infections occurred in five patients in the reduced-dose group and 20 serious infections occurred in 13 patients in the high-dose group.

With regard to opportunistic infections, the investigators documented only two cases of Pneumocystis pneumonia in the lose-dose group. In contrast, the high-dose group had one case of varicella, one case of miliary tuberculosis and two cases of invasive aspergillosis.

“The results are mostly consistent with the results of the PEXIVAS trial,” says Dr. Hojjati, “except in this trial patients were not as sick as in the PEXIVAS trial, and patients with severe glomerulonephritis or alveolar hemorrhage were excluded from this trial.”

These most recent data, in combination with the previous research, collectively indicate that, for most patients with ANCA-associated vasculitis, the total dose of glucocorticoids during the remission-induction phase could be reduced when glucocorticoids are combined with appropriate, potent treatment, such as rituximab.

“Rheumatologists can achieve similar results using only half the standard dose of steroids currently being used for remission induction in patients with ANCA-associated vasculitis [without severe glomerulonephritis or alveolar hemorrhage] and experience lesser side effects in their patients,” says Dr. Hojjati.

References

1. Furuta S, Nakagomi D, Kobayashi Y, et al. Effect of reduced-dose vs high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: A randomized clinical trial. JAMA. 2021. 325(21):2178–2187.
2. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl JMed. 2021. 384(7):599–609.
3. Smith RM, Jones RB, Specks U, et al. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis. 2020;79(9):1243–1249.
4. Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382(7):622–631.