Infection Risk Associated with Steroid-Sparing Therapies in GCA, PMR, and ANCA-Associated Vasculitis: A Systematic Review

Abstract

Objective

Giant cell arteritis (GCA), polymyalgia rheumatica (PMR), and ANCA-associated vasculitis (AAV) often require prolonged glucocorticoid therapy. Steroid-sparing biologic and small molecule therapies reduce glucocorticoid exposure, but may increase infection risk, particularly in older adults. We evaluated infection risk associated with these therapies with concomitant glucocorticoid treatment, versus glucocorticoid treatment alone, in vasculitis/PMR clinical trials.

Methods

We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov using terms related to GCA, PMR, AAV, biologics (tocilizumab, sarilumab), small molecule therapies (upadacitinib, avacopan), glucocorticoids, and infection outcomes. We included randomized controlled trials (RCTs) comparing biologics or small molecules plus glucocorticoid (active intervention) versus glucocorticoid monotherapy (comparator) reporting infection outcomes. We calculated the relative risk (RR) of infection and difference in glucocorticoid dose between the comparator and active intervention groups.

Results

We included 10 RCTs (1,487 patients total, enrolling adults averaged ≥50 years): 4 tocilizumab, 3 avacopan, 2 sarilumab, and 1 upadacitinib. When the active intervention had much lower glucocorticoid dosing than the comparator, the RR for infection was either close to 1 or <1. When the active intervention glucocorticoid dose was comparable to the comparator, the RR for infection was >1.

Conclusion

Steroid-sparing therapies reduced glucocorticoid exposure with varying magnitudes but were not consistently associated with lower infection risk. These findings underscore the heightened risk of infection when these novel therapies are used in combination with glucocorticoids when the glucocorticoid dose cannot be adequately tapered, particularly in older adults.

Introduction

Giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are systemic inflammatory diseases that frequently require long-term immunosuppressive therapy, including an often prolonged glucocorticoid course and taper [1–3]. GCA and PMR predominantly affect older adults, and while AAVs can affect any age, peak age of AAV onset is in the 60s-70s [4]. Older adults are inherently at higher baseline risk for infections due to immunosenescence, comorbidities such as diabetes, cardiovascular disease, chronic lung disease, and physiologic frailty [5]. This vulnerability translates into higher rates of hospitalization, complications, and infection-related mortality compared to younger populations [6]. Glucocorticoids remain the cornerstone of treatment for these conditions, but their prolonged use, particularly at higher doses, is associated with substantial morbidity, particularly an increased risk of bacterial, viral, and opportunistic infections as well as metabolic complications, and other adverse effects [7–9]. The glucocorticoid burden in these conditions is considerable. For GCA, initial therapy typically involves high-dose glucocorticoids (e.g., prednisone 40–60 mg/day or higher depending on ischemic complications). [10]. Tapering is gradual, aiming for ≤5 mg/day by 12 months, but many patients require treatment for 1–2 years or longer, and relapses are common. In PMR, initial glucocorticoid doses are lower, typically prednisone 12.5–25 mg/day, but many patients still require extended courses [10]. Approximately, one-fourth of patients with GCA and PMR require glucocorticoid therapy for three years or longer. [11]. Glucocorticoid burden in AAV is substantial, with high initial doses, typically prednisone 1 mg/kg/day, followed by a gradual taper over several months; cumulative exposure often exceeds several grams over the first year, and maintenance therapy may extend for 6–12 months or longer depending on disease activity and relapse risk [12,13].

To mitigate glucocorticoid-related toxicity, steroid-sparing strategies, including biologic agents (tocilizumab, sarilumab) and targeted small molecules (upadacitinib, avacopan) have gained increasing use, with the rationale that use of immunosuppressant agents will allow for more rapid taper of glucocorticoids. Randomized controlled trials (RCTs) have demonstrated that these agents can reduce relapse rates compared to glucocorticoid therapy alone and reduce cumulative glucocorticoid exposure [14–23]. While reducing glucocorticoid use may lower infection risk, biologics and small molecules themselves carry immunosuppressive effects that independently increase infection risk [24,25]. The risk associated with these steroid-sparing therapies, particularly in the context of concomitant glucocorticoid use, remains incompletely defined, especially in those who have tapered to low dose prednisone but are unable to discontinue entirely. To our knowledge, there is no direct comparative evidence that evaluates infection risk between steroid-sparing therapy used in combination with glucocorticoids versus glucocorticoid monotherapy in individuals with GCA, PMR, or AAV.

This systematic review aims to address this gap by evaluating the infection risk associated with steroid-sparing therapies, including biologics and small molecules, in the context of concomitant glucocorticoid use, compared with glucocorticoid monotherapy. The ultimate goal is to inform clinical decision-making regarding optimal immunosuppressive strategies that balance disease control with infection risk mitigation; this is especially important for older adults who are already at higher risk of infection.

Methods

This systematic review was registered with PROSPERO (CRD420251010910) and conducted in accordance with the PRISMA 2020 guidelines [26].

Selection criteria

We included RCTs published in English that addressed the following PICO question: in adult patients (≥18 years) with GCA, PMR, or AAV (population), does treatment with biologics such as tocilizumab, sarilumab or small molecule therapies such as upadacitinib, avacopan (intervention), in combination with glucocorticoids, compared to glucocorticoid monotherapy or placebo plus glucocorticoids (comparator), affect the risk of infection (outcome)?

Studies were included if they met the following criteria: (1) adult patients (≥18 years) with GCA, PMR, or AAV; (2) treatment intervention with biologics including tocilizumab, sarilumab or small molecules including upadacitinib, avacopan; (3) included a comparator group of glucocorticoid therapy alone or placebo with glucocorticoid; and (4) reported infection outcomes. We excluded the following: (1) non-RCT designs; (2) studies in pediatric populations; (3) studies that did not report infection outcomes; (4) studies that included patients with conditions other than GCA, PMR, or AAV; and (5) non-English language publications.

We restricted inclusion to RCTs to improve internal validity and limit bias in reported results related to confounding. Randomization reduces bias from baseline differences between treatment groups, allowing for a more accurate estimation of infection risk. We also limited inclusion to English language publications to ensure accurate data extraction and interpretation.

Data Sources and Search Strategy

We conducted a comprehensive search of multiple databases including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL, via the Cochrane Library) and ClinicalTrials.gov from database inception through April 2025. A medical librarian (David Flynn) developed a search strategy using MeSH terms and keywords related to vasculitis subtypes, biologic and small molecule therapies, glucocorticoids, and infections. Full search terms are included in Supplementary Data S1.

Outcomes

The primary outcome of this review was the frequency of any infection, defined as the proportion of patients with at least one reported infection in each treatment or study arm. We extracted the number of participants in each arm with infection outcomes, when reported. If only serious infections were reported (defined in studies as those requiring hospitalization or intravenous antibiotics), these were used as a proxy for overall infection events. In studies that reported only the number of infection events, we used infection events as a proxy for the number of participants with infection, acknowledging that this may overestimate infection frequency if multiple events occurred in the same individual.

Data Extraction

Two reviewers (DS, BL) independently screened titles and abstracts, reviewed full text articles, and extracted data from each included study using a standardized form. Any disagreements were resolved by consensus and, when needed, a third reviewer. Extracted data included study characteristics (design, population, vasculitis subtype), intervention and comparator descriptions, sample sizes, duration of follow-up, the frequency of infections in each study arm, the cumulative glucocorticoid dose in each group, infection outcomes. We assessed the risk of bias in included studies using the Cochrane Risk of Bias 2 (RoB 2) tool [27].

Data Synthesis/ Statistical Analysis

Because person-time data were not available, we calculated the crude risk ratio (RR) of infection within each trial, dividing the proportion of infections in the intervention arm by the proportion of infections in the comparator arm under the assumption that the follow-up duration was approximately the same across arms within each individual trial. Because glucocorticoid exposure between study arms and between studies differed, we calculated the difference in the mean cumulative glucocorticoid dose between the comparator and intervention arms within each study. For example, if the cumulative glucocorticoid dose was 43 mg/kg in the intervention arm and 110 mg/kg in the comparator arm, and assuming an average adult weight of 70 kg, this translates to 3,010 mg and 7,700 mg, respectively, yielding a difference of 4,690 mg (comparator – intervention). In the same trial, if the infection risk was 40% in the intervention group and 10% in the comparator group, then the resulting RR would be 4. We then plotted the RR of infection (intervention/comparator) against the difference in cumulative glucocorticoid exposure (comparator minus intervention) for each study to evaluate the extent to which differences in glucocorticoid dose exposure between study arms were related to risk of infection. This figure was constructed as a descriptive display. Only trials reporting both an infection outcome and the mean cumulative glucocorticoid dose in each arm were included. Relative risks are displayed on a logarithmic scale so that estimates above and below the null are weighed symmetrically. Because individual patient-level data were not available, estimates are unadjusted.

Due to clinical heterogeneity across trials in terms of study population, vasculitis subtype, intervention type, glucocorticoid tapering protocol, and infection outcome definitions, we did not perform a meta-analysis.

Results

A total of 1154 abstracts were identified through searches across all databases. After removing duplicates and screening titles and abstracts, 18 full-text articles were assessed for eligibility. Of these, 10 RCTs met the inclusion criteria and were included in the final analysis. The study selection process is detailed in the PRISMA flow diagram (Figure 1).

Figure 1.

PRISMA FLOW DIAGRAM OF STUDY INCLUSION AND EXCLUSION

The 10 included RCTs enrolled a total of 1,487 participants across three disease groups: GCA (n=4), PMR (n=3), and AAV (n=3). Four trials evaluated tocilizumab (all in GCA or PMR), two evaluated sarilumab (GCA and PMR), one evaluated upadacitinib (GCA), and three evaluated avacopan (AAV). All studies included adults with mean ages ≥50 years and follow-up durations ranging from 6 to 18 months. Table 1 summarizes the key characteristics of included trials. Most studies demonstrated low risk of bias across key domains including randomization, deviations from intended interventions, outcome measurement, and selective reporting. However, one included trial (Jayne et al., 2021) has since been retracted, and its results should be interpreted with caution, though reported infections are unlikely to have been impacted. All trials implemented steroid-sparing protocols. In most studies, the active intervention group had lower mean cumulative glucocorticoid doses than the comparator group receiving glucocorticoid monotherapy. However, this difference varied in magnitude across studies (see Table 1).

Table 1.

CHARACTERISTICS OF INCLUDED STUDIES, INCLUDING GLUCOCORTICOID EXPOSURE AND INFECTION OUTCOMES BY INTERVENTION VERSUS COMPARATOR

Disease	Trial	Year	Intervention/Comparator	Dose/Route	Sample Size	Mean age; % female	Cumulative GC dose	% infection	Trial Time
GCA	1	2016	Tocilizumab	8 mg/kg q 4 w IV	20	68; 56	43 mg/kg	40	52 weeks
			Placebo	Q 4 w	10	67; 58	110 mg/kg	10
	2	2017	Tocilizumab	162 mg q w SC	100	69.5; 78	1862 mg	75	52 weeks
			Tocilizumab	162 mg q 2 w SC	50	69.4; 70	1862 mg	73
			Placebo	Weekly	50	69.3; 76	3296 mg	76
			Placebo	Weekly	51	67.8; 73	3818 mg	65
	3 **	2023	Sarilumab	200 mg q 2 w SC	27	73.4; 65	1643.1 mg	7	52 weeks + 24 week follow up
			Sarilumab	150 mg q 2 w SC	14	67.1; 93	2177.1 mg	0
			Placebo	Q 2 w	28	71.4; 79	2577.3 mg	3.5
			Placebo	Q 2 w	14	69.5; 64	2270.7 mg	7
	4 **	2025	Upadacitinib	15 mg daily PO	209	70.8; 74.6	1615 mg	5.7	52 weeks
			Upadacitinib	7.5 mg daily PO	107	71; 74.8	1905 mg	5.6
			Placebo	Daily	112	71.6; 68.8	2882 mg	10.7
PMR	5	2022	Tocilizumab	8mg/kg q 4 w IV	49	68; 69.4	1380 mg	46.9	24 weeks
			Placebo	Q 4 w	51	67; 64.7	1591 mg	39.2
	6	2022	Tocilizumab	162 mg q w SC	19	68.8; 52.6	781 mg	63	24 weeks
			Placebo	Weekly	17	71; 52.9	1290 mg	35
	7 *	2023	Sarilumab	200 mg q 2 w SC	60	69; 75	777 mg	8.4	52 weeks
			Placebo	Q 2 w	58	70; 63.8	2044 mg	10.3
AAV	8 **	2017	Avacopan	30 mg BID PO	22	57; 36.3	NR	4.5	24 weeks
			Avacopan	30 mg BID PO	22	57.4; 27.3	NR	4.5
			Placebo/Pred	BID	23	59.1; 26	NR	4.3
	9	2020	Avacopan	10 mg BID PO	13	60; 38	NR	24	12 weeks
			Avacopan	30 mg BID PO	16	55.3;56	NR
			Placebo	BID	13	58.5; 69	NR	15
	10	2021	Avacopan	30 mg BID PO	166	61.2; 41	1675.5 mg	68.1	52 weeks
			Prednisone	Wt based PO taper	165	60.5; 46.3	3846.9 mg	75.6

^**These studies only reported serious infection

^*These studies only reported events of special interest

Q = everyday BID = twice daily NR = data not reported Wt = weight IV = intravenous %= percentage SC = subcutaneous

Number = Trial number from Table 1

There was heterogeneity across the included trials in infection outcome definitions, reporting methods, glucocorticoid tapering protocols, and study populations. This heterogeneity limits direct quantitative comparisons across studies and should be considered when interpreting the results below. Results are presented by disease group to preserve clinical context.

All included studies reported infection outcomes, though definitions and reporting of infections varied. The frequency of infections ranged widely across trials and treatment arms (Table 1). Some studies reported the number of participants with any infection, others reported only serious infections, and a few reported only the number of infection events, rather than the number of participants who experienced an infection (including if there were multiple events per participant).

Among GCA trials, infections, reported as ‘any infection’, occurred in 40% to 75% of participants receiving tocilizumab, compared to 10% and 76% in the comparator arms. In contrast, the sarilumab trial in GCA and the upadacitinib trial reported only serious infections: 0% and 7% in the sarilumab arms versus 3.5% and 7% in comparator; 5.7% and 5.6% in the upadacitinib arms versus 10.7% in comparator.

Similarly, in PMR trials, two tocilizumab trials reported any infection, ranging from 46.9% to 63% in intervention arms versus 35% to 39.2% in comparator. In contrast, the sarilumab trial in PMR reported infections in 8.4% of the intervention arm and 10.3% of the comparator arm. This trial reported adverse events of special interest without stating whether these were serious infections or any infection.

In AAV, the 2021 trial reported any infections in 68.1% of patients treated with avacopan versus 75.6% in the prednisone taper/comparator group. Smaller avacopan trials reported serious infection rates ranging from 4% to 24% in intervention arms and 4.3% to 15% in comparator groups.

The most commonly reported serious infections across trials included pneumonia, urinary tract infections, cellulitis, and sepsis. Opportunistic infections were variably reported; herpes zoster was the most frequently identified opportunistic infection, occurring in both intervention and comparator arms. However, not all trials systematically distinguished opportunistic from non-opportunistic infections, limiting the ability to draw definitive conclusions regarding the effect of steroid-sparing therapies on opportunistic infection risk specifically. Detailed trial characteristics and infection data for all included trials are provided in Supplementary Tables S1 and S2.

In trials where the comparator group received substantially higher cumulative glucocorticoid doses, the RR of infection in the intervention group was generally ≤1, suggesting a potential benefit of steroid-sparing approaches in reducing infection risk (Figure 2). In trials where the glucocorticoid doses were similar between arms, the RR for infection was generally >1 in the intervention group, suggesting that the addition of biologics or small molecules may contribute to increased infection risk in the absence of adequate glucocorticoid reduction. Two trials (AAV trials 8 and 9 from table 1) were excluded from Figure 2 because cumulative glucocorticoid dose data were not reported.

Figure 2.

INFECTION RISK RATIOS VERSUS DIFFERENCE IN MEAN CUMULATIVE GLUCOCORTICOID DOSING BETWEEN ACTIVE INTERVENTION AND COMPARATOR

Discussion

In this systematic literature review evaluating steroid-sparing therapies in GCA, PMR, and AAV, we found that the addition of biologic or small molecule therapies generally reduced cumulative glucocorticoid exposure compared with placebo or standard of care. However, this reduction did not consistently translate into a lower risk of infection, particularly evident when the difference in glucocorticoid exposure between the study arms was not large. This systematic review extends prior work by integrating recent data on biologic and small molecule therapies in GCA, PMR and AAV, and quantifying the infection risk in the context of glucocorticoid tapering in these three diseases that primarily affect older adults and often entail prolonged glucocorticoid use. Our analysis suggests that the infection risk associated with steroid-sparing agents is influenced by the extent of glucocorticoid tapering achieved and the relative difference in glucocorticoid exposure between study arms. The findings support a nuanced approach to immunosuppression in AAV, GCA, PMR - balancing disease control, glucocorticoid toxicity, and infection risk – related to both glucocorticoids as well as the steroid-sparing agent.

Prior studies have established that infection is a leading cause of morbidity and mortality in systemic vasculitides, particularly in the first year after diagnosis [8]. In AAV and GCA, higher glucocorticoid doses—especially prednisone >10 mg/day at one year—are associated with increased infection-related mortality [8,28]. Large observational studies and registry data indicate that a substantial proportion of patients with GCA and PMR remain on glucocorticoids for extended periods, often exceeding one to three years [29,30]. The introduction of biologic and small molecule agents has enabled more effective glucocorticoid tapering and improved disease control in GCA, PMR, and AAV [31]. Meta-analyses confirm that biologic agents significantly improve relapse-free survival and enable safer glucocorticoid tapering in large vessel vasculitis [32].

Despite these advances, infection risk remains a central concern. Biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) are associated with an increased risk of serious infections compared to conventional DMARDs, as shown in rheumatoid arthritis and other immune-mediated inflammatory diseases [24,25, 33]. The risk profile is further heightened in older patients, who experience higher rates of infection with biologic therapy [25]. Meta-analyses indicate that older users of biologic agents have increased risk of infection compared to younger users or older patients not receiving biologics [25,34]. This evidence is particularly relevant for GCA, PMR, and AAV, where prevalence of these diseases increases with age.

Our review found that trials in which the intervention group received significantly lower cumulative glucocorticoid doses tended to show a neutral or reduced infection risk in the intervention arm, suggesting a possible protective effect of glucocorticoid reduction. In contrast, in trials where glucocorticoid exposure was comparable between groups, the intervention arm often demonstrated a higher infection risk, likely due to the additive immunosuppressive effects of biologics/small molecules. This raises concerns about the safety of continued use of these agents when meaningful glucocorticoid tapering is not achieved or in patients maintained on low dose glucocorticoids (example, equivalent to prednisone 5 mg daily). Cohort studies in rheumatoid arthritis have demonstrated a dose-dependent increase in infection risk with glucocorticoid therapy, with statistically significant risk observed even at doses ≤5 mg/day prednisone [35]. In such cases, the incremental benefit of biologics or small molecules is uncertain, especially considering the elevated baseline infection risk in older adults with comorbidities. Clinicians should carefully weigh the possibility of excess infection risk when considering the addition or continuation of these therapies in patients with low glucocorticoid exposure.

It is important to note that AAV patients differ from those with GCA and PMR in their degree of background immunosuppression. AAV induction regimens typically include rituximab or cyclophosphamide, which may independently increase infection risk. This additional immunosuppressive burden limits direct comparability of infection risk across disease groups, and findings related to AAV should be interpreted in this context. However, evidence from studies outside our inclusion criteria provides additional perspective. In the PEXIVAS trial, which did not include small molecule intervention, both arms received the same background immunosuppression, and the only difference was a reduced-dose versus standard-dose glucocorticoid regimen; the reduced-dose regimen was associated with fewer serious infections [36]. This suggests that glucocorticoid dose reduction contributes to lowering infection risk and is consistent with the pattern observed in our review, that the magnitude of glucocorticoid reduction between study arms appears to be an important determinant of infection risk.

Within the studies included, relative risk of infection appeared higher in trials evaluating tocilizumab, specifically in the Villiger, et al. trial of intravenous tocilizumab in GCA. However, this trial enrolled only 30 patients (20 intervention, 10 comparator) thus the RR should be interpreted with caution. Notably, no direct comparative trial data are available to determine relative infection risk between tocilizumab and other steroid-sparing agents. Moreover, there is a paucity of mechanistic data to suggest that interleukin-6 receptor blockade confers a higher intrinsic infection risk compared with other biologic or targeted synthetic therapies. Observational studies in rheumatoid arthritis populations have reported higher rates of serious bacterial infections, skin and soft tissue infections, and diverticulitis among tocilizumab initiators compared with tumor necrosis factor inhibitor initiators [37,38], however, these findings are from a different disease population and cannot be directly extrapolated to GCA, PMR. Although route of administration has been considered as a contributing factor, available data suggests comparable safety between subcutaneous and intravenous dosing. In the SUMMACTA trial, subcutaneous tocilizumab demonstrated similar efficacy and safety to intravenous administration through week 97, with no meaningful differences in serious infection rates [39].

The cumulative glucocorticoid exposures observed in our analysis warrant careful consideration. Using the example described in our methods, the calculated doses of 3,010 mg in the intervention arm versus 7,700 mg in the comparator arm over 52 weeks represent average daily exposures of approximately 8mg/day and 21 mg/day prednisone equivalent, respectively. Importantly, despite being described as ‘steroid-sparing’, the intervention arm maintained patients on an average of 8 mg/day prednisone equivalent for the entire year-long study period. These findings highlight that even interventions intended to reduce glucocorticoid use can result in substantial cumulative exposure, emphasizing the need to develop strategies that further minimize steroid burden while maintaining disease control.

Our review has several limitations. First, heterogeneity across studies in terms of populations, interventions, infection definitions, and reporting precluded performing a meta-analysis. Although 10 trials met inclusion criteria, these spanned three disease populations, four interventions, and non-uniform infection outcome definitions, such that any clinically meaningful subgroup would have included only 2–4 trials, below the threshold at which pooled estimates are considered reliable, and at which random-effects models tend to yield unreliably narrow confidence intervals [40]. We therefore took a descriptive approach intended to characterize the pattern of infection risk in relation to glucocorticoid exposure, rather than generate a pooled estimate that could be more misleading than informative [41]. The lack of person-time data also precluded computation of infection rates. Our calculations of RRs may be thus be biased since we could not account for incomplete follow-up for all participants. In addition, these trials were not designed specifically to detect infections, and infection outcomes were variably defined and reported, where some trials reported the number of participants with any infection, others reported only serious infections, and a few reported only the total number of infection events rather than the number of affected participants. For example, most tocilizumab trials in GCA reported occurrence of any infection as a safety outcome, whereas sarilumab trials in PMR reported only serious infections. This inconsistency limits the ability to make direct quantitative comparisons across treatments. Third, data were limited on infection risk stratified by glucocorticoid dosing. Individual patient-level data were not available, precluding identification of a specific glucocorticoid dose threshold below which the addition of a biologic or small molecule clearly shifts the risk-benefit ratio in favor of safety. Similarly, the lack of individual patient-level data precluded temporal stratification of infections, limiting the ability to attribute infections to a specific treatment phase or to distinguish the relative contributions of glucocorticoids versus the biologic or small molecule agent over time. Relatedly, Figure 2 is descriptive and hypothesis-generating; individual patient-level data were not available, and the figure does not adjust for potential confounders such as age, comorbidities, disease severity. Findings should be interpreted with caution given the small number of trials and differences in infection outcome definitions. Finally, the number of eligible RCTs was small and RCTs are inherently limited for safety assessment due to limited follow-up and being powered for efficacy rather than safety endpoints. At the time of revision of this manuscript, the ADVOCATE trial (Jayne et al., 2021), one of the three included AAV trials, was retracted by the New England Journal of Medicine (June 2026) at the request of the two academic authors after an FDA investigation revealed that primary end-point assessments in nine patients were readjudicated after database lock and trial unblinding without disclosure. Findings related to infections from this trial are unlikely to be impacted; nonetheless, AAV should therefore be interpreted with caution.

Despite these limitations, this review has important strengths. By restricting inclusion to randomized controlled trials, we minimized confounding and enhanced internal validity when assessing infection risk. Our analysis uniquely examined infection risk in relation to differences in cumulative glucocorticoid exposure between study arms, providing a clinically relevant framework that extends beyond simple treatment comparisons.

Overall, findings from our study carry practical implications. First, the infection risk benefit of steroid-sparing agents cannot be assumed, and it depends on achieving glucocorticoid dose reduction. In patients whose glucocorticoid doses cannot be adequately tapered, particularly older adults with comorbidities, the priority should be on achieving further glucocorticoid reduction rather than solely relying on the steroid-sparing agent to mitigate infection risk. In such cases, the overall immunosuppressive burden, including both the steroid-sparing agent and glucocorticoid components, should be reassessed. Second, even in the steroid-sparing arms of these trials, cumulative glucocorticoid exposure remained substantial, underscoring the need for strategies that more effectively minimize glucocorticoid burden. The current data do not support identification of a specific glucocorticoid dose threshold below which the addition of a biologic clearly shifts the risk-benefit ratio; individual patient data and larger studies are needed to define such thresholds.

Conclusion

While biologics and small molecule therapies offer a glucocorticoid-sparing benefit in management of GCA, PMR, and AAV—three diseases that predominantly affect older adults—their impact on infection risk is variable and appears tied to the extent of glucocorticoid dose reduction achieved. Given the vulnerability of the predominantly older patient population affected by GCA, PMR, and AAV, there remains a critical need for therapies that are more effectively steroid sparing, as well as strategies that can be individualized to reduce infection risk and other long-term complications of glucocorticoid therapy. To better guide clinical decision making that balances disease control with infection risk, future trials should incorporate detailed glucocorticoid exposure data and longer-term follow-up in diverse patient populations, particularly older adults and those with multiple comorbidities. Such studies will be essential to optimize immunosuppressive strategies that minimize infection risk without compromising efficacy.

Highlights.

• Steroid-sparing therapies reduced cumulative glucocorticoid exposure in GCA, PMR, and AAV trials.

• Lower infection risk was observed only when substantial glucocorticoid dose reduction was achieved.

• When glucocorticoid doses were similar, adding biologics or small molecules increased infection risk.