For decades, steroids have been considered a necessary evil to control ANCA-associated vasculitis. Yet today, more patients die from complications associated with glucocorticoid treatment than from the underlying disease. An insightful new review in The Lancet paints the most comprehensive picture to date of evolving diagnostic and therapeutic strategies for this rare but devastating autoimmune disorder. Charting developments over nearly four decades, the findings highlight why reduction of steroid-toxicity must remain a high priority in development of new treatment strategies.
 

Looking back to move forward

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic, severe and progressive autoimmune inflammatory condition that has devastating consequences for patients. With a complex pathophysiology that is not completely understood, this rare but potentially lethal disease can affect almost any organ, mimic a variety of other conditions, and follow a variable course of progression—all of which make it difficult to diagnose and control.
 
In the 21st century, we’ve seen substantial progress in the management of ANCA-associated vasculitis, with a concerted shift away from cytotoxic therapies in favor of more targeted drugs and biologics like rituximab. In 2021, the US Food and Drug Administration approved the C5a receptor inhibitor avacopan—the first new-drug approval in a decade for this disease.^[1] Despite encouraging developments like these, the mortality rate for patients with ANCA-associated vasculitis is 2-3 times higher than for the general population, and patients often suffer as much from the toxic side-effects of standard treatments as from the underlying disease. 
 
In particular, cumulative doses of glucocorticoids, which have been integral to treatment regimens since the 1950s, are associated with a wide range of adverse side-effects that cause undue suffering and contribute to elevated mortality rates.

“More patients with ANCA-associated vasculitis die from steroid-toxicity associated infection than they do from their underlying disease.”
--John Stone, MD MPH

Where do we go from here? To gain perspective, a new review published in The Lancet follows developments in the diagnosis and treatment of ANCA-associated vasculitis since 1985, when ANCA were first described in granulomatosis with polyangiitis, one of the two main types of ANCA-associated vasculitis.^[2]

Steroid-toxicity: acknowledging the elephant in the room

Glucocorticoids were the first drugs found to have any measure of efficacy in the treatment of what we now know to be ANCA-associated vasculitis.^[3,4] However, the condition was nearly always fatal before the 1970s, when high-dose glucocorticoids were combined with the cytotoxic alkylating agent cyclophosphamide (CP).  
 
Encouraged by dramatic disease remissions with this approach, early clinical trials focused more on mitigating the side-effects of CP toxicity than on limiting glucocorticoid-toxicity, even though it was known from outset that high-doses of glucocorticoids could cause severe and often incapacitating side-effects.
 
Having become integral to standard protocols, glucocorticoid treatment regimens were carried over into trials of new therapeutic agents. In this way, their use has been perpetuated and accepted as an unavoidable necessity, despite a lack of evidence supporting their utility.
 
As the Lancet article highlights, it is only in the last four years that clinical trials have begun to systematically evaluate established and novel agents for their safety and efficacy in reducing cumulative exposure to glucocorticoids. The results have been encouraging. Trials like PEXIVAS^[5] and ADVOCATE^[6] have shown that it is possible to significantly reduce glucocorticoid exposures and associated toxicities through the use of reduced-dose regimens and steroid-sparing alternatives.
 
Notably, the PEXIVAS reduced-dose protocol has since been acknowledged as the new standard of care in all three major guidelines and recommendations.^[7] At last, like the proverbial elephant in the room, steroid-toxicity is being exposed as a burden that we can no longer afford to tolerate.
 

Measured progress

One reason that concerns about steroid-toxicity have remained in the background for so long is that until recently, there were no standardized tools to measure it. The ADVOCATE trial marked a turning point in this respect, as it was the first to use the Glucocorticoid Toxicity Index (GTI), which enables quantitative assessment of changes in steroid-toxicity. The GTI played an essential role in gaining FDA approval of avacopan as an adjunctive treatment for ANCA-associated vasculitis.
 
The positive trend toward lower doses and shorter courses of glucocorticoids in clinical trials is encouraging. Nevertheless, it is clear that the overall glucocorticoid burden for this disease remains too high. The authors of the review point out that in clinical practice patients are likely to be prescribed larger doses for longer than they would in clinical trials - further emphasizing the importance of prioritizing strategies that reduce steroid-toxicity.
 

Positive outlook

Building on substantial progress made over the last twenty years, the outlook for the coming decades is looking bright. With a number of novel targeted drugs and treatment strategies in the pipeline, and continued research to unravel the complex biology of ANCA-associated vasculitis, patients can look forward to more precise and tailored steroid-sparing treatments that significantly improve outcomes and quality of life. Measurement tools like the GTI will be crucial in demonstrating the safety and efficacy of these novel approaches and steroid-sparing alternatives.
 

References

1. “FDA approves add-on drug for adults with rare form of blood vessel inflammation.” News and Events for Human Drugs, U.S. Food and Drug Administration, 13 October 2021, https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-drug-adults-rare-form-blood-vessel-inflammation
2. Kronbichler A et al. Diagnosis and management of ANCA-associated vasculitis. The Lancet (2024) 403:683-698.
3. Baggenstoss AH, Shick RM, Polley HF. The effect of cortisone on the lesions of periarteritis nodosa. Am J Pathol (1951) 27:537-559.
4. Treatment of polyarteritis nodosa with cortisone: results after three years: report to the Medical Research Council by the Collagen Diseases and Hypersensitivity Panel. Br Med J (1960) 1:1399-1400.
5. Walsh M et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med (2020) 382: 622–31.
6. Jayne DRW et al. ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med (2021) 384: 599–609.
7. Moura MC et al. Management of antineutrophil cytoplasmic antibody associated vasculitis with glomerulonephritis as proposed by the ACR 2021, EULAR 2022 and KDIGO 2021 Guidelines/Recommendations. Nephrol Dial Transplant (2023) 38: 2637–51.