Symposium 3.6 – ANCA vasculitis prognostic and treatment

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

Would you like to know more?

ANCA vasculitis and treatment – Where are we now?

David Jayne, United Kingdom

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder that predominantly affects small blood vessels. It is a rare, but potentially serious and life-threatening condition, with variable clinical presentation dependent on organ involvement and disease stage and activity. In the last decades, significant progress has been made in understanding the pathogenesis and improving the treatment and prognosis of these patients. Nevertheless, the most acute and severe disease manifestations, including kidney disease and alveolar haemorrhage, continue to be associated with increased mortality from disease activity or treatment complications and risk for the development of end-stage kidney disease.

Management of ANCA vasculitis consists of remission induction, maintenance, and relapse therapy. High-dose glucocorticoids administered for 3 to 6 months remain the cornerstone of induction therapy, but this treatment is associated with numerous dose-dependent adverse effects. In more severe disease presentations, cyclophosphamide, rituximab, or their combination, with or without glucocorticoids, represent an effective and relatively safe alternative. Plasma exchange (PLEX) has long been proposed and used for the most severe disease manifestations, but its role remains controversial. Recently published results from the PEXIVAS study did not report substantial benefits from adding plasma exchange to standard therapy in patients with severe ANCA-associated vasculitis. Patients in this study were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids, and the infectious complications were significantly less common in the reduced-dose group.

Figure 1. The current standard of care for ANCA-associated vasculitis

Remission maintenance in ANCA vasculitis still represents a challenge. Azathioprine and methotrexate have been demonstrated as safe and effective alternatives to oral cyclophosphamide to maintain remission. Mycophenolate-mofetil is another option with a similar safety profile, but has not been shown to be superior to azathioprine. Rituximab has also been studied in this context with promising results as it ensured higher relapse-free survival during periods of treatment than azathioprine. The RITAZAREM trial demonstrated a high level of efficacy of rituximab and glucocorticoids as a therapy to induce remission after relapse in ANCA vasculitis.

The concerns that remain with the current treatment options for ANCA-associated vasculitis include high relapse rates, limited effect on preserving renal function, detrimental or no effect on the quality of life, and high levels of toxicity, especially with glucocorticoid use. Targeting complement component 5a with avacopan, an orally administered selective C5a receptor inhibitor, was effective in replacing high-dose glucocorticoids, but more studies are needed to confirm these results.

Urinary CD163 in antineutrophil cytoplasm antibody-associated glomerulonephritis

Gema Fernandez-Juarez, Spain

CD 163 is a transmembrane protein mainly expressed by macrophages type 2 (M2) that infiltrate tissues during the “healing phase” of inflammation. CD 163 positive M2 are largely present in endocapillary, extra capillary and peritubular areas in patients with early stages of ANCA-associated glomerulonephritis (GN), as well as in those with fibrinoid necrosis and cellular crescents. However, this phenomenon is not restricted to ANCA vasculitis and can also be found in pauci-immune necrotizing GN, anti-glomerular basement membrane GN and immune complex-mediated GN. Thus, the question arises whether there is a correlation between the intensity of infiltration with CD 163 positive M2 and urinary CD 163 levels and whether CD 163 positive M2 may be useful in clinical practice, given their lack of specificity.

Figure 2. Changes in usCD163 concentrations following treatment and during follow-up of patients with ANCA-associated glomerulonephritis

A recent study reported an excellent correlation between urinary soluble CD 163 and histologic features of ANCA GN, such as fibrinoid necrosis, capillary breaks, and/or crescent formation. Furthermore, active renal ANCA vasculitis is associated with markedly higher urinary CD 163 levels than the inactive or extrarenal form of the disease. Especially high levels of urinary CD 163 were found with the crescentic form, followed by the mixed-class and sclerotic form of the disease. Therefore, urinary CD 163 is found to be closely associated with disease activity thus representing an accurate biomarker for the detection of active renal vasculitis and relapse. Even more so, urinary CD 163 levels’ decline corresponded well with response to treatment. Otherwise, an increase of 20 ng / mmol as absolute change, or an increase of 20% as relative change, with respect to the previous value in each patient makes it possible to discriminate the presence of renal relapse with a sensitivity of 100% and, a specificity of around 89%. All this findings suggest that in the future this marker may have an important role in monitoring the response to treatment and disease activity and may even eventually lead to the abolishment of biopsies for these purposes.

Renal risk score for ANCA vasculitis

Juan Manuel Mejia Vilet, Mexico

Renal involvement in ANCA vasculitis varies in the diversity of the histopathological findings and clinical presentation. The timely establishment of disease development prognosis remains the ultimate goal and the most challenging task for clinicians involved in the treatment of these patients as it provides the foundation for therapeutic considerations, resource administration, and timely arrangement of renal replacement therapy. Among the predictors studied so far, the level of renal function at disease presentation has received the most attention. However, when adjusted to the histopathological class of the disease, the crescentic and mixed histological forms seem to exhibit a similar prognosis, regardless of the baseline eGFR. Therefore, two scoring systems have been introduced to contribute to treatment decisions and more accurate prognosis.

The Chronicity Score is a systematic and semiquantitative approach to assessing and reporting chronic lesions. It grades the level of irreversible changes in the renal tissue, including glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis. The Renal Risk Score, on the other hand, combined clinical and histological parameters to classify the risk of end-stage renal disease development into low, medium, and high based on the proportion of normal glomeruli, eGFR at presentation, and proportion of interstitial fibrosis and tubular atrophy. Neither of these scoring systems took crescents as a parameter to predict renal outcome and both proved to be applicable in small cohorts. The Renal Risk Score proved to be properly calibrated for use in patients with mixed and sclerotic classes, but it was observed that other parameters, not included in this score, are also associated with renal prognosis. Nevertheless, both scores provided reproducible results in different patient groups and appear predictive of long-term kidney survival in ANCA-associated vasculitis. They exhibited significantly greater discrimination than histopathological classification alone, with Renal Risk Score demonstrating a slight superiority over the Chronicity Score.

Figure 3. Current strengths and further potentials of the Renal Risk Score

Even with these promising results, there is still room for improvement as neither of these scores can be used to guide therapeutic decisions, and their baseline predictive power declines with time.

Prognostication in AAV is not exclusively performed at baseline (where the RRS is calculated), but also in other important timepoints in the course of the disease, such as post-treatment or during relapses. A limitation of the RRS is that estimates prognosis at baseline, excluding from the score important variables for prognosis on follow up as response to therapy and disease relapses.

Therefore, large international cohort studies and adaptations to these instruments are needed in the future to improve their accuracy and applicability.

Further reading

Walsh M, Merkel PA, Peh CA; PEXIVAS Investigators. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/NEJMoa1803537.

Smith RM, Jones RB, Specks U; RITAZAREM co-investigators. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis. 2020;79(9):1243-1249. doi: 10.1136/annrheumdis-2019-216863.

Jayne DRW, Bruchfeld AN, Harper L; CLEAR Study Group. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017;28(9):2756-2767. doi: 10.1681/ASN.2016111179.

Mejia-Vilet JM, Zhang XL, Cruz C, et al. Urinary Soluble CD163: a Novel Noninvasive Biomarker of Activity for Lupus Nephritis. J Am Soc Nephrol. 2020;31(6):1335-1347. doi: 10.1681/ASN.2019121285.

Aendekerk JP, Timmermans SAMEG, Busch MH; Limburg Renal Registry. Urinary Soluble CD163 and Disease Activity in Biopsy-Proven ANCA-Associated Glomerulonephritis. Clin J Am Soc Nephrol. 2020;15(12):1740-1748. doi: 10.2215/CJN.07210520.

Villacorta J, Lucientes L, Goicoechea E, et al. Urinary soluble CD163 as a biomarker of disease activity and relapse in antineutrophil cytoplasm antibody-associated glomerulonephritis. Clin Kidney J. 2020;14(1):212-219. doi: 10.1093/ckj/sfaa043.

Sethi S, D’Agati VD, Nast CC, et al. A proposal for standardized grading of chronic changes in native kidney biopsy specimens. Kidney Int. 2017;91(4):787-789. doi: 10.1016/j.kint.2017.01.002.

Brix SR, Noriega M, Tennstedt P, et al. Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int. 2018;94(6):1177-1188. doi: 10.1016/j.kint.2018.07.020.

van Daalen EE, Wester Trejo MAC, Göçeroğlu A, et al. Developments in the Histopathological Classification of ANCA-Associated Glomerulonephritis. Clin J Am Soc Nephrol. 2020;15(8):1103-1111. doi: 10.2215/CJN.14561119.

An XN, Wei ZN, Yao XY, et al. Evaluating renal outcome of ANCA-associated renal vasculitis: comparative study of two histopathological scoring systems. Clin Exp Rheumatol. 2021;39 Suppl 129(2):39-45.

Mejía-Vilet JM, Martín-Nares E, Cano-Verduzco ML, Pérez-Arias AA, Sedano-Montoya MA, Hinojosa-Azaola A. Validation of a renal risk score in a cohort of ANCA-associated vasculitis patients with severe kidney damage. Clin Rheumatol. 2020;39(6):1935-1943. doi: 10.1007/s10067-020-04936-5.