Supplementary material Ann Rheum Dis

Supplementary Methods

Polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA, Wegener’s), microscopic

polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss)

were defined according to the Chapel Hill definitions. In ANCA-associated

patients, serum samples were tested for ANCA by means of indirect immunofluorescence and

tested for anti–proteinase 3 ANCA and anti-myeloperoxidase ANCA with an enzyme-linked

immunosorbent assay. Virus-associated vasculitides were excluded from all these trials and

patients with a previous history of cancer of less than 3 or 5 years were ineligible for all trials.

Patients were prospectively evaluated at diagnosis, at randomization, every 2-3 months

thereafter during the first two years of follow-up, and then every 6 months until the end of

follow-up. Long-term follow-up after the end of the protocol was planned for each protocol

using the FVSG database. Severe adverse events, including malignancy, were prospectively

collected. Lifestyle factors such as smoking were not included in this analysis

Association of baseline characteristics and therapeutic strategies with the occurence of

malignancy was investigated by univariate analyses using Cox regression models. Variables

associated with malignancies with a P value <0.05 in univariate analysis were included in a

backward-selection Cox regression analysis. Person-years of follow-up were calculated using

the total follow-up and stratified by sex and 5-years age groups. Incidence rates were

calculated for all cancers and compared to the French National registry, with indirect

standardization on sex and 5-years age groups. Standardized incidence ratios were calculated

as the ratio between the observed and the expected number of cancer. Data were analyzed

using R software version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria;

https://www.R-project.org/).

Lafarge A, et al. Ann Rheum Dis 2020; 79:1–2. doi: 10.1136/annrheumdis-2019-216452 Supplementary material Ann Rheum Dis

Supplementary Table S1. Summary of the five randomized controlled trials pooled in

the present study.

CHUSPAN1–4 aimed to analyze to the treatment of PAN, MPA and EGPA without and with

poor-prognosis factors. CHUSPAN 25 aimed to determine whether the addition of

azathioprine to glucocorticoids could achieve a higher sustained remission rate of newly

diagnosed non-severe EGPA, MPA, or PAN. WEGENT6 trial aimed to compare azathioprine

to for the maintenance of remission for GPA and MPA. CORTAGE7 trial aimed

to investigate a new therapeutic strategy, with rapid dose tapering and limited

exposure, for older patients ≥65 years with PAN, GPA, MPA, or EGPA.

MAINRITSAN8,9 trial aimed to compare versus azathioprine for the maintenance

of remission in GPA and MPA. In all 5 trials, cyclophosphamide dosing was adjusted to renal

function.

Trials CHUSPAN1-4 CHUSPAN 25 MAINRITSAN8,9 CORTAGE7 WEGENT6 Sample size 293 95 115 104 126 Recruitment period 1993-2005 2008-2012 2008-2010 2005-2008 1999-2004

Follow-up (years) – 8.1 (5.6-10.4) 2.0 (1.9-2.1) 5.1 (5.0-5.2) 3.0 (2.6-3.4) 11.1 (8.5-12.4) median (IQR) SNV PAN, MPA, PAN, MPA, GPA, MPA PAN, GPA, MPA, GPA, MPA EGPA EGPA FFS=0 EGPA ≥65 years Induction therapy FFS=0: GC alone GC + GC + 6 IV CYC GC alone or + IV GC + 6 IV CYC then AZA vs. IV AZA vs. CYC (500 mg/m2) CYC placebo for 12 according to FFS FFS>0: GC + 6 months vs. vs. 12 IV CYC GC + 6 IV CYC at 500 mg fixed dose

Maintenance therapy None None AZA vs. RTX GC alone AZA vs. MTX or GC + AZA

SNV: systemic necrotizing vasculitides; PAN: polyarteritis nodosa: GPA: granulomatosis with polyangiitis; MPA: ; EGPA: eosinophilic granulomatosis with polyangiitis; FFS: Five-Factor score; GC: glucocorticoids; AZA: azathioprine; CYC: cyclophosphamide; MTX: methotrexate; RTX: rituximab.

1. Guillevin L, Cohen P, Mahr A, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: a prospective trial comparing

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glucocorticoids and six or twelve cyclophosphamide pulses in sixty-five patients. Arthritis Rheum 2003;49:93 100. doi:10.1002/art.10922 2 Cohen P, Pagnoux C, Mahr A, et al. Churg-Strauss syndrome with poor-prognosis factors: A prospective multicenter– trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum 2007;57:686 93. doi:10.1002/art.22679 3 Ribi C, Cohen P, Pagnoux C, et al. Treatment of polyarteritis nodosa and microscopic– polyangiitis without poor-prognosis factors: A prospective randomized study of one hundred twenty-four patients. Arthritis Rheum 2010;62:1186 97. doi:10.1002/art.27340 3 Ribi C, Cohen P, Pagnoux C, et al. Treatment of Churg-Strauss syndrome– without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 2008;58:586 94. doi:10.1002/art.23198 4 Puéchal X, Pagnoux C, Baron G, et al. Adding Azathioprine to Remission-Induction Glucocorticoids for Eosinophilic Granulomatosis With– Polyangiitis (Churg-Strauss), Microscopic Polyangiitis, or Polyarteritis Nodosa Without Poor Prognosis Factors: A Randomized, Controlled Trial. Arthritis & (Hoboken, NJ) 2017;69:2175 86. doi:10.1002/art.40205 5 Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated– vasculitis. N Engl J Med 2008;359:2790 803. doi:10.1056/NEJMoa0802311 6 Pagnoux C, Quéméneur T, Ninet J, et al. Treatment of systemic– necrotizing vasculitides in patients aged sixty-five years or older: results of a multicenter, open- label, randomized controlled trial of corticosteroid and cyclophosphamide-based induction therapy. Arthritis & Rheumatology (Hoboken, NJ) 2015;67:1117 27. doi:10.1002/art.39011 7 Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for – maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371:1771 80. doi:10.1056/NEJMoa1404231 8 Terrier B, Pagnoux C, Perrodeau É, et al. Long-term efficacy of remission-– maintenance regimens for ANCA-associated vasculitides. Ann Rheum Dis 2018;77:1150 6. doi:10.1136/annrheumdis-2017-212768

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Lafarge A, et al. Ann Rheum Dis 2020; 79:1–2. doi: 10.1136/annrheumdis-2019-216452