Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors

doi:10.1016/j.autrev.2013.10.001

Autoimmunity Reviews

Volume 13, Issue 2, February 2014, Pages 197-205

https://doi.org/10.1016/j.autrev.2013.10.001 Get rights and content

Abstract

The purpose of this study was to assess the long-term outcomes of patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS)-defined poor-prognosis factors (FFS = 0) and enrolled in a prospective clinical trial. Patients were followed (2005–2012) under routine clinical care in an extended study and data were recorded prospectively. Long-term survival, disease-free survival (DFS), relapses, therapeutic responses and sequelae were analyzed. Mean ± SD follow-up was 98.2 ± 41.9 months. After having initially received glucocorticoids (GC) alone, according to the study protocol, 82% (97/118) patients achieved remission but 18% (21/118) required ≥ 1 immunosuppressant(s) (IS) before 19/21 achieved remission. Two patients died before entering remission. After remission, 53% (61/116) patients relapsed 25.6 ± 27.9 months after starting treatment. The 5- and 8-year overall survival rates were 93% and 86%, respectively, with no difference between PAN and MPA, and between relapsers and nonrelapsers. DFS was shorter for MPA than PAN patients (P = 0.02). Throughout follow-up, 47% of patients required ≥ 1 IS. At the last follow-up visit, 44% were still taking GC and 15% IS. The mean vasculitis damage index score was 1.9 ± 1.9; the most frequent sequelae were peripheral neuropathy, hypertension and osteoporosis. For PAN or MPA patients without poor-prognosis factors at diagnosis and treated initially with GC alone, long-term survival was excellent. However, relapses remained frequent, requiring IS introduction for nearly half of the patients. To lower the frequencies of relapses and sequelae remains a challenge for FFS = 0 PAN and MPA patients.

Introduction

Polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) are 2 vasculitides characterized by necrotizing inflammation of the vessel wall. They share several clinical features and may be treated the same way, with the exception of hepatitis B virus-associated PAN (HBV–PAN) [1], [2] which requires a specific antiviral approach. PAN is a necrotizing arteritis of medium- and small-sized arteries not associated with anti-neutrophil cytoplasm antibodies (ANCA) [3], [4]. In contrast, MPA is an ANCA-associated small-vessel vasculitis, mainly anti-myeloperoxidase (MPO) [3], [5], [6], [7], in which glomerulonephritis and pulmonary capillaritis often occur. More than the type of vasculitis, we hypothesized that its severity should determine the therapeutic strategy. The Five-Factor Score (FFS), in its original version [8] and revisited in 2011 [9], can predict patient mortality depending on the presence of poor-prognosis factors.

To date, only the 1996 version of the FFS had been validated in prospective trials to guide the treatment of vasculitides. Nonsevere PAN and MPA manifestations, as defined by the 1996 FFS = 0 (1996 version), responded to glucocorticoids (GC) alone in 79% of the patients [2]. GC failure or relapse requiring immunosuppressants (IS) occurred in 40% after a mean follow-up of 5 years [2].

Data on the long-term follow-up of these patients treated initially with GC alone are lacking. In this study, we took advantage of the FVSG patient cohort, followed prospectively and homogeneously treated, to describe the long-term outcomes of PAN or MPA patients: survival, disease-free survival (DFS), causes of death, relapses, clinical and laboratory findings, therapeutic responses and sequelae.

Section snippets

Patient population

Patients had been included between November 1993 and January 2005, and treated in France and the UK in a prospective randomized controlled trial [2]. Each participant gave signed informed consent. Once the diagnosis of PAN or MPA was confirmed, patients were stratified according to the presence or absence of 1996 FFS-defined poor-prognosis factors [8]: serum creatinine > 140 μmol/l, proteinuria > 1 g/day, severe gastrointestinal tract involvement, cardiomyopathy and/or central nervous system (CNS)

Baseline characteristics

Among the 124 patients screened, 6 were excluded (2 FFS ≥ 1, 4 other vasculitides; Fig. 1).

For each of the 118 patients (61 MPA and 57 PAN) analyzed, at least 1 biopsy was available, showing necrotizing vasculitis in 107/118 (91%) patients. A total of 187 biopsies were analyzed: 46 neuromuscular, 43 muscular, 51 cutaneous and 26 temporal artery biopsies, showing vasculitis in 87%, 74%, 80% and 38%, respectively; 21 biopsies of other tissues were obtained: minor labial salivary glands, liver,

Discussion

Despite their being 2 distinct entities [3], nonHBV–PAN and MPA without FFS-defined, poor-prognosis factors can be treated with the same strategy, relying on the hypothesis that the treatment should be adapted to disease severity, as defined by the 1996 FFS [8], rather than the type of vasculitis [17].

Herein, we report the long-term follow-up of this prospective trial [2], demonstrating the excellent overall survival of a large cohort of 118 FFS = 0 MPA or PAN patients [8]. Even after this

Conclusion

For baseline FFS = 0 PAN or MPA patients, overall survival at 96 months is excellent, with first-line GC alone achieving remission in > 80% of them. However, relapses are common, so that 47% of our patients received an IS during follow-up. Moreover, sequelae were common, essentially being neuropathy and associated with prolonged GC use. Even though relapses did not affect overall survival during long-term follow-up, their impact on the extent of disease- or treatment-related damage is not known and

Take-home messages

•
For baseline PAN or MPA patients without poor-prognosis factors (FFS = 0), overall survival at 96 months is excellent.
•
First-line glucocorticoids (GC) achieve remission in > 80% but relapses are common, so that an immunosuppressant is prescribed in 47% of patients.
•
Sequelae are common, essentially being neuropathy and associated with prolonged GC use.
•
Relapses do not affect overall survival but their impact on sequelae is not known and should be examined in future studies.
•
The future and ongoing

Role of the funding sources

ClinicalTrials.gov no. NCT00400075.

Supported by: the Société Nationale Française de Médecine Interne (SNFMI), Hospices Civiles de Lyon, Groupe d'Intérêt Scientifique Maladies Rares, Assistance Publique des Hôpitaux de Paris, Groupe d'Études et de Recherche sur les Maladies Orphelines Pulmonaires (GERMOP) and the FVSG. The Ministère de la Recherche and the Institut National de la Santé et la Recherche Médicale (INSERM) awarded grants, which were used to monitor the therapeutic studies.

Acknowledgments

FVSG members (city) who included patients are: Michel Alcalay (Centre Hospitalier Universitaire (CHU), Poitiers), Christophe Arnal (CHU Tenon, Paris), Jean-Paul Battesti (CHU Avicenne, Bobigny), Alain Bergère (Pôle Santé Sarthe et Loir, La Flèche), Christophe Bernardeau (CHU Lariboisière, Paris), Nadine Boullanger (Centre Hospitalier (CH), Le Mans), Anne Buu Sao (CHU Avicenne, Bobigny), Jean-Jacques Buzon (Avesnes-les-Aubert), Jean Cabane (CHU Saint-Antoine, Paris), Patrice Cacoub (CHU

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Though these patients behave similarly to the prototypical MPA cases described in other cohorts where major clinical features include kidney (79%−98% of cases) and pulmonary disease (25%−53%)7–10,26; the younger age at diagnosis and the increased prevalence of ENT symptoms more closely resembled that reported in GPA and PR3-ANCA vasculitis.14–16,18 In previous studies, upper respiratory tract involvement was described only in 0% to 20% of MPA patients,7–10,26,39,48 which markedly contrast with the 44% observed in our population. Although ENT manifestations such as sinusitis, otitis media, epistaxis, or rhinitis have never been emphasized as part of MPA phenotype, available information shows that these symptoms may be observed both at initial presentation and during relapses48; and in contrast to GPA, lesions tend to be mild and not destructive in nature.9,48
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Patients with PR3-ANCA MPA were younger (53 years vs. 62 years, P = 0.0007) and had increased prevalence of joint involvement (56% vs. 40%, P = 0.0115) and ear, nose, and throat (ENT) involvement (44% vs. 26%, P = 0.002) than MPO-ANCA MPA. Relapses, ESKD, and survival were similar between both MPA subsets. Within the GPA group, patients with MPO-ANCA GPA were older (61 years vs. 46 years, P = 0.0007) and more likely female (56% vs. 35%, P = 0.027) than PR3-ANCA GPA patients. MPO-ANCA GPA was also characterized by less prevalent ENT manifestations (58% vs. 77%, P = 0.028) and neurologic manifestations (5% vs. 25%, P = 0.0029), and increased ESKD and mortality.
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Comme il n'y a pas de consensus actuellement. Ce cas clinique montre l'expérience de notre service dans la gestion d'un cas d'ischémie subaiguë des membres sur polyartérite noueuse.
L'ischémie aiguë du membre est rarement vue dans la périartérite noueuse .
Ici, on présentn cas avec pathologie vasculaire périphérique des membres inférieurs se manifestant par des signes d'ischémie subaiguë avec des plages nécrotiques larges. L'angioscanner a montré une occlusion des 2 artères fémorales superficielles. L'artériographie a objectivé des anomalies sur les artères de moyen calibre. L'étude anatomopathologique de la biopsie artérielle du membre inférieure amputé a confirmé le diagnostic de périartérite noueuse. Elle a bénéficié d'un pontage fémoro-poplité pour les 2 membres inférieurs associés au traitement anticoagulant et corticoïdes. La non amélioration clinique du membre inférieur gauche a abouti à son amputation. Le membre droit a été sauvé.
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Despite being considered a rare disease, PAN is an underdiagnosed, fearsome disease, potentially leading to death and severe disability. Due to its remitting-relapsing course, patients often require long-term treatment [22] and more powerful and less toxic drugs are needed. A total of 51 papers [17,25–57,61–77], published between 2005 and 2020, about patients affected by PAN and DADA2 and treated with bDMARDs, have been reviewed.
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¹: Current address: Vasculitis Clinic, Division of Rheumatology, Mount Sinai Hospital, University Health Network, Toronto, Ontario, Canada.

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ReviewLong-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors

Abstract

Introduction

Section snippets

Patient population

Baseline characteristics

Discussion

Conclusion

Take-home messages

Role of the funding sources

Acknowledgments

Autoimmun Rev

Autoimmun Rev

Mayo Clin Proc

Presse Med

Presse Med

Autoimmun Rev

Kidney Int

Presse Med

Autoimmun Rev

Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients

Medicine (Baltimore)

Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: a prospective randomized study of one hundred twenty-four patients

Arthritis Rheum

2012 revised international chapel hill consensus conference nomenclature of vasculitides

Arthritis Rheum

Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database

Arthritis Rheum

Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients

Arthritis Rheum

Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome. A prospective study in 342 patients

Medicine (Baltimore)

The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort

Medicine (Baltimore)

Review
Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors