A case of ANCA-associated vasculitis presenting de novo in pregnancy, successfully treated with rituximab

Short abstract

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are rare small vessel vasculitides of unknown cause. The pathogenic role of MPO-ANCA in the vasculitides has been supported using various animal models, with B-cells playing a role in the disease pathogenesis. Pregnancy in the presence of an autoimmune disease such as vasculitis is often associated with significant morbidity. Little is known about the outcomes when women present with de novo vasculitis during pregnancy, and the appropriate management of such presentations is unclear. We describe a case of a 33-year-old female presenting in her second pregnancy with new onset ANCA vasculitis at 12 weeks’ gestation. She was successfully treated with prednisolone and rituximab, and delivered a healthy 2.8 kg boy at 36 weeks’ gestation with no clinical manifestations of vasculitis or neutropenia in the neonate.

Introduction

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are rare small vessel vasculitides of unknown cause. The two relevant target antigens detected by ELISA are proteinase 3 (PR3) and myeloperoxidase (MPO). The pathogenic role of MPO-ANCA in the vasculitides has been supported using various animal models, with B-cells playing a role in the disease pathogenesis.¹ Pregnancy in the presence of an autoimmune disease such as vasculitis is often associated with significant morbidity.² Little is known about the outcomes when patients present with de novo vasculitis during pregnancy, and the appropriate management of such presentations is unclear. The gestational age at presentation should be an important determinant when considering treatment options.

Case report

A 33-year-old female in her second pregnancy presented to her local medical practitioner with persistent olecranon bursitis and new-onset renal impairment at 12 weeks’ gestation. She had a history of Raynaud’s disease and superficial thrombophlebitis; both known associations with autoimmune rheumatic diseases. On presentation, there were no systemic or constitutional symptoms, she was normotensive, had 0.97 g/day proteinuria, glomerular haematuria and Cr 120 µmol/L (baseline Cr 67 µmol/L, normal creatinine reference range in pregnancy 35–80 µmol/L). MPO ANCA titre was over 200 U/ml (normal < 20 U/ml) with normal serum complement levels and normal extractable nuclear antigen (ENA) level. Antinuclear antibody was positive at 1:80 (normal <80). In view of her renal impairment and underlying proteinuria, she was started on aspirin to decrease risk of pre-eclampsia and intra-uterine growth retardation. A renal biopsy indicated crescentic glomerulonephritis (60% crescents). IgG, IgA and C3c immunoperoxidase staining was negative, with some C1q staining of mesangium and sclerotic lesions (Figure 1). Successful induction of remission for ANCA-associated glomerulonephritis was achieved with weekly doses of 375 mg/m² rituximab for four weeks (commencing at 13 weeks’ gestation) and  500 mg prednisolone daily for 3 days. This was followed by oral prednisolone at weekly weaning dosages of 60 mg/45 mg/30 mg/25 mg/20 mg followed by a slower reduction to 10 mg. She remained on this dose until the end of pregnancy. Eight weeks after the initiation of treatment, her symptoms had resolved with undetectable MPO ANCA titres and an improvement in her proteinuria, haematuria and creatinine. B-cell counts were not regularly monitored. They were, however, assessed as deplete (0.5 × 10⁹/L (7–15)), when she developed late-onset asymptomatic neutropenia (nadir 0.1 × 10⁹/L) at 26 weeks’ gestation (14 weeks post rituximab), which responded to a single dose of G-CSF. Whilst this was thought to be viral in aetiology, neutropenia has been observed following the use of rituximab, and is associated with a period of B-cell depletion. The mechanism behind ‘late-onset neutropenia’, and the role of growth factors once ‘late-onset neutropenia’ appears, is unknown.³

Figure 1.

Segmental necrotising lesion and a globally sclerosed glomerulus.

The patient was closely monitored in the Maternal Fetal Medicine Clinic, with regular fetal scans indicating normal growth (90th centile) and morphology. The patient remained normotensive and well throughout the remainder of the pregnancy. A healthy 2.8 kg boy was delivered at 36 weeks’ gestation after preterm premature rupture of membranes and induction of labour with no significant complications. Whilst MPO-ANCAs are known to be immunopathogenic,⁴ there was no evidence of pathogenic transplacental transfer of anti-MPO antibodies with no clinical manifestations of vasculitis or neutropenia in the neonate. B cells were present, making up 6% of lymphocytes, with normal CD20 expression in the neonate. At eight months’ follow-up, the patient remains on a weaning dose prednisolone with no steroid sparing maintenance agent. The disease remains in remission with an inactive sediment and mild ongoing proteinuria (likely secondary to sclerosis seen on renal biopsy) (Figure 2). She has been commenced on an angiotensin-converting-enzyme inhibitor and continues to breastfeed.

Figure 2.

Graph showing the serum creatinine and urine protein-creatinine ratio over the treatment period.

Discussion

Maternal and fetal outcomes of autoimmune diseases such as vasculitis during pregnancy are less favourable if the disease is not in remission prior to conception. Known complications include spontaneous miscarriage, stillbirth, preterm delivery, low-birth weight, and maternal disease flare.⁵ Little is known of outcomes when women present with de novo vasculitis during pregnancy, and the appropriate management of such presentations is unclear.

There are a few case reports of de novo vasculitis during pregnancy with various treatments and outcomes.⁶ Most pregnancies finish successfully; however, there are reports of medical termination⁷ and maternal death due to intracranial bleeding⁸ in a woman who presented during the first trimester. There are case reports of de novo ANCA-associated vasculitis during pregnancy which did not require any treatment,⁹ another effectively treated with prednisolone and IVIG,¹⁰ and another treated with prednisolone and cyclophosphamide¹¹ with good fetal outcomes. There are no case reports in the literature of de novo ANCA vasculitis during pregnancy treated with rituximab.

Furthermore, Seo et al. (2007) published three case reports of neonatal ANCA-associated vasculitis, presumably caused by passive transfer of ANCA from mothers with MPO-ANCA-associated microscopic polyangiitis.¹² Neonates had documented elevated MPO-ANCA titres with signs of vasculitis.⁴ These titres gradually declined from birth to undetectable levels at three months.¹³ Placental transfer of maternal IgG antibodies to the fetus is mediated by FcRn expressed on syncytiotrophoblast cells.¹⁴ Whilst this is an important mechanism protecting the infant whilst their humoral response is inefficient, placental transfer of pathogenic IgG autoantibodies may occur, resulting in neonatal disease.¹⁵

Current treatment for ANCA vasculitis includes remission induction therapy based on a combination of glucocorticoids and an additional immunosuppressive agent. Immunosuppressive therapy is warranted in all patients with active disease, and complete remission is defined as the absence of active disease.¹⁶ Once remission is achieved, maintenance therapy is continued. Large randomised controlled trials (RITUXVAS and RAVE) have shown rituximab to be non-inferior to cyclophosphamide in induction remission at six months, with comparable rates of side effects including infections.¹⁷ The safety data on B-cell depleting therapies in pregnancy are lacking due to paucity of adequate and well-controlled studies.¹⁸ Drugs that are acceptable during pregnancy include hydroxychloroquine, prednisolone and azathioprine,¹⁹ whilst cyclophosphamide (first trimester), methotrexate and mycophenolate are teratogenic and contraindicated.²⁰ Rituximab is a chimeric (mouse-human) IgG1 kappa monoclonal antibody to CD20, which is found on the surface of B-lymphocytes. Rituximab can cross the placenta and can deplete fetal B-lymphocyte production, increasing the chances of infection. Studies of cynomolgus monkeys exposed to therapeutic doses of rituximab during pregnancy showed no evidence of teratogenic effects; however, B cells were reduced in the offspring and returned to normal within six months after birth.²¹ There are no controlled trials assessing the outcomes of rituximab use in autoimmune diseases during pregnancy. Chakravarti et al. described a large series of 231 patients who received rituximab for the treatment of lymphoma, autoimmune disease and autoimmune cytopenias. These patients inadvertently conceived during or after rituximab exposure. They reported an increased rate of premature deliveries, one neonatal death and haematological abnormalities and infections. Two neonates had congenital abnormalities (club foot and cardiac malformations).¹⁸

Only nine women exposed to rituximab during pregnancy (trimesters 1–3) have been described in case reports.²² These women had a diagnosis of either lymphoma (n = 6), thrombotic thrombocytopenic purpura (n = 1), autoimmune haemolytic anaemia (n = 1) and idiopathic thrombocytopenic purpura (n =1). All of the pregnancies resulted in life births. Rituximab levels were measured at birth in three of the neonates, with detectable levels which declined over the subsequent weeks. In five neonates, CD 19+ B cell levels were measured at birth and/or at one week and were undetectable or significantly decreased in all but one child, who was exposed only during the first trimester. B-cell levels returned to normal in three to six months in all children who had follow-up testing. Whilst a low granulocyte count was initially observed in two neonates, no infection developed. Moreover, an adequate response to standard immunisations was evaluated and found to be normal in four of the nine children.²²

There are little data in the literature regarding the outcomes of pregnancy in women with ANCA-associated vasculitis who received biologics during pregnancy due to the demographics of the condition and the rarity of this condition in women of child-bearing age. This is the first known case report of de novo ANCA-associated vasculitis presenting during pregnancy successfully treated with rituximab, with no adverse outcomes to the neonate. Rituximab was administered in the first trimester when IgG transfer to the fetus would be expected to be low. IgG transfer to the fetus begins as early as 13 weeks’ gestation and increases linearly with gestational age.¹² The timing of rituximab administration may have to be taken into consideration when contemplating the use of this drug in pregnancy.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Informed consent was obtained from the patient for publication of case report and associated images.

Guarantor

KP.

Contributorship

All authors have contributed to the case report and guarantee the accuracy and authenticity of this case. Pefanis, Skryzpek, Fung and Paizis were directly involved in the patient’s care, and together with Williams, provided intellectual input with this case. Williams provided the pathology images, and the interpretation of the biopsy. All authors contributed to the writing and editing of the case report.