Anti-synthetase syndrome diagnosed during pregnancy: a case report and literature review

Anti-synthetase syndrome (ASS) is characterized by auto-antibodies (aAbs) against cytoplasmic aminoacyl-t-RNA-synthetases and the triad of myositis, arthritis, and interstitial lung disease (ILD) (1). Here, we report a case of ASS diagnosed during pregnancy.

A 36-year-old female was referred to our tertiary care high-risk pregnancy clinic for dyspnea, polyarthritis, and myalgia, with onset at 7 weeks’ gestation. She was pregnant for the sixth time. Three of her past pregnancies had resulted in live births, although complicated by pre-eclampsia (33–36 weeks) and intrauterine growth restriction (IUGR). She had also had two medically terminated pregnancies for personal reasons.

The patient was assessed at 15 weeks’ gestation and was hospitalized for further investigations. Clinical examination revealed polyarthritis, proximal muscle weakness [Medical Research Council (MRC)-5 scale 4/5], and lung crackles. Creatinine kinase (CK) levels reached 4244 IU/L. Serological work-up demonstrated negative anti-nuclear antibodies (ANAs) and anti-phospholipid aAbs. She had positive anti-Jo1 (3+) and anti-Ro52 (3+) aAbs on a myositis panel (Euroimmun). Magnetic resonance imaging of the thighs demonstrated T2/STIR hypersignals. Nailfold videocapillaroscopy (NVC) showed dystrophic capillaries. A previous computed tomography (CT) scan of the thorax performed at 7 weeks’ gestation, when the pregnancy was unknown, had revealed ILD with a non-specific interstitial pneumonia pattern. Pulmonary function tests (PFTs) showed a restrictive pattern [forced expiratory volume in 1 s (FEV₁) 44%, forced vital capacity (FVC) 44%, diffusing capacity of the lungs for carbon monoxide (DLCO) 48% of predicted value]. After multidisciplinary assessment, muscle biopsy was not performed in this pregnant patient as there was a correlation between the clinical phenotype and serology results. ASS was diagnosed, with moderate ILD, polyarthritis, and myositis.

The patient wished to pursue her pregnancy and was treated with prednisone 20 mg/day, hydroxychloroquine 5 mg/kg/day, azathioprine 2 mg/kg, and monthly intravenous immunoglobulin 2 g/kg. The arthritis and myositis improved significantly. PFTs at 19 weeks remained stable (FEV₁ 46%, FVC 47%, DLCO 44% of predicted value). She received aspirin 160 mg/day to prevent pre-eclampsia, and insulin as she had developed gestational diabetes. Foetal ultrasound was normal, with no signs of neonatal lupus. At 21 weeks’ gestation, an emergency caesarean section (C-section) was performed for acute placental abruption complicated by haemorrhagic shock. Foetal autopsy revealed IUGR and placental abruption secondary to a 4 × 4 cm clot.

In the immediate post-partum period, the patient experienced a disease flare with relapsing polyarthritis, myalgia, and proximal weakness. CK reached 2998 IU/L. ILD remained stable, although severe. After multidisciplinary discussion, prednisone was increased to 1 mg/kg/day and azathioprine was switched to mycophenolate mofetil. At 8 months post-partum, the patient is now stable on progressive tapering of prednisone currently at 15 mg/day, mycophenolate mofetil 1500 mg bid, and hydroxychloroquine 5 mg/kg/day. Intravenous immunoglobulins have successfully been tapered. Polyarthritis is in remission and proximal muscle weakness has resolved, with the last CK at 527 IU/L. PFTs have improved (FEV₁ 61%, FVC 61%, DLCO 54% of predicted value) and thorax CT showed a clear improvement of ILD. The obstetrician provided counselling regarding future pregnancies and the patient is now on highly effective long-acting reversible contraception.

We searched for cases of anti-Jo1-positive ASS in pregnancy (PubMed, MEDLINE, Embase) and summarized the data in Table 1. Ten anti-Jo1-positive ASS cases have been reported, including seven diagnosed before pregnancy and three diagnosed during pregnancy. Multidisciplinary management of ASS in pregnancy is discussed in Figure 1.

Figure 1. Key points to consider regarding the management of anti-synthetase syndrome (ASS) in pregnancy. (i) Corticosteroid dosing should be minimized to prevent the risk of infections and maternal–foetal complications, and pregnancy-compatible medication should be used. (ii) Anti-Ro/SSA auto-antibodies (aAbs) increase the risk of interstitial lung disease (ILD) in patients with ASS (16, 17). (iii) Anti-Ro/SSA and anti-La/SSB increase the risk of neonatal lupus. Women who test positive for anti-Ro/SSA and/or anti-La/SSB should be screened for neonatal lupus and receive hydroxychloroquine during pregnancy (18). (iv) Anti-phospholipid (APL) aAbs increase the risk of adverse pregnancy outcomes, and prophylactic treatment with low-dose aspirin and/or low molecular weight heparin is recommended (18). (v) Screening for ILD and assessment of severity should be performed with pulmonary function tests (PFTs), as exposure to radiation should be minimized. (vi) Obstetric medicine follow-up is essential to prevent and treat diabetes, pre-eclampsia, and anaemia (19). Obstetric expertise is needed for prevention and screening of prematurity, foetal growth restriction, and neonatal lupus secondary to anti-Ro/SSA aAbs. During childbirth, anaesthesiology should monitor for adrenal and respiratory insufficiency.

Table 1. Literature review of anti-Jo1-positive anti-synthetase syndrome (ASS) foetal and maternal outcomes in pregnancy.

Case	ASS phenotype	Immunosuppressive regimen	Maternal outcomes	Fetal outcomes
ANTI-JO-1 POSITIVE ASS DIAGNOSED PRIOR PREGNANCY
F, 25 yo ASS diagnosed at 23 yo Alshwairikh et al (2)	ILD Arthritis Mechanic’s hands	Azathioprine	Vaginal delivery 39 weeks	Oligohydramnios
F, 22 yo ASS diagnosed at 19 yo Dumitrascu et al (3)	Myositis ILD Arthritis	Prednisone Rituximab	C-section at 34 weeks	Oligohydramnios
F, 26 yo ASS diagnosed at 21 yo Kowitz et al (4)	Myositis ILD Arthritis Mechanic’s hands	Prednisone Hydroxychloroquine Tacrolimus IVIg	C-section at 24 weeks	Intra-uterine growth restriction
F, 27 yo ASS diagnosed at 26 yo Mayu et al (5)	Myositis ILD Arthritis	Prednisone Cyclosporine	C-section at 34 weeks	Intra-uterine growth restriction, Hypoglycemia
F, 36 yo ASS diagnosed at 34 yo Green et al (6)	Myositis ILD Fever	Prednisone Azathioprine	Vaginal delivery at 40 weeks	Healthy
F, 35 yo ASS diagnosed at 18 yo Dalmau-Carolà et al (7)	Myositis ILD Arthritis Mechanic’s hands	Rituximab for 5 years, none given during pregnancy	C-section at 35 weeks	Healthy
F, 25 yo ASS diagnosed at 20 yo Vancsa et al (8)	Myositis ILD Arthritis Mechanic’s hands Raynaud	Prednisone	Vaginal delivery at 35 weeks	Healthy
ANTI-JO-1 POSITIVE ASS DIAGNOSED DURING PREGNANCY
F, 30 yo ASS diagnosed at 20 weeks gestation Okada et al (9)	Myositis ILD	Prednisone Tacrolimus	Severe ILD treated with cyclophosphamide	Induced abortion during the 2^nd trimester
F, 30 yo ASS diagnosed at 8 weeks gestation Tojyo et al (10)	Myositis DM rash Fever	Prednisone	Refractory myositis	Fetal loss at 11 weeks gestation
F, 24 yo ASS diagnosed at 2^nd trimester Satoh et al (11)	Myositis	Prednisone Azathioprine	Refractory myositis	Fetal loss during the 2^nd trimester

C-section, caesarean section; DM, dermatomyositis; ILD, interstitial lung disease; IUGR, intrauterine growth restriction; IVIg, intravenous immunoglobulins; F, female; yo, years old.

All cases of anti-Jo1-positive ASS diagnosed during pregnancy were associated with severe maternal disease (ILD or refractory myositis) and foetal death. In cases diagnosed before pregnancy, no foetal deaths occurred. In 2003, Silva et al. suggested that foetal prognosis mirrors the level of maternal disease activity (12).

We hypothesize that adverse foetal prognosis may be secondary to ASS-mediated placental dysfunction. In 2021, Kowitz et al described a pregnant 26-year-old female with ASS (anti-Jo1 and anti-Ro52/SSA aAbs), diagnosed at 21 years of age, who underwent emergency C-section at 24 weeks for IUGR and foetal decelerations (4). Placental histology revealed placental hypoperfusion. As ASS is characterized by vasculopathy (13, 14), we hypothesize that it may lead to a decrease in placental blood flow.

One study analysed NVC in 190 non-pregnant ASS patients, 70% of whom were positive for anti-Jo1 aAbs (15). NVC abnormalities were associated with the presence of anti-Jo1 aAbs (p = 0.008) and ILD (p = 0.002). NVC abnormalities that were significantly associated with anti-SSA and anti-Jo1 aAbs were avascular areas, suggesting that ASS may induce vasculopathy. Moreover, concurrent anti-Ro aAbs increase the risk of ILD (16, 17).

In conclusion, while favourable outcomes have been described with ASS diagnosed before pregnancy, disease onset during pregnancy was associated with poor outcome in our patient and three other published cases (foetal mortality rate of 100%). Management of ASS in pregnancy is challenging owing to contraindications to several immunosuppressive agents and the increased risk of maternal–foetal complications. Multidisciplinary management is essential to optimize maternal–foetal outcomes.

Author contributions

The authors thank Drs Sophie Grand’Maison, Nazila Bettache, and Vincent Williams, experts in obstetrical medicine at the CHUM, for their contribution in the management of the reported case.

Ethical statement

Approval by our local ethics committee (Comité d’Éthique, Centre de Recherche du CHUM, Université de Montréal) is not required for case reports on fewer than four patients. Nevertheless, written informed consent was obtained from the patient.

Disclosure statement

This case was presented as an abstract at the North American Society of Obstetrical Medicine (NASOM) conference on 14 October 2023 in Quebec City, Canada. No potential conflict of interest was reported by the authors.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.