Aromatase inhibitors and anti-synthetase syndrome

Abstract

Adjuvant therapy in postmenopausal women with endocrine-responsive breast cancer (BC) is actually centered on the use of anti-aromatase inhibitors (AI). Several reports, however, are emerging in literature associating the use of this drugs to rheumatic disorders. This case report describes the first case of anti-synthetase syndrome diagnosis after treatment with anti-estrogen agents in a patient with pre-existing rheumatoid arthritis.

Introduction

Third generation aromatase inhibitors (AIs) are to be preferred to tamoxifen in postmenopausal women with endocrine-responsive breast cancer (BC), in both advanced and early disease. Their use is recommended as adjuvant treatment after surgery in postmenopausal patients, either upfront or following tamoxifen, ¹ and they are also going to play a role in premenopausal women. Side effects of AIs are mainly related to their impact on bone-mineral density, lipid profile, cardiovascular system, and musculoskeletal symptoms,^2,3 and some evidence exists for a possible role on the onset of rheumatoid arthritis (RA) and other connective tissue diseases.^{4 –7} Here we describe the first case in which anti-synthetase antibody syndrome (ASAS), a rare autoimmune disease with variable systemic symptoms (myositis, arthritis, fever, interstitial lung disease, skin lesions, and Raynaud’s phenomenon), was diagnosed after treatment with AIs in a patient with a pre-existing diagnosis of RA.

Case presentation

In January 2012, a 55-year-old postmenopausal woman was referred to our Rheumatic Diseases Department for suspected RA. Diagnosis was suggested by the following clinical observations: synovitis involving eight small joints, high C-reactive protein levels, presence of high title IgM rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA). All symptoms lasted for more than 8 weeks. Chest X-ray, serum creatinine, and liver enzymes levels were normal and anti-nuclear antibody test was negative. Treatment with methotrexate (15 mg per week) and corticosteroid (low dose, daily) was commenced, with quick clinical remission.

In June 2012, the patient underwent left mastectomy and sentinel node biopsy for a stage pT2(3.5 cm), pN0(itc+), grade II infiltrating ductal breast carcinoma, with focal lymphovascular invasion. Cancer cells were estrogen receptor-positive (100%), progesterone receptor-positive (100%), human epidermal growth factor receptor type 2-negative; Ki67 was 25%. Chest X-ray, abdominal ultrasonography, and bone scan did not reveal metastatic disease, while RA was in clinical remission. Methotrexate was stopped, low dose corticosteroids were continued, and adjuvant hormonal treatment with Letrozole at the dose of 2.5 mg per day was started in July 2012.

In October 2012, the patient was admitted to our hospital for dyspnea and asthenia started 2 weeks before. Hypossiemia and hypocapnia were present; chest X-ray and computed tomography (CT) revealed a severe bilateral interstitial lung disease (Figure 1). Bronchoalveolar lavage showed lymphocytosis and neutrophilia; all cultures were negative. Creatinine kinase (CK) level was greater than 5000 U/L; anti-Jo1 and anti-RO52 antibodies, RF, ACPA were positive at high titration. Electromyogram results were consistent with a necrotizing myopathy; muscular biopsy revealed scattered degenerating muscle fibers. Abdominal ultrasound and leg vein echo color Doppler examination did not show signs of metastasis or deep vein thrombosis. PET-CT scan demonstrated a diffuse muscular uptake without signs of cancer metastases. There were no aspects of synovitis.

Figure 1.

CT scan showing bilateral interstitial lung disease.

A diagnosis of ASAS was made and treatment with high dose corticosteroid (6-methylprednisolone, three 500-mg bolus injections followed by 1 mg/kg per day) plus azathioprine (100 mg per day) was started. Letrozole was withheld, with progressive improvement of respiratory symptoms and CK level normalization.

In November 2012, dyspnea was significantly improved, chest CT scan showed a clear-cut improvement, corticosteroids were progressively tapered to 7.5 mg per day, continuing azathioprine 100 mg per day. In March 2013, hormonal treatment was resumed and Anastrozole was chosen for its weaker estrogen-suppressive properties, but the patient reported slight muscle weakness exacerbation and initial CK elevation. In the following months (Figure 2), a slow, but progressive CK raise was confirmed; immunosuppressive treatment was not changed (Azathioprine 100 mg/day + prednisone 7.5 mg/day) but Anastrozole was stopped and a progressive decrease and normalization of CK was observed without signs of cancer recurrence at last clinical follow-up.

Figure 2.

CK trend according to hormonal treatment.

Discussion

A close correlation between AIs and ASAS development in our patient is suggested by several factors: the temporal correlation between Letrozole initiation and symptoms emergence, the slow syndrome re-exacerbation after re-introduction of a weaker AI, and the CK value normalization after definitive Anastrozole withdrawal without modification of immunosuppressive treatment or disease recurrence.

It is reasonable to hypothesize that the patient was affected by ASAS already at time of symptoms appearance. In 25% of cases, in fact, ASAS presents at onset with arthritic symptoms and RA behavior.^8,9 Therefore, treatment with AI could have anticipated the onset of myositis and ILD, according to the natural history of the disease.

The rapid myositis recurrence at AI rechallenge and the remission obtained after their definitive withdrawal support a strong etiological relationship between AIs and ASAS for this patient.

Immuno-modulating effects of AIs have been extensively investigated in clinical studies and reviews ¹⁰ but no definitive conclusions about their effect in vivo can be assumed. AI treatment has been related with the onset of multiple rheumatic disorders as RA, ⁴ Sjogren’s syndrome,^5,6 Shöenlein Henoch vasculitis, ¹¹ cutaneous lupus erythematosus, ¹² and now ASAS. Diverging results are also available, showing a clinical improvement in rheumatic disorders after AI introduction as reported by Wood et al., ¹³ who describes a complete remission of para-neoplastic syndrome with myositic manifestation or by Sereda et al. ¹⁴ presenting two cases of dermatomyositis complete remission. Beneficial effects of AI in experimental models of systemic lupus erythematosus have also been reported. ¹⁵

Our case report highlights that AI treatment can induce or fasten the onset of rheumatic disorders, but the physio-pathology model behind this interaction still remains to be clarified. Also, clinical, genetic, pharmacological, and environmental factors might interfere with AIs immuno-modulating properties, thus deserving further investigations.