One of the major side effects of AIs is the development of musculoskeletal symptoms. These symptoms were originally referred to as Arthralgia Syndrome, but more recently the term AI-induced musculoskeletal symptoms (AIMSS) has been used to describe the constellation of joint pain, symmetric morning stiffness improving with activity, a sensation of abrupt aging, and soft tissue thickening. Carpal tunnel syndrome has also been demonstrated in a group of women with other symptoms of AIMSS. The hands and wrists are the most common sites of pain, but any joint may be affected. While these features have all been recognized under the auspices of AIMSS, there are no formal diagnostic criteria for this syndrome. Most studies rely on elevation of pain scores in conjunction with AI use to define the syndrome.
Reports on the incidence of AIMSS in patients using AIs vary widely due to differing definitions of the syndrome. In adjuvant trials of third generation AIs (anastrozole, letrozole, and exemestane), the prevalence of bone and joint symptoms was between 5 and 36%. However, more recent studies performed outside of clinical trials suggest that the prevalence is even higher. In a cross sectional survey of women on AIs, 47% of women had joint pain, and 44% had joint stiffness attributable to AIs. Development of musculoskeletal symptoms is thought to contribute to the poor compliance associated with AIs; however, studies also suggest that joint complaints are also associated with better outcomes and less risk of breast cancer recurrence.
The mechanisms by which AIMSS develop remain unknown, and several studies have incorporated rheumatologic assessment to investigate whether the symptoms can be attributed to an underlying rheumatologic process. The results are conflicting.
Based on the results of this study, researchers did not find evidence to support an inflammatory basis for AIMSS. They identified a higher than expected frequency of positive ANA and previously undiagnosed autoimmune disease, but these issues were evenly distributed among cases and controls, suggesting they are likely not related to medication exposure, and simply reiterating the importance of a thorough rheumatologic work-up for symptomatic patients.
Shanmugam V, McCloskey J, Elston B, Allison S, Eng-Wong J. The CIRAS study: a case control study to define the clinical, immunologic, and radiographic features of aromatase inhibitor-induced musculoskeletal symptoms. Breast Cancer Research and Treatment 2011:1-10. The CIRAS study: a case control study to define the clinical, immunologic, and radiographic features of aromatase inhibitor-induced musculoskeletal symptoms
Aromatase inhibitors (AIs) are widely prescribed for post-menopausal hormone receptor-positive breast cancer; however, musculoskeletal symptoms limit their tolerability. The purpose of this study was to determine whether joint pain in women receiving AIs is associated with inflammatory arthritis as measured by the disease activity score-28 (DAS-28), and to evaluate association with tenosynovitis on ultrasound. A total of 48 postmenopausal women with stage I–III breast cancer and hand pain were recruited from the Lombardi Comprehensive Cancer Center.
Those receiving AIs were cases (n = 25), and those not receiving AIs were controls (n = 23). During a single study visit, subjects underwent blinded rheumatologic evaluation, DAS-28, health assessment questionnaires, autoantibodies, inflammatory markers, hand X-ray, and hand Duplex ultrasound.
There were no significant differences between cases and controls in DAS-28, or inflammatory markers. A positive ANA (titer > 1:160) was found in ten patients, four of whom met criteria for autoimmune disease (two with rheumatoid arthritis and two with Sjogren’s syndrome, equally distributed among cases and controls). This highlights the importance of considering underlying autoimmune disease in subjects with musculoskeletal complaints. Morning stiffness was more prolonged in women receiving AIs, but this did not reach statistical significance (P = 0.07). Ultrasound evidence of flexor tenosynovitis was common in both groups. Although tenosynovitis was not correlated with AI use (P = 0.26), there was a trend toward an association between tenosynovitis and morning stiffness (P = 0.089).
While aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) were more common in subjects receiving AIs, they were not unique to AI users. There was no association between presence of AIMSS features and other chemotherapy or medication exposures. Although the majority of subjects had been using AIs for more than 6 months, this study did not find evidence for inflammatory arthritis in women with hand pain receiving AIs. Further studies are needed to develop a case definition of AIMSS, and to confirm whether these symptoms are attributable to AI use.
