Joint pain linked to breast cancer drug not inflammatory arthritis or autoimmune disease

A new study suggests joint complaints attributed to aromatase inhibitors (AI), popular breast cancer drugs, are not associated with inflammatory arthritis or autoimmune disease. Because of that, researchers say women who were primarily concerned about the threat of arthritis should be encouraged to continue taking the medication. The findings of the study will be presented Tuesday, Nov. 9 at the 74th Annual Scientific Meeting of the American College of Rheumatology in Atlanta, Georgia

For many post-menopausal women with breast cancer promoted by the hormone estrogen, AIs can dramatically reduce the risk of their cancer coming back. Doctors say the AIs must be taken for five years to gain the full benefit, however the development of joint complaints in up to 35 percent of women forces many of them to stop early.

“It’s not clear why these joint symptoms occur, but we wondered if they could be related to inflammation or an autoimmune disease,” says Victoria K Shanmugam, MBBS, MRCP, assistant professor in the Division of Rheumatology, Immunology and Allergy at Georgetown University Medical Center, who led the study. “Our research ruled out both.”

The case-controlled study included 25 postmenopausal breast cancer patients with hand pain and no known autoimmune disease who were treated for their cancer at Georgetown Lombardi Comprehensive Cancer Center. Another 23 participants who were not receiving the drugs enrolled as a control group.

Subjects were evaluated after abstaining from non-steroidal anti-inflammatory drugs for 48 hours. Signs of inflammation from arthritis would reappear in that time frame, the researchers reasoned. They completed a health assessment questionnaire. The rheumatologist completed a history and physical, and disease activity score. Various blood tests were conducted and x-rays and ultrasounds of all participants’ hands were performed.

The rheumatologist and radiologist did not know which participants were taking AIs and which were not.

“We did find 4 of 48 women with autoimmune disease – 2 in each group—that had previously been undiagnosed, but the frequency was similar both in women receiving AIs and those who were not receiving AIs,” Shanmugam says. “We found that several patients in the control arm had a similar constellation of symptoms to those receiving AIs.”

But Shanmugam and her team did not find any conclusive evidence from their tests of inflammatory arthritis in the women with breast cancer.

“Although our study helps to rule out inflammatory arthritis or autoimmune disease, we do not know why women using AIs have these musculoskeletal symptoms. Still, knowing that the drugs are not promoting inflammatory arthritis may be beneficial to a number of women,” she concludes.

“It would be prudent to refer those experiencing joint pain to a rheumatologist to rule out a previously undiagnosed autoimmune disease, and so that we can help address the symptoms,” Shanmugam says. “Since the syndrome doesn’t appear to be related to inflammatory arthritis, women should be encouraged to stay on their medication so they can gain the full benefit from it.”

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The study was supported by funds from the Georgetown University Department of Medicine, Grant and the National Institutes of Health. Shanmugam’s research is funded by the American College of Rheumatology, Research and Education Foundation, Physician Scientist Development Award and the National Center for Research Resources.

Claudine Isaacs, a co-author, is part of a speakers bureau for AstraZeneca, which makes an aromatase inhibitor. No other authors report related financial interests.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis—or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Georgetown Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO). In fiscal year 2009-2010, GUMC accounted for 79 percent of Georgetown University’s extramural research funding.

Research to be presented Tuesday, November 9, 2010, 9:00 am / Halls B1 & B2 Abstract: [912] - The CIRAS Study: A Case Control Study To Define the Clinical, Immunologic and Radiographic Features of the Aromatase Inhibitor Arthralgia Syndrome.

Victoria K Shanmugam, MBBS, MRCP1,James McCloskey, MD2,Elizabeth Elston, MSc (PT)3,Sandra J. Allison, MD4,Claudine Isaacs, MD5,Jennifer Eng-Wong, MD, MPH5. 1Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, DC,2Department of Internal Medicine, Georgetown University Medical Center, Washington, DC,3Georgetown University,4Department of Radiology, Georgetown University Medical Center, Washington, DC,5Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC

Background: Aromatase inhibitors (AIs) reduce recurrence in post-menopausal hormone-receptor positive breast cancer. However, development of joint pains (Arthralgia Syndrome) limits compliance. The pathophysiology of this syndrome is unknown, but morning stiffness suggests an inflammatory etiology. Associations have been reported with tenosynovitis and autoimmune diseases. The CIRAS study was designed to determine the evidence for an inflammatory etiology.

Methods: Postmenopausal breast cancer patients followed at Lombardi Cancer Center with hand pain but without known autoimmune disease were recruited. Subjects receiving AIs were cases (n=25) while those not receiving AIs were controls (n=23).

Subjects were evaluated after abstaining from non-steroidal anti-inflammatory drugs for 48 hours. They completed a health assessment questionnaire (PROMIS-HAQ). The rheumatologist completed a history and physical, and disease activity score (DAS-28). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibody (ANA), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), vitamin D and cytokine levels were tested. Bilateral hand radiographs and ultrasound were performed. The hand ultrasound was scored for presence of flexor tenosynovitis, fluid in the metacarpophalangeal joints, tissue edema, and tendon sheath enhancement for each digit on both hands, and a total ultrasound score was computed. The rheumatologist and radiologist were blinded as to study group. Data was analyzed using t-test and Fisher’s exact test.

Results: Patients in both groups were predominantly Caucasian and of similar age. Neither the DAS-28 nor the ESR was significantly different between cases and controls.

Hypovitaminosis D was found in 1 case and 5 controls (p 0.06).There was no significant difference in mean vitamin D. In each group two subjects had previously undiagnosed autoimmune disease (8.3%). A positive ANA was identified in 6 controls and 4 cases (20.8%). While cases experienced more prolonged morning stiffness, this did not reach statistical significance (p= 0.07). PROMIS-HAQ, global-HAQ and mean pain scores were not significantly different. There was no difference in ultrasound score or tendon nodules, Dequervain’s tenosynovitis, ganglion cysts or flexor tenosynovitis. Several patients in the control arm had a similar constellation of symptoms to those receiving AIs.

Conclusions: The arthralgia syndrome may not be unique to patients receiving AIs. This syndrome warrants further investigation since development affects compliance with AI therapy.

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