BOSTON—Associations between rheumatic diseases and cancer have been noted clinically for many decades, but only recently have some of the risk factors and possible mechanisms become clear. Rheumatologists should be aware of which connective tissue disease patients may be at increased malignancy risk and when it’s time to screen for cancer.
“It is our responsibility as rheumatologists to include cancer screening as part of our practice,” said Ami Shah, MD, MHS, assistant professor of medicine at Johns Hopkins Scleroderma Center in Baltimore. Dr. Shah and two other experts spoke on the latest research on the connections between autoimmunity and cancer, and what steps rheumatologists may take to diagnose malignancies quickly and refer those patients for therapy, at the ACR/ARHP Annual Meeting in Boston on Nov. 16, 2014. At the session, Current Understanding of Malignancies in Connective Tissue Diseases, they discussed risk factors that may prompt cancer screening.
Cancer–Myositis Connection
Although over the last century many anecdotal reports pointed to a connection between cancer and myositis, the association between the two diseases has long been questioned by scientists due to referral biases, small studies without appropriate control groups or unclear diagnostic criteria, said Frederick W. Miller, MD, PhD, chief of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences in Bethesda, Md. Only in the past several decades have data drawn from Swedish and Australian registries confirmed increased rates of cancers in myositis patients, especially ovarian, breast and pancreatic malignancies. Most patients developed cancer within two to three years of their myositis diagnoses, and dermatomyositis patients had the highest risk, Dr. Miller said.
“Many studies have also suggested that cancer is the leading cause of death when it occurs with either polymyositis or dermatomyositis, and thus, the focus should really be on treating the cancer in these patients,” said Dr. Miller. Rheumatologists should look for important risk factors to identify candidates for more careful cancer screening, he said.
Patients who are 45 years or older and male; have rapid unexplained weight loss after a myositis diagnosis; present with cutaneous necrosis, vasculitis or dysphagia; have high erythrocyte sedimentation rates (ESR) or high C-reactive protein levels; or are found to have autoantibodies to p155 may be at higher risk of malignancy, Dr. Miller noted. In addition, autoantibodies to nuclear matrix protein (NXP-2) or transcriptional intermediary factor (TIF1ɣ) may also be associated with cancer in myositis patients.
“However, some features appear to make it less likely that some myositis patients will develop cancer,” said Dr. Miller. Patients with anti-Jo1 antibodies; those with arthritis, arthralgia, interstitial lung disease or Raynaud’s phenomenon; or with autoantibodies to extractable nuclear antigens of any type may be less likely to develop malignancies.
Rheumatologists should carefully evaluate adults with myositis with hallmark risk factors in order to rule out cancer as the cause of some of those symptoms. Screening methods include a careful medical history; physical examination; general laboratory screening; chest X-ray; stool hemoccult three times annually; a prostate exam and prostate-specific antigen testing in males; and a careful gynecological examination, pap smear and mammography in females, Dr. Miller said. In female myositis patients, rheumatologists should also consider transvaginal sonography and testing for cancer antigen 125 (CA-125). Of course, it’s important to take individual cancer risk factors, such as smoking or family history of cancer, into account, too, when choosing screening evaluations, he said.
If cancer is confirmed, a clinician’s immediate therapeutic focus should be on the malignancy, said Dr. Miller, since “if you can completely resolve the cancer, in some cases you can completely resolve the myositis.”
Scleroderma Raises Risk
A systemic sclerosis (scleroderma) diagnosis may also raise a patient’s risk of cancer, particularly lung, bladder in females, hematologic, liver and nonmelanoma skin cancer in males, said Dr. Shah. In the Johns Hopkins Scleroderma Center cohort, about 12% of patients have a history of malignancy, she said. Cancer is a major nonscleroderma cause of death in systemic sclerosis patients.
Scleroderma patients with diffuse disease, those who are older at the first clinical signs of systemic sclerosis, patients with prior immunosuppressant use or chronic inflammation and organ damage may have a higher risk of malignancy, Dr. Shah said. Often, patients develop both systemic sclerosis and cancer within a close interval of each other, similar to dermatomyositis, she said. This has been commonly noted with breast cancer, but has also been observed with other tumor types.
‘It is our responsibility as rheumatologists to include cancer screening as part of our practice.’
Possible explanations for this temporal link between cancer and the onset of autoimmunity include the use of cytotoxic therapies (to treat cancer or scleroderma) or radiation therapy for cancer, a shared genetic susceptibility for both cancer and autoimmunity, commonly inciting environmental exposures or the possibility that systemic sclerosis is paraneoplastic, Dr. Shah said.
Significant data suggest that scleroderma is paraneoplastic in some patients, she said. Scleroderma patients with anti-RNA polymerase III antibodies have a greater-than-fourfold increased risk of cancer within a few years of scleroderma onset, and biological studies have demonstrated that anti-RNA polymerase III antibodies may be the manifestation of an immune response to tumor antigens, she said. Testing for this antibody may help rheumatologists identify scleroderma patients who should undergo more extensive cancer screening at disease onset.
Rheumatologists should perform a comprehensive physical examination on all new systemic sclerosis patients, and colonoscopy should be considered for patients who are 50 years of age or older. Female patients should have mammography at diagnosis and annually at 40 or older, pap smear every three years at 21 to 65, updated pelvic and gynecological examinations and, in some patients, transvaginal ultrasound or CA-125 testing, Dr. Shah said. Male patients should have an updated digital rectal exam and PSA test, and testicular examination should be performed in men under 40. All systemic sclerosis patients should be advised about the importance of smoking cessation and the use sunscreen to protect against cancer, she said.
As in myositis, effective cancer therapy may also be effective scleroderma therapy. Therefore, early identification and treatment of an underlying malignancy should be an important priority in patients with new-onset scleroderma.
Complex Associations
Why are autoimmunity and malignancy potentially linked? The clinical associations may be incredibly complex, said Antony Rosen, MD, director of rheumatology at Johns Hopkins Arthritis Center in Baltimore. “Even though we see cancer and autoimmunity largely as separate issues, sometimes, in rheumatic disease patients, they come together in time,” he said.
Dr. Rosen used the analogy of similar animals or land formations on distant continents that were once joined as part of the primordial land mass. Similarly, cancer and autoimmunity may cocluster, and immunoediting may help us understand why, he said.
Some autoantibodies may be an immunologic response to cancer in these patients. In one study of 16 scleroderma patients who also had cancer, eight had autoantibodies to (RNA polymerase III) RPC1 and had a very short duration to onset of cancer, he said. Of these eight, three also showed the very rare POLR3A mutation. When examining test results, look for a loss of heterozygosity, he said. “There was a striking loss of heterozygosity at the POLR3A locus exclusively in patients who had antibodies against RPC1,” something not seen in patients with other antibody specificities, he said. Patients may specifically respond to mutated antigens, responding by producing distinct sets of T cells. “Likely, the mutant form turns the immune response on; the antibodies are turned on, and this enables the patient to capture that antigen and make T cells to respond” to the tumor’s threat.
Cancer immunoediting includes three phases: elimination, equilibrium and escape. Early on, the body senses cancer and offers a potent immune response to eliminate it. “But cancer didn’t get to be where cancer is by being nonplastic, nondynamic or unable to evolve. Cancer will do everything it can to shake that negative force,” said Dr. Rosen. During equilibrium, cancer cells move, and the immune response follows to fight it—a highly dynamic and plastic process. However, the cancer is not gone, but unable to grow and spread due to the immune forces. As time goes by, cancer may become more mutated, dealing the immune system a “death blow,” and escape to cause damage, Dr. Rosen said.
In systemic sclerosis patients with autoantibodies to POLR3 (RNA polymerase III), the immune response may be due to a mutated autoantigen, said Dr. Rosen. Immunoediting occurs in human tumors as a potent anticancer mechanism, and this mechanism may help protect these patients by either killing the cancer or keeping it in the equilibrium phase, he said.
Susan Bernstein is a freelance medical journalist based in Atlanta.
