New-onset malignancies can mimic rheumatic disease, and viral infections may present with rheumatic symptoms.
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CHICAGO—David Daikh, MD, PhD, professor of medicine at the University of California San Francisco and chief of the Rheumatology Division at the San Francisco VA Medical Center, said the overlap between malignant disease and rheumatic disease means rheumatologists should stay aware that more may be going on than just a rheumatic disorder.
He made his remarks in a session on rheumatic disease “mimics” at the American College of Rheumatology’s 2015 State-of-the-Art Clinical Symposium in May in a session that also covered statin-induced myopathy and infections that might bring on arthritis.
A malignancy can bring on rheumatic and musculoskeletal disease through primary or metastatic disease’s direct or indirect involvement of musculoskeletal structures, and through activation of autoimmune responses, he said.
Paraneoplastic syndromes can show rheumatic manifestations—skin and connective tissue symptoms, paraneoplastic arthritis or vasculitis—and malignancy that’s linked with using antirheumatic therapy.
Sclerodermatous skin changes, for example, have been associated with breast, ovarian, pulmonary and gastrointestinal cancers, and Raynaud’s phenomenon can also be a main manifestation of a malignancy.
“Carcinoma polyarthritis”—an inflammatory neoplastic arthropathy similar to late-onset RA—has been linked to solid tumors.
It’s a two-way street, Dr. Daikh said: RA, Sjögren’s syndrome and inflammatory myopathies can bring an increased risk of malignancy.
An association has been found between dermatomyositis and malignancy, particularly in those older than 45, with most cancers presenting within a year before or after the myositis diagnosis.
If an older patient has an unexplained or atypical myositis and responds poorly to therapy, an aggressive work-up of signs and symptoms is in order, Dr. Daikh said.
In one of his cases, a 59-year-old man with typical signs of dermatomyositis was put on prednisone. After two weeks, he reported some improvements, but then also reported abdominal pain and nausea. He immediately got an abdominal CT, and multiple liver masses were found.
“The take-home message that I’ve had from my patients,” Dr. Daikh said, “is that my threshold has to be lower for going beyond age-appropriate screening.”
Statin-Induced Myopathy
Dr. Mammen
Andrew Mammen, MD, PhD, an investigator with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, stood next to a slide listing 40 medications—all of which can cause myotoxicity.
“This is just a partial list,” Dr. Mammen said. Statins are prominent on the list because they’re so widely prescribed—13 million Americans are treated with them and to great benefit.
But, Dr. Mammen said, 5–10% of patients develop myalgias, and about 0.5% will develop CK elevations. Symptoms tend to go away after statins are stopped, but it can sometimes take as long as a year.
Certain statins come with greater risk of causing myopathy.
“Not all statins are created equal,” Dr. Mammen said. Those metabolized through the CYP3A4 pathway in the liver are more myotoxic, and those that aren’t are less so. Part of the reason for this is probably because so many other drugs are also metabolized through this pathway, he said, including HIV protease inhibitors. One study found that those given simvastatin had a 3,000% increase in statin concentration after HIV protease inhibitors were added. However, patients taking either of two other statins actually saw decreased statin concentrations after HIV protease inhibitors were added.1
Genetics can also increase the risk for developing myopathy. A genome-wide association study of 12,000 patients found that a single SNP—one found in organic anion-transporting polypeptide (OATP1B1), which regulates the hepatic uptake of statins—had a strong correlation for statin-induced myopathy, accounting for 60% of the incidence of statin toxicity in the patients.2
Also, Dr. Mammen said, the SNP distinguishes between the C allele and the T allele—and those with the CC genotype are at the highest risk of myopathy development.
“It won’t surprise me if we start to look for this genotype before prescribing statins to patients,” he said, because it could mean those patients should get a lower dose.
He also talked about the discovery of autoantibodies to HMG-CoA reductase (HMGCR), the pharmacological target of statins, in necrotizing myopathy patients. The investigation began with a 71-year-old man who had started a statin and developed myopathy symptoms, but the symptoms did not dissipate once the statin was stopped.
Through further studies, researchers found that this type of myopathy is rare, but for patients who have it, treatment is required. A study of 12 patients found that immunosuppressive treatment, mostly prednisone along with other therapies, lowered creatinine kinase levels and increased strength. Anti-HMGCR levels were lowered, but not reduced to normal levels.3
In treating patients who develop elevated CK levels, Dr. Mammen will generally continue statin use unless the CK gets to be triple baseline levels or they become weak—in which case, he’ll discontinue use and see if they improve. If they don’t, he’ll look for another type of myopathy.
He emphasized the continued benefit of statins despite these potential problems.
“Statins, despite everything I just spent the last half-hour telling you, are really great medications, and for most of our patients, the benefits of these medications far outweigh the risks,” Dr. Mammen said.
Viral Infections with Rheumatic Manifestations
Dr. Jonas
Beth Jonas, MD, associate professor of medicine at the University of North Carolina School of Medicine’s Thurston Arthritis Research Center, reviewed viral infections that may present with rheumatic symptoms.
Hepatitis A, B and C infections can bring about these symptoms, but rheumatologists in the U.S. are most likely to see chronic hepatitis C (HCV) patients. Chronic HCV infection is associated with cryoglobulinemic vasculitis, arthritis and, sometimes, polyarteritis nodosa. The arthritis associated with HCV is usually non-erosive, but the disease can be difficult to distinguish from RA because many patients are RF positive, although a negative CCP antibody can help. HCV arthritis is more often seen in women, in older patients and in patients with more advanced fibrosis of the liver.
Physicians need to know that RA and HCV can coexist.
Patients treated with interferon for HCV can see their RA worsen, Dr. Jonas cautioned.
“I’ve seen patients who were diagnosed with HCV and thought to have HCV-related arthritis. Treatment with interferon led to a complete virologic response, but the arthritis persisted. In retrospect, the arthritis was likely RA.”
She also warned clinicians to be on the lookout for patients infected with the Chikungunya virus, which was first seen in Africa but has now spread to the Americas. Hundreds of cases have been seen in the U.S., mostly in Florida and New York in patients who have returned from the Caribbean.
Symptoms include fever, arthralgia and arthritis, and myalgia that can render some patients bedridden. In most patients, the fever and rash resolve in one to two weeks, but the arthritis can persist past six weeks or even much longer.
A 2012 study from India after an outbreak there found that arthritis or arthralgia lasted more than six weeks in 315 of 509 patients, and 5% had arthritis more than two years later.4
A recent study out of Washington University—involving 10 patients who had traveled to Haiti in 2014 and were found to be positive for the virus—reported that eight of 10 developed arthritis that lasted at least six weeks and that all of them met 2010 ACR/EULAR criteria for RA, showing how difficult this viral illness can be to distinguish from RA.5 RF and CCP tests were negative in all of them.
A mass cytometry analysis of these patients, RA patients and healthy controls found similar NK and T cell profiles in both. But they found differences in the activated T killer cells compared to the healthy controls, and a trend toward higher L-selectin expression in CD4+ T cells in the RA patients.
“These preliminary data suggest that it may be possible to differentiate chronic Chikungunya virus arthritis from early rheumatoid arthritis,” Dr. Jonas said.
“We should be asking patients if they’ve come back from the Caribbean, the U.S. Virgin Islands or other locations where the virus is transmitted. Because the patient may present many weeks or months after their travel, physicians and patients might be not making the connection,” she said. “You have to have a high degree of suspicion.”
Thomas R. Collins is a freelance medical writer based in Florida.
References
- Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS. 2002 Mar 8;16(4):569–577.
- SEARCH Collaborative Group, Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy—A genomewide study. N Engl J Med. 2008 Aug 21;359(8):789–799.
- Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum. 2012 Dec;64(12):4087–4093.
- Chopra A, Anuradha V, Ghorpade R, et al. Acute Chikungunya and persistent musculoskeletal pain following the 2006 Indian epidemic: A 2-year prospective rural community study. Epidemiol Infect. 2012 May;140(5):842–850.
- Miner JJ, Aw Yeang HX, Fox JM, et al. Brief report: Chikungunya viral arthritis in the United States: A mimic of seronegative rheumatoid arthritis. Arthritis Rheumatol. 2015 May;67(5):1214–1220.
