Steroids for Rheumatoid Arthritis

Steroids for RA: The argument heats up again
Oct 18, 2005
by Janis Kelly, Rheumawire

St Louis, MO and Rochester, MN - A group of researchers from the Mayo Clinic propose in an editorial in the October 2005 issue of the Journal of Rheumatology that, far from harming the cardiovascular (CV) system, glucocorticoids (GCs) "might actually reduce the risk of cardiovascular disease (CVD) in patients with [rheumatoid arthritis] RA" by lowering the background level of inflammation [1].

Although GCs have been implicated in increased CVD risk in several settings, Drs John M Davis III, Hilal Maradit-Kremers, and Sherine E Gabriel think that the situation in RA patients might be different. They suggest that RA patients differ from the general population because of their high level of inflammatory mediators and that "antagonism of such mediators by GCs might lead to reduced risk of CVD."

GCs linked to contradictory CV effects
This is an interesting proposal, since steroid exposure has been suspected in the twofold increased risk of CVD in patients with RA, and other traditional CV risk factors do not fully explain the high rate of CV problems associated with RA. With the growing recognition of the role of inflammation in CV damage, other effects of steroids are attracting research attention. "Inflammation plays a fundamental role in the pathogenesis of CVD in RA," Davis writes.

Davis notes that 30% to 50% of RA patients in recent therapeutic trials report having taken GCs and that rheumatologists commonly use these drugs as "bridge therapy" while waiting for slow-acting DMARDs (or insurance reimbursement) to kick in and as treatment for RA flares. Despite decades of use, surprisingly little is known about the long-term effects of GCs in RA patients, particularly with regard to the cardiovascular system.

For example, GCs might worsen CVD risk by increasing lipid levels, worsening glucose tolerance, increasing hypertension, or increasing obesity. Conversely, GCs might reduce CVD risk by reducing systemic inflammation. The fact that effective treatment of systemic inflammation with DMARDs is associated with reduced CV mortality suggests that the latter effect is important, Davis says.

An intriguing finding from epidemiologic studies is that RA flares might trigger CV events. Davis et al point out that the risk of a CV event is independent of the duration of RA and that the risk of sudden CV death and silent myocardial infarction increases very early in the RA disease process. "These associations between episodic fluctuations in level of systemic inflammation and onset of cardiovascular events suggest the possibility that using GCs to control flares of disease activity may actually lower the risk of cardiovascular events," the authors write.

Obviously, the tangled relationship between GC exposure, RA, cardiovascular risk factors, and CVD requires a lot more research. Meanwhile, Davis et al write, "[E]radication of inflammation in RA appears important, not only for the joints, but also for the longevity of the cardiovascular system. Use of GCs in early RA and targeted use to treat flares continues to be reasonable and possibly beneficial. However, limiting chronic exposure and employing careful measures to prevent osteoporosis, infection, and other steroid-induced sequelae are critical."

In a second editorial in the same issue of the journal, Drs Liron Caplan, Anthony S Russell, and Frederick Wolfe advise a considerably more cautious approach [2].

"Short-term outcomes are clearly improved with glucocorticoids. Studies that employ a brief exposure to steroids and subsequent tapering are similarly encouraging. In the small minority of patients uncontrolled on traditional DMARDS in combination with biologics, a regimen of limited steroid use probably still makes sense," Caplan (Washington University School of Medicine, St Louis, MO) tells rheumawire.

Caplan predicts that as pharmacoepidemiologic techniques become more powerful, evidence of toxicity at progressively lower levels of GC exposure will emerge. He says that physicians should be aware of the adverse effects associated with GCs and take practical steps to prevent them.

"For example," Caplan says, "Limit exposure, use prophylactic calcium and vitamin D, and in patients with lung disease, consider pneumococcal vaccine. It would not be unreasonable to systematically monitor patients on steroids for the broad spectrum of adverse outcomes attributed to their use."

Aromatase Inhibitors and the Syndrome of Arthralgias With Estrogen Deprivation

From ARTHRITIS & RHEUMATISM Research News Alerts
Aromatase Inhibitors and the Syndrome of Arthralgias With Estrogen Deprivation
Posted 10/10/2005
Recent evidence suggests caution in prescribing hormone therapy for breast cancer and sheds new light on "menopausal arthritis."
One of the most effective new treatments for breast cancer is a hormone therapy. Aromatase inhibitors work by powerfully blocking the conversion of androgen precursors into estrogens, which lowers estradiol levels in the bloodstream and estrogen levels in peripheral tissues. Because aromatase inhibitors reduce the rates of recurrence in women with early-stage postmenopausal breast cancer, these agents are not only becoming widely used in breast cancer treatment, but also being explored for their potential to prevent the disease in women at high risk. While focusing on this therapy's promise, advocates have tended to downplay one of its drawbacks. Women treated with aromatase inhibitors often experience joint pain and musculoskeletal aching -- severe enough, in some cases, to make them stop the treatment.
Two noted researchers, David T. Felson, M.D., of Boston University Clinical Epidemiology Unit, and Steven R. Cummings, M.D., of California Pacific Medical Center Research Institute and University of California, San Francisco, have thoroughly examined the evidence linking aromatase inhibitors and, more broadly, estrogen deprivation joint pain. In the September 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), they share their insights to alert oncologists, primary care physicians, and other health care professionals to this widely overlooked, potential problem for women.
"Estrogen's effects on inflammation within the joint are not well known," Dr. Felson and Dr. Cummings observe. Yet, as they note, estrogen has well-established tissue-specific effects on inflammatory cytokines. Estrogen's role in joint inflammation could account for the increased sensitivity to pain that some women suffer with estrogen depletion. Citing studies of pharmacological suppression of estrogen and studies of natural menopause, the authors offer a look at compelling evidence associating estrogen deprivation with joint pain, including:
Aromatase inhibitors have been linked to higher rates of joint and muscle pain than tamoxifen and placebo in various clinical trials for breast cancer treatment and prevention. One example: In a National Cancer Institute of Canada study, 5,187 postmenopausal women who completed a 5-year course of tamoxifen therapy for breast cancer were randomized to a further 5 years receiving the aromatase inhibitor letrozole or a placebo. 21 percent of women taking letrozole reported joint pain compared with 16 percent of the women receiving placebo.
In a study of leuprolide, a hormonal agent used to treat infertility and a variety of gynecological disorders, 102 premenopausal women experienced symptoms of estrogen deprivation, such as vaginal dryness, after 2 weeks of treatment, and suffered joint pain between weeks 3 and 7 of treatment. Overall, 25 percent of the women developed persistent joint pain, affecting the knees, elbows, ankles, and other areas, during the study. The pain was resolved in all women between 2 and 12 weeks after stopping the leuprolide therapy.
In a postmenopausal estrogen/progestin intervention trial, women who received estrogen had a significantly decrease chance of musculoskeletal symptoms -- between 32 and 38 percent -- compared with women randomly assigned placebo. Symptoms reported in the placebo group included joint pain, muscle stiffness, and skull and neck aching. In other studies, however, estrogen replacement therapy had no beneficial effect on musculoskeletal pain.
Dr. Felson and Dr. Cummings also highlight recent data showing that Asian women undergoing menopause have lower estradiol levels than Caucasian women and seem to be more vulnerable to a syndrome commonly known as "menopausal arthritis." They also note the high rate of both osteoarthritis and rheumatoid arthritis in postmenopausal women. They conclude by stressing the need for further research into the contribution of estrogen deficiency to arthritis, as well as for recognizing the risks of musculoskeletal syndrome when prescribing aromatase inhibitors and other estrogen-depleting treatments.

Long-Term NSAID Use Cuts Oral Cancer Risk, but Raises Cardiovascular Mortality

By Anthony J. Brown, MD
NEW YORK (Reuters Health) Oct 07 - Long-term use of NSAIDs can reduce the risk of oral cancer, but careful monitoring is required because these drugs may also raise the risk of death from cardiovascular disease, according to a report in the October 7th online issue of The Lancet.
"When we analyzed the data, NSAID use was tied to a reduced risk of oral cancer, similar to what has been seen with colorectal cancer, but that didn't translate into a survival benefit," lead author Dr. Jon Sudbo, from The Norwegian Radium Hospital in Norway, told Reuters Health. "So, we went back and looked for an explanation and that's when we found a doubling of the risk of cardiovascular death."
The COX enzymes are thought to play a role in the development of oral cancer. Therefore, treatment with NSAIDs, which are known to block COX activity, could help prevent this malignancy. Two previous studies have investigated this topic, but they only included aspirin use and yielded conflicting results.
The findings are based on a comparison of NSAID use between 454 heavy smokers with oral cancer and 454 matched smokers without cancer. Overall, 263 subjects had used NSAIDs for at least 6 months, 83 had used acetaminophen, and 562 had used neither drug.
NSAID use cut the risk of oral cancer by 53% (p < 0.0001), whereas acetaminophen use did not have a significant effect. Moreover, the reduction in risk tended to increase with duration of NSAID use, reaching a maximum of 70% for 15 or more years of use.
Consistent with previous reports, smoking cessation was also tied to a reduced risk of oral cancer (p < 0.0001), the authors note.
As noted, long-term use of NSAIDs, but not acetaminophen, raised the risk of cardiovascular mortality by twofold.
Despite the concern over adverse cardiovascular effects, Dr. Sudbo believes that there may still be a role for NSAIDs in preventing oral cancer. "If you want to use these agents on a long-term basis (for any indication), you need to monitor patients carefully for cardiovascular events. If you're using them for cancer prevention, be sure you select patients at high risk for cancer."
Unfortunately, he said his team was unable to identify any factors that could predict which patients are likely to experience cardiovascular morbidity and mortality when using NSAIDs.
Dr. Sudbo said that his team is now planning a randomized trial to further investigate the anti-oral cancer effect of NSAID use. If all goes well, he expects the study to be completed in 7 years.
Lancet 2005.

FDA Approves Humira for Psoriatic Arthritis

by Yael Waknine, Medscape News

Adalimumab (Humira) Approved for Psoriatic Arthritis and Early RA On Oct. 3, the FDA approved a new indication and expanded the rheumatoid arthritis (RA) indication for adalimumab subcutaneous injection (Humira, made by Abbott Laboratories, Inc.), allowing its use in the treatment of psoriatic arthritis, and as first-line treatment for severe, active, and progressive RA in methotrexate (MTX)-naive adults.Approval of the psoriatic arthritis indication was based on the results of two clinical studies, including the phase 3 placebo-controlled Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) in 313 patients.Data from the ADEPT trial showed that nearly 60% of adalimumab-treated patients achieved a 20% improvement in arthritis signs and symptoms (American College of Rheumatology [ACR] 20) at week 12. The response was sustained through week 24, at which point nearly 25% of patients demonstrated a 70% improvement in ACR score (ACR 70). Adalimumab-treated patients also demonstrated significantly less bone erosion and joint-space narrowing at week 24 compared with placebo (increase in modified Total Sharp Score [mTSS] > 0.5 units: 9% vs 28.9%). Inhibition of disease progression was maintained through week 48 in patients continuing treatment during an open-label extension period.In addition, 42% of adalimumab-treated patients with more than 3% body surface involvement at baseline demonstrated a 90% improvement in Psoriasis Area and Severity Index score at 24 weeks compared with none of those receiving placebo. Approval of adalimumab as first-line therapy for RA was based on results from the PREMIER/early RA trial, showing that treatment with adalimumab plus MTX successfully inhibited radiographic progression in patients with recently diagnosed RA of fewer than three years' duration. In the trial, addition of adalimumab to MTX therapy yielded significant decreases in mTSS from baseline and nearly doubled remission rates at one and two years compared with use of MTX alone (mean, 1.3 vs 5.7 and 1.9 vs 10.4, respectively; Disease Activity Score <>

Infliximab May Reduce Progression of Ankylosing Spondylitis

By Megan Rauscher
NEW YORK (Reuters Health) Sept 30 - Treatment with the tumor necrosis factor (TNF) alpha antibody infliximab may slow radiographic progression of spinal lesions in patients with ankylosing spondylitis (AS), German researchers report in the October issue of Annals of the Rheumatic Diseases.
As senior investigator Dr. Juergen Braun from Ruhr University in Bochum, told Reuters Health, anti-TNF therapy is a "major advance in the treatment of AS, an, in part, debilitating disease that mainly affects rather young male and female patients."
"There is evidence that therapy for example with infliximab leads to significant and clinically relevant improvement of signs and symptoms of the disease" he added, "which also includes improvement of function and quality of life."
To study the effect of infliximab on the radiographic course of AS, the investigators analyzed complete sets of lateral radiographs of the cervical spine and lumbar spine in 82 patients. Forty-one were treated with infliximab 5 mg/kg intravenously every 6 weeks and 41 were treated conventionally.
Patients treated with infliximab showed less radiographic change over 2 years, despite being older, having AS for a longer period of time and having a higher level of radiographic damage at baseline, all of which were predictive of more damage over time.
Nevertheless, the authors conclude that "larger studies are needed to prove that anti-TNF treatment inhibits structural damage" in AS.
Ann Rheum Dis 2005;64:1462-1466.

TNF Blockers Do Not Raise Cancer Risk

NEW YORK (Reuters Health) Sept 27 - Although rheumatoid arthritis (RA) is associated with an increased risk of hematopoietic malignancies, tumor necrosis factor (TNF) antagonists used in the treatment of RA do not appear to raise the risk of lymphoma or solid tumors, Swedish investigators report.
Much of the data regarding cancer risk in RA patients are relatively old, Dr. Johan Askling, from Karolinska University Hospital in Stockholm, and colleagues note in two reports, both published in the October issue of the Annals of The Rheumatic Diseases. There has been evidence that TNF blockers raise the risk of lymphoma, but to assess the risk of cancer associated with these drugs, contemporary and comparable data on the expected incidence in RA are required.
Dr. Askling's group therefore assessed cancer risk in three groups of RA patients: a prevalence cohort of 53,067 subjects diagnosed with RA between 1990 and 2003, an incidence cohort of 3703 patients (<1 year from RA onset), and a TNF antagonist cohort of 4160 patients treated with etanercept, infliximab, or adalimumab between 1999 and 2003.
Through linkage to the Swedish Cancer Register 1964-2003, the authors observed the standardized incidence ratio (SIR) for lymphoma was 1.9 in the prevalence cohort and 2.0 in the incident cohort. The corresponding SIRs for leukemia were 2.1 and 2.2, respectively.
When compared with the lymphoma incidence in the prevalence and incident RA cohorts, the adjusted relative risk of lymphoma in the TNF antagonist cohort was 1.1. This "marginally augmented lymphoma risk...must be judged in the light of a higher disease activity among patients who are offered TNF antagonist treatment," the authors note.
"The extent to which the increased leukemia risk is caused by the RA itself, its treatment, or both, remains unknown," they add.
In the second paper, Dr. Askling's group analyzed the same patient cohorts for the incidence of solid tumors.
Overall, the SIR for solid cancer was 1.05 in the prevalence cohort and 1.1 in the incidence cohort. The risk appeared to be greater in men, largely because of a decreased risk of breast cancer.
The SIR among patients treated with TNF antagonists was 0.9.
The gastrointestinal cancer risk was marginally reduced in the prevalent cohort (SIR = 0.85), and slightly increased in the TNF-antagonist cohort (SIR = 1.2).
"Our results suggest that TNF antagonists as actually used in practice are not associated with a cancer pattern that differs from that of other patients with RA," the authors conclude, "although the non-decreased colorectal cancer occurrence may be a concern."
Ann Rheum Dis 2005;64:1414-1426.