While recently published studies have suggested potential benefits of etoricoxib (Arcoxia, Merck) in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA), the Food and Drug Administration (FDA) recently issued a non-approvable letter to Merck in regard to the use of etoricoxib for OA.
In the letter, the FDA asked for additional data on the benefit/risk profile of the drug. The non-approvable letter comes shortly on the heels of a 20 to one vote by an advisory panel to the FDA, recommending against the agency’s approval of etoricoxib for OA.

Panel members cited safety concerns over potential cardiovascular (CV) risks of etoricoxib. Similar concerns over CV side effects have led to the recall of cyclooxygenase-2 (Cox-II) inhibitors such as valdecoxib (Bextra, Pfizer) and rofecoxib (Vioxx, Merck) in recent years.

While some people with arthritis have been waiting for the availability of another Cox-II medication, the FDA recently declined to approve etoricoxib, citing the need for more evidence on the benefit to risk profile of the medication.

However, recent studies have examined the use of etoricoxib for the treatment of OA and RA, and have found reduced gastrointestinal (GI) side effects and similar CV risks in comparison to the non-selective nonsteroidal antiinflammatory drug (NSAID) diclofenac.

In a randomized, double-blind trial involving 7,111 patients with OA, researchers found that etoricoxib 90 mg qd had significantly better GI tolerability and similar rates of thrombotic CV events with the comparator drug diclofenac sodium 50 mg tid. According to the study, which was published in the Journal of Rheumatology, there was a significantly higher incidence in the etoricoxib group of patients discontinuing treatment due to hypertension-related adverse events (AEs) but the authors note that few of these AEs were severe.

Two studies published separately in The Lancet in recent months discussed results from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study, which involved 34,701 patients with OA or RA. Comparing dosing of etoricoxib at 60 mg and 90 mg daily with diclofenac 150 mg for an average treatment duration of 18 months, researchers found similar rates of thrombotic CV events between the two drugs and significantly fewer upper GI side effects with etoricoxib.

Another double-blind, controlled study, published in BMC Musculoskeletal Disorders in late 2005, compared the aforementioned drugs in 617 patients with knee OA. According to the study, researchers found that etoricoxib demonstrated similar efficacy to diclofenac and had a lower incidence of GI-related side effects.

Weighing In On The Study Findings
Critics of the studies have questioned the use of diclofenac as a comparator drug, saying it has elevated CV risks. Yet others have noted that diclofenac is one of the more commonly prescribed NSAIDs worldwide for OA.

While she would like to see more details on the studies, Eileen Rogers, PA-C, calls the study results promising.
“Based on the information from these studies, I would certainly consider using etoricoxib if it is eventually approved by the FDA,” says Rogers, a clinical instructor at Lexington Medical Specialists in Columbia, S.C.
Gastrointestinal tolerability goes a long way toward considering etoricoxib as a treatment option if it is approved, notes Don Flinn, PA-C, the Vice-President of the Society of Physician Assistants in Rheumatology. If etoricoxib receives FDA approval down the line, Flinn says it could conceivably be an option to try if celecoxib is ineffective.

Recognizing The Need For Patient Education
That said, Flinn recognizes there is still quite a bit of trepidation over Cox-II drugs among patients and emphasizes the importance of patient education.

“I spend long minutes explaining that there is still one Cox-II selective inhibitor, celecoxib (Celebrex, Pfizer), that has not been recalled and that has been studied extensively and has proven to be as safe as any NSAID, whether it is a Cox-II inhibitor or not, when it comes to CV risk,” emphasizes Flinn, who works at McBride Clinic Orthopaedics and Arthritis in Oklahoma City, Okla.

Emphasizing Caution And A Stepwise Progression To OA Treatment
Mike Rudzinski, PA-C, says he tends to be conservative when it comes to prescribing any new pharmaceuticals.

“I like the new agents to pass a tincture of time test,” explains Rudzinski, who is affiliated with the Buffalo Veterans Affairs Medical Center. “I would expect minimal (if any) prescribing of the agent over the first six to 12 months after an FDA approval.”

Rudzinski emphasizes a stepwise approach to OA, opting for nonpharmacologic therapies first and then moving on to topical capsaicin. If there are no results, Rudzinski says he would try acetaminophen if there are no contraindications. For single joint OA, he says he would consider a corticosteroid injection before using a Cox-II agent. Then he would consider celecoxib if there are no contraindications. Similar to Flinn, Rudzinski would subsequently consider etoricoxib — if it receives approval in the future — if celecoxib is not effective.
Agreeing with Flinn, Rogers and Rudzinski note it is important to discuss the benefit/risk ratio of any medication with patients, whether the medications are traditional NSAIDs, nonpharmocological treatment options or Cox-II inhibitors.

Combination Therapy For Early RA: What One Study Reveals
By Aaron Becker, Associate Editor

When it comes to early rheumatoid arthritis (RA), initial combination therapy provides “earlier clinical improvement and less progression of joint damage” than initial monotherapy, according to a recent study published in Annals of Internal Medicine.

The study, which consisted of 508 patients with early RA, assessed four treatment groups that were divided as follows: group 1-sequential monotherapy; group 2-step-up combination therapy; group 3-initial combination therapy with tapered high-dose prednisone; and group 4-initial combination therapy with methotrexate and infliximab (Remicade, Centocor).

At the end of two years, 36 percent of group 3 made the transition to monotherapy and 31 percent of group 2 made the transition, according to the study. In comparison, 53 percent of those who were initially prescribed the combination of infliximab and methotrexate were able to transition to monotherapy.

Could early combination therapy make a difference in rheumatoid arthritis? A new study suggests possible benefits in the combination of infliximab and methotrexate.

“This is very important and really exciting,” says Kevin Latinis, MD, PhD, an Assistant Professor in the Department of Internal Medicine at the University of Kansas Medical Center. “(The study) is getting at the idea that we can really change the course of the disease and maybe even ‘cure’ the disease in some cases.”

Dr. Latinis says the study validates numerous other studies that support the idea that initial combination therapy leads to better clinical progress and reduced progression of joint damage.

While Dr. Latinis says initial combination therapy is the “ideal approach” in treating early RA, he notes that it is difficult to incorporate this approach into private practice.

Information overload can be challenging for newly diagnosed patients with RA just coming to grips with the disease. Accordingly, Dr. Latinis says educating a patient on the wealth of treatment options, including modalities such as various disease modifying antirheumatic drugs (DMARDs) and biologics, can be a daunting task.

He also notes that insurance can be an obstacle when it comes to early combination therapy.
“Insurance almost universally limits the ability to start with combination therapies, which include biologics at the first visit,” notes Dr. Latinis.

While there are obstacles, Dr. Latinis says studies like this one show the promise of combination therapy, noting that developments like these help rheumatologists in their efforts to successfully treat RA.

Cetrolizumab Pegol: A New Option For RA?
By Aaron Becker, Associate Editor

Results from a phase III trial of nearly 1,000 patients with RA suggest that certolizumab pegol (Cimzia, UCB) may provide a viable alternative for the treatment of moderate to severe RA.

Radiographic data from the study showed the combination of certolizumab pegol and methotrexate was significantly more effective at preventing structural joint damage than a combination of placebo and methotrexate after one year of treatment.

Nathan Wei, MD, says there are a number of potential benefits to the drug, a PEGylated, Fc-free anti-TNF medication. Given that certolizumab pegol is a nanobody, Dr. Wei says the drug may penetrate tissue more easily than monoclonal antibodies. He also notes that the drug lasts longer than other anti-TNF therapies and accordingly has less frequent dosing.

“(Certolizumab pegol) is given subcutaneously once a month,” adds Dr. Wei, a Fellow of the American College of Rheumatology. “It has a more favorable dosing schedule than etanercept (Enbrel, Amgen/Wyeth) or abalimumab (Humira, Abbott). The subcutaneous route might be more attractive than the intravenous route required for infliximab (Remicade, Centocor).”

Dr. Wei adds that certolizumab pegol retains biologic potency without the cytotoxicity mediated by the Fc portion present in the original monoclonal antibodies. Accordingly, there may be fewer immune-related side effects, suggests Dr. Wei, a Fellow of the American College of Physicians. He also notes that 95 percent of the drug is of human origin so there may be less allergic reactions.

New Guidelines Emerge For Intraspinal Pain Management
By Aaron Becker, Associate Editor

Pain management options such as intraspinal infusion are constantly evolving and changing. Accordingly, reassessing these modalities for safety provides added peace of mind for patients and practitioners alike.

With this in mind, the 2007 Polyanalgesic Consensus Panel recently convened and made changes to their guidelines for pain management via intraspinal infusion. The panel, consisting of national thought leaders in the arena of chronic pain management, made its recommendations based on a review of recently published data as well as changes in FDA status for emerging modalities.

One of the panel recommendations was adding ziconotide (Prialt, Elan Corp.) as a first-line treatment alternative to opoids such as morphine and hydromorphone. The panel also noted that clinicians could use ziconotide in combination with those opoids.

The 2007 Polyanalgesic Consensus Panel has made some changes and alterations to its guidelines on intraspinal infusion.

“Many patients have side effects from opoids, even when they are given intrathecally,” explains Timothy Deer, MD, a lead panelist at the 2007 meeting. “The addition of (ziconotide) makes it easier for doctors to use the drug for those patients and for those who have a neuropathic component to their complaints.”

The new guidelines also moved fentanyl from a fourth-line to a second-line treatment option. Dr. Deer says the move was prompted because fentanyl has a low incidence of complications compared to morphine and hydromorphone, including a lower risk of granuloma. He adds that fentanyl seems to work well in patients who have a pain generator near the catheter tip.

Dr. Deer says the revised guidelines, which will be published in a peer-reviewed journal later this year, offer insights on new modalities that pain management clinicians may feel more comfortable in using, and may also impact patient selection for pump and catheter drug delivery.

“Many patients who were not pump candidates in the past may now be proper to consider,” offers Dr. Deer, who is affiliated with the Center for Pain Relief in Charleston, W.V.

Study Says Infliximab Has Long-Term Benefits For AS
By Aaron Becker, Associate Editor

A recent study found that infliximab was effective and well tolerated in nearly 78 percent of patients with ankylosing spondylitis (AS) after four years of treatment.

The study, which was recently published in Rheumatology International, involved 35 patients with AS. Researchers noted in the study that infliximab facilitated a rapid improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Assessment Study scores after the first year of the treatment, and sustained these improvements through the fourth year.

Charles Moxin, MPAS, PA-C, is impressed with the compliance and tolerance that the study revealed with infliximab treatment.

“(The study) demonstrates that infliximab (Remicade, Centocor) is a viable treatment for patients with AS in conjunction with physical therapy and other alternate therapies,” notes Moxin, the President of the Association of Family Practice Physician Assistants.

Curt C. Stilp, MS, PA-C, says the study results are promising. However, he does recommend starting with conservative therapies first.

“Physical therapy is a very well tolerated and effective approach to patients with AS,” notes Stilp, an Instructor in the Physician Assistant Department at Rosalind Franklin University in Chicago. “If physical therapy fails, then you can proceed down the road to medications, possibly with infliximab.”

Moxin agrees. He says he would consider infliximab in patients who have had “minimal response to conservative therapies or in patients who have symptoms that are more severe.”

Study Finds Higher Mortality Rate In Patients With Arthritis And Cancer
By Aaron Becker, Associate Editor

People with either rheumatoid arthritis (RA) or inflammatory polyarthritis (IP) and cancer have a 40 percent higher mortality rate than patients with cancer and no inflammatory conditions. These findings emerged from a recent study published in Arthritis and Rheumatism.

The study, which was conducted by researchers in the United Kingdom over the course of 10 years, initially recruited 2,105 patients with a recent onset of IP. During the study, 123 of these patients were diagnosed with cancer. While researchers did not find any differences in the incidence of cancer among patients with IP as opposed to the general regional population, the significantly increased mortality rate in patients with IP and cancer in comparison to patients with cancer only was a startling finding.

A new study found a 40 percent higher mortality rate among patients with inflammatory arthritis or rheumatoid arthritis and cancer in comparison to those with cancer alone.

Jarrod Franklin, BSc, one of the study investigators, says there are many possible reasons for the reduced survival among patients with IP/RA and cancer. He says it may be related to differences in the way cancer is treated in patients with rheumatic disease but cautions that more research is needed on this issue. Franklin also says the type of cancer is another factor that researchers and health care providers need to consider.

“I suspect (the direct influence of RA or IP on cancer incidence) would largely depend on the site/type of cancer diagnosed,” says Franklin, who suggests more research into this area as well.

While Franklin comments that it is too early to know how or why the association between IP and RA and cancer survival exists, practitioners should be wary of the association, given the possibility that cancer-related pain reported by a patient with IP may be misconstrued as pain resulting from a rheumatic condition.

FDA Approves New Monthly Dosing For Risedronate
By Aaron Becker, Associate Editor

In a potentially promising development for postmenopausal women with osteoporosis (OA), the FDA has approved monthly dosing for risedonate sodium tablets (Actonel, Proctor and Gamble/Sanofi-Aventis).

Michael McClung, MD, FACP, says the new dosing is important as “compliance with both daily and weekly dosing regimens of bisphosphonates is poor.” The new dosing for risedronate sodium allows patients to take 75 mg tablets on two consecutive days per month as opposed to once-a-week dosing.

Monthly dosing of risedronate sodium tablets (Actonel) was recently approved by the FDA.

“Having the monthly treatment option with Actonel will provide my patients with an additional choice of how to take a medicine with proven effectiveness,” notes Dr. McClung, the Founding Director of the Oregon Osteoporosis Center in Portland, Ore.

The FDA approval was reportedly based upon results from a double-blind trial of over 1,200 postmenopausal women with OA. All patients in the study were age 50 or older. The study compared risedronate 75 mg on two consecutive days per month with 5 mg of risedronate daily. The study found the two different dosages had similar efficacy and were both well tolerated.

The new monthly dosing for risedronate also provides practitioners with an alternative to ibandronate (Boniva, Roche) that also offers monthly dosing for postmenopausal women with OA.

While Dr. McClung notes that both drugs appear to be generally well tolerated in clinical trials and clinical practice, he points out that multiple studies have shown that risedronate “consistently reduced” the risk of spine fracture in postmenopausal women with OA. He adds that risedronate has also proven to reduce the risk of non-spinal fractures in these patients. In comparison, Dr. McClung says the one study that evaluated the impact of ibandronate on fracture risk found a reduced vertebral fracture risk but no effect on the incidence of other types of fractures.

Study Says: Hip Replacement Complications More Common In Obese Women
By Aaron Becker, Associate Editor

A recent study published in Arthritis Care and Research found a higher risk of complications with primary total hip arthroplasty (THA) in obese women.

The authors of the study evaluated 817 patients five years after they had undergone a primary THA. They found that obese women had considerably higher rates of infection and dislocation, and moderately lower functional outcome and slightly less satisfaction. Interestingly enough, obesity reportedly had little or no effect on infection, dislocation or functional outcome in men who underwent a primary THA.

Researchers of the study suggest the increased number of dislocations in obese women may be attributed to lower peripheral muscle strength. They also note that the lower functional outcomes could be due to factors such as a higher incidence of osteoarthritis (OA).

Rick Pope, MPAS, PA-C, the President of the Society for Physician Assistants in Rheumatology, says he sees a much higher incidence of obesity among patients with knee OA than he does in patients with hip OA.
In regard to the study, Pope says most orthopedists are aware of the increased risk for hip replacement complications in obese patients. Accordingly, Pope notes that in his clinical experience, surgery is frequently delayed while these patients attempt to lose weight.

“We recommend exercise programs that will not aggravate their underlying joint pain but will increase their overall metabolism and make dietary intervention more effective,” explains Pope, the senior PA at the Arthritis Center of Connecticut in Waterbury, Ct. He adds that swimming is “an excellent exercise that takes weight off the joint and provides increased calorie consumption.”

When patients have a BMI of 40 and over, Pope says various surgical procedures have been recommended at his practice, and notes that he has seen success with gastric bypass and stapling in this patient population.

Editor’s note: The following are exclusive news articles available only on www.arthritispractitioner.com.

What A New Study Reveals About Depression In Patients With RA Or SLE
By Aaron Becker, Associate Editor

One often overlooked aspect of managing rheumatic diseases is the possible psychological impact of these diseases on the patients.

Accordingly, a recent study published in Arthritis and Rheumatism assessed appearance concerns and psychological issues among 157 patients with chronic rheumatoid arthritis (RA), newly onset RA or systemic lupus erythematosus (SLE). Researchers found that “appearance was predictive of depression in patients with RA and SLE.” Disability was also predictive of depression among patients with RA, according to the study.

In her clinical experience, Judith James, MD, PhD, notes that patients with SLE often have appearance concerns “as skin manifestations can be a significant part of the illness.” Dr. James, the Lou Kerr Chair in Biomedical Research at the Oklahoma Medical Research Foundation, adds that some of the medications (especially steroids) used by patients with lupus can also lead to side effects (such as acne), which can also be a significant issue.

However, Dr. James notes that practitioners tend to concentrate more on the vital or life-threatening manifestations of any particular ailment as opposed to issues of appearance that may signal a more serious concern.

In regard to the possible link between appearance concerns and depression, Dr. James notes depression is common in many of the patients she sees with SLE. She adds that sleep disturbances, chronic diffuse pain, loss of enjoyment and depressed mood are also common among patients with SLE.

When clinicians suspect that a patient with SLE has symptoms of depression, Dr. James emphasizes appropriate referral to psychiatrists with an interest in treatment for depression among patients with chronic disease. However, she notes it is not always easy to find these specialists.

While the study suggests that cognitive behavioral therapy can be effective for patients with depression, Dr. James notes she has referred SLE patients for this type of therapy. However, she says it can be difficult to find practitioners in her geographic area who perform this therapy and are covered by her patients’ insurers.

Study Reveals Rituximab’s Impact On Synovial B-Cells
By Aaron Becker, Associate Editor

A recent study published in Arthritis and Rhuematism confirmed that rituximab facilitates a rapid and significant decrease in the number of synovial B-cells.

The authors of the study evaluated the use of rituximab (Rituxan, Genentech) in 17 patients with rheumatoid arthritis (RA). According to the study, all the patients underwent an arthroscopic synovial biopsy prior to the first infusion of rituximab and one month after receiving the second infusion.

While researchers did not see a significant change in the Disease Activity Score 28-joint assessment, they noted that B-cells were almost completely depleted in peripheral blood and were significantly depleted at sites of inflammation.

Paul Emery, MD, FRCP says that the study results were “expected but (still) a helpful confirmation.” Jonathan Edwards, MD, concurs that the findings were not unexpected.

“We have known for some time that B cell numbers in the synovium go down but do not necessarily go away,” explains Dr. Edwards, a Professor in the Centre of Rheumatology at the University College London.

Dr. Edwards says the study findings are “probably of little relevance” to the improvement of patients with RA who are taking rituximab. In his opinion, B-cells in the lymphoid tissues are more important than local B cells when it comes to the development of RA.

Dr. Emery, an Arc Professor in The Molecular Medicine Unit in the University of Leeds in The United Kingdom, says he typically sees a reduction in the disease activity score for patients with RA eight to 12 weeks after initiating treatment with rituximab. In the study, researchers noted little change in the disease activity score at four weeks.