Tag Archives: rheumatoid arthritis

New Anti-Inflammatory Drugs Will End Anti-TNF Dominance

Tumor necrosis factor inhibitor drugs began to dominate treatment of inflammatory diseases like rheumatoid arthritis, psoriasis, and the inflammatory bowel diseases ulcerative colitis and Crohn’s disease a little over a decade again. Now, the time when the importance of the anti-TNFs will wane and newer drugs will take their place is clearly visible on the horizon. It hasn’t happened yet, but the era of anti-TNF dominance for treating inflammatory diseases that persisted throughout the 2000s will end in the next 5 years.

The anti-TNF era began in 1998 with the approval of etanercept (Enbrel) for rheumatoid arthritis and infliximab (Remicade) to treat Crohn’s disease. In subsequent years, the list of approved anti-TNFs expanded to include adalimumab (Humira), golimumab (Simponi), and certolizumab (Cimzia), and the approved indications grew to include many inflammatory disease of joints, the GI tract, and skin. The anti-TNFs revolutionized inflammatory disease treatment and made treatment to remission possible for many patients.

tumor necrosis factor (green, purple, black) and TNF receptors (blue)/courtesy Bassil Dahiyat; Science

But reports from just the past month show that new agents are overtaking the anti-TNFs.

In May, I reported from Digestive Disease Week on phase III trial results with vedolizumab, which was compared against placebo for patients with ulcerative colitis. One of the study investigators noted that vedolizumab beat the placebo arm for steroid-free clinical remission by 30 percentage points. “Nothing else is that good,” Dr. William Sandborn, professor of medicine and chief of gastroenterology at the University of California, San Diego, told me, and the benchmark he had in mind was the performance of the anti-TNFs in similar patients.

More recently, at the European Congress of Rheumatology earlier this month I heard a report on a head-to-head comparison of the anti-IL-6 drug tocilizumab (Actemra) and the anti-TNF adalimumab in patients with rheumatoid arthritis. After 24 weeks of monotherapy, patients on tocilizumab had nearly a fourfold higher remission rate than patients on adalimumab. Though the monotherapy trial design did not mimic the way most rheumatoid arthritis patients get treated, the new drug tocilizumab absolutely blew adalimumab out of the water in a rare head-to-head comparison among different classes of anti-inflammatory drugs.

And at the same meeting several talks highlighted another new anti-inflammatory class of agents coming soon to the U.S. market, the Janus kinase (JAK) inhibitors, such as tofacitinib, which is expected to received FDA approval later this summer. Phase III results show that tofacitinib has safety and efficacy that seems at least comparable to anti-TNF drugs, with the advantage of oral dosing.

Vedolizumab, tocilizumab, and tofacitinib are just the tip of new waves of anti-inflammatory drugs that will soon substantially alter a landscape that the anti-TNFs have mostly had to themselves for the past 14 years. For the moment, the anti-TNFs have the advantage of a longer track record for safety, but changing that is only a matter of time.

—Mitchel Zoler (on Twitter “mitchelzoler)

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At 25 Years, NIAMS Celebrates Progress, But Has a Long Way to Go

It’s been 25 years since the establishment of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and great strides have been made in diagnosis, treatment, and management of numerous conditions, “but you ain’t seen nothing yet,” said Dr. Francis Collins, director of the National Institutes of Health.

Opportunities for medical research have never been as great as they are today, said Dr. Collins, who gave the welcome address for NIAMS’ 25th anniversary at the NIH campus in Bethesda, Md.

Although prominent researchers in the field agreed that research has come a long way in the past 25 years, they stressed that there is still a long way to go. Currently, the molecular basis for 4,000 diseases is known, said Dr. Collins. “But we have effective treatment for only 200.”

In broad strokes, the day-long event touched on the past, present, and future of major diseases of bones, joints, muscles, and skin – including muscular dystrophies, osteoporosis, rheumatoid arthritis, and lupus – through panels and discussion involving prominent researchers, physicians, and patient advocates.

“These diseases are chronic, crippling, and common,” said Dr. Stephen Katz, director of NIAMS, in his opening address. “They affect every family in the United States.”

Among the attendees were many researchers and clinicians who said they felt loyalty and appreciation for receiving funding from NIAMS at some point in their career. For some, the progress in the past 2 decades was quite tangible.

“Public investment in osteoporosis research has really changed how we take care of the patients,” said Dr. Sundeep Khosla, president of the American Society for Bone and Mineral Research. Dr. Khosla, professor at the Mayo Medical School, Rochester, Minn., recalled a time more than 2 decades ago when calcium, vitamin D, and estrogen were the only options he could offer to patients with osteoporosis.

A few years later, bisphosphonates became available, then came anabolic drugs, and now more drugs are in the pipeline. Patient diagnosis also has advanced, he said. Although he agreed that the field still has a long way to go, he was optimistic about more progress. “Who knows what will happen in the next 25 years?” he asked.

There was talk of individualized therapy, balancing research and treatment, and a closer collaboration among scientists, all in the spirit of bringing better diagnosis and treatment to patients.

“We’re in a different world from when all we had was aspirin,” said Dr. Daniel Kastner, a scientific director at the National Human Genome Research Institute. “But what we really want is a cure. And we’re not there yet.”

Naseem S. Miller (@ReportingBack)

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Rheumatology’s PR Problem

Overheard on the steps of the ExCeL London convention center on the last day of the annual European Congress of Rheumatology:

Attendee 1: “What is rheumatism?”

Attendee 2: “You know. Achy legs and such.”

Attendee 1: “Sounds dull.”

Attendee 2: “They’re probably saying that about us.”

Attendee 1: “Doubt it.”

In the interest of full disclosure, I should explain that not only was it the last day of this year’s EULAR congress, it was also the second day of the MCM Expo London Comic Con, which was taking place at the west end of the same convention center. The above discourse occurred between a giant insect and an anime character.

Photo by Diana Mahoney

It was impossible not to be amused by the unlikely juxtaposition of the two gatherings, particularly because the facility’s main entrance was on the building’s west side,. To get to the EULAR events, thousands of suited and serious rheumatologists had to weave in, out, and around the Comic Con crowd, all of whom were dressed as their favorite comic, manga, anime, film, game, and cult entertainment stars and were engaged in various modes of role play.

Despite the apparent incongruity, however, the above discourse seemed inherently relevant, as it came on the heels of a presentation that elucidated some persistent obstacles to the early diagnosis and optimal treatment of early rheumatologic disease, which I have come to think of as collective symptoms of rheumatology’s PR crisis.

In short, a lot of people don’t know what rheumatology is, and the opinions of those who have some vague sense of it continue to be colored by myths and misconceptions, including the belief that arthritis (or “rheumatism,” as per the arachnid quoted above) is a single entity and that there’s not much that can be done for it.

With respect to rheumatoid arthritis, in particular, this lack of awareness contributes to diagnostic and treatment delays that can have devastating consequences. While much effort has been spent recently on the development of early arthritis clinics within rheumatology centers as a way to streamline patient management, their success is limited. They can address the needs of only those patients who walk through the doors, not those of people who don’t seek treatment when their symptoms develop and persist or whose symptoms are inadequately assessed and managed initially by primary care physicians, according to session panelist Dr. Vivian Bykerk from Brigham and Women’s Hospital in Boston. “We have to remove all of the  roadblocks that are keeping very early inflammatory arthritis patients from getting to the rheumatologist,” she said.

Among the strategies recommended by Dr. Bykerk and co-panelist Dr. Paul Emery, EULAR president and head of musculoskeletal diseases at Chapel Allerton Hospital in the United Kingdom, were the possibility of prescreening referrals, the development of a specialized rheumatology referral form to help primary care physicians identify urgent referrals, the implementation of central triage clinics, and protocols for educating physicians and patients about the signs and symptoms of rheumatologic diseases and the value of early intervention. In other words, rheumatology needs better PR.

—Diana Mahoney

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Giving Nurses More Room in Rheumatology

At this year’s annual European Congress of Rheumatology (EULAR) in London, researchers presented data showing that an oral medication, tofacitinib, was more effective than a placebo for treating rheumatoid arthritis symptoms. The key word here is “oral.”

Read Sharon Worcester’s story for the details and an interview with investigator Dr. Joel Kremer. 

Some buzz around EULAR was that this drug, if it becomes widely used, might put some rheumatology nurses out of work if more patients opt out of infusion treatments.

courtesy of flickr user Shoreline (creative commons)

But never fear, nurses: the EULAR Nursing Task Force, a joint effort by rheumatologists, nurses, an occupational therapist, a psychologist, and epidemiologist, and patient representatives, is recommending ways to expand the role of nurses in arthritis care (no needles involved).

Ms. Yvonne van Eijk-Hustings of Maastricht University Medical Centre in the Netherlands emphasized that nurses can help in many other aspects of rheumatology care. For example, nurses in a rheumatology practice can serve as patient educators, and provide psychosocial support as well as disease management.  With that in mind, the recommendations call for improving access to training for rheum nurses so they can boost their knowledge and skills in these non-clinical areas.

Read my colleague Denise Napoli’s story on the Task Force recommendations.

What’s next for rheum nurses? They shouldn’t put away their needles just yet. More EULAR buzz suggests that the price of tofacitinib may be prohibitive for many patients for the immediate future. And in the meantime, the EULAR Nursing Task Force recommendations will be reviewed and disseminated, Ms. van Eijk-Hustings said.

Related News: Read Doug Brunk’s story on patients’ positive feedback after tofacitinib.

–Heidi Splete (on twitter @hsplete)

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Researchers Urged to Empower Arthritis Patients

 The European League Against Rheumatism (EULAR) has developed recommendations on how clinical researchers can partner with patient representatives. They’re not talking about simply including patients as the subjects of studies, but about having selected patients team up with the researchers in every step, from identifying what needs to be studied to how to conduct the study.

Apparently, having one or more patient representatives in EULAR scientific projects has become standard practice. Until now, however, researchers had no guidelines for the best ways to put this concept into practice, M.P.T. de Wit of VU Medical Centre, Amsterdam and associates wrote in an article published by the Annals of Rheumatic Diseases.

They crafted eight recommendations and bounced them off 28 patients and 53 professionals, who didn’t always see eye to eye. For example, a recommendation to include a minimum of two patient research partners in every project was embraced by 93% of patients but by only 68% of professionals. Read more in my full story.

The article points to previous efforts that successfully employed advance concepts of patient participation, including the Cochrane Musculoskeletal Consumer Group, which invites consumers to fill out an online survey and help set research priorities. The article also cites patient participation efforts at conferences on Outcome Measures in Rheumatology (OMERACT), and in creating the Rheumatoid Arthritis Impact of Disease (RAID) scoring system.

I have to admit, this was all news to me. I’m wondering if this is a concept that has taken hold in the United States, and in other fields besides rheumatology. If you’re a clinician, a clinical researcher, or a patient research partner, I’d love to hear your thoughts and experiences.

– Sherry Boschert (@sherryboschert on Twitter)

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The Top-Viewed Posts of 2010

Well, it’s that time of year: A time for reflection, a time for too much fattening food and drink, and probably way too much togetherness with relatives you spend the rest of the year trying to avoid. Here at Notes From the Road, we’d like to take a moment to reflect on the bounty that medicine has provided us in 2010 by sharing our most-viewed posts, as nearest as we can determine.

Via Flickr Creative Commons user yoppy

10. Would an Artificial Pancreas be a Diabetes “Cure?” By Miriam E. Tucker

The Juvenile Diabetes Research Foundation’s announcement yesterday of a partnership with Animas Corp. and DexCom Inc. to develop a first-generation automated insulin delivery system brought to my mind a question that is often debated in diabetes circles: Would a fully automated “artificial pancreas” represent a “cure” for type 1 diabetes? (Read more.)

9. Placebos vs. Antidepressants: Not Quite a Draw By Bob Finn

There’s a fascinating study in today’s Journal of the American Medical Association. It’s a meta-analysis of randomized controlled trials comparing antidepressants vs. placebo. And it showed that the placebo effect is so strong in depression that placebos work as well as paroxetine (Paxil) and imipramine (Tofranil) for all patients except those with major depressive disorder that’s classified as “very severe.” Placebo tied active medication for “mild,” “moderate,” and even “severe” depression. (Read more.)

8. Tocilizumab Approval Causes Buzz by Diana Mahoney

One year after asking the Roche group to submit additional data for its monoclonal antibody tocilizumab, the FDA has approved the biologic agent for the treatment of moderate to severe rheumatoid arthritis. (Read more.)

7. Head Injuries Predict Persistent, Bad Headaches by Sherry Boschert

Like many of the neurologists attending the annual meeting of the American Headache Society, I slipped into the hotel lobby during breaks in the program to watch World Cup soccer in bits and pieces. The images of players heading the ball caught my eye in a new way after hearing a couple of presentations about the associations between head injuries and persistent, more frequent, and disabling headaches. (Read more.)

6. Using Hemoglobin A1C to Diagnose Diabetes: What’s Your Take? By Miriam E. Tucker

The American Diabetes Association’s decision earlier this month to officially endorse hemoglobin A1c as a diagnostic test for diabetes is either timely, inappropriate, or long overdue, depending on whom you talk to. (Read more.)

5. Can Hemoglobin A1C Go Too Low? By Miriam E. Tucker

A new study showing increased mortality among type 2 diabetes patients at hemoglobin A1c levels below 7.5% raises a new question: Should diabetes guidelines be revised to include a minimum hemoglobin A1c level? (Read more.)

4. New Clues to the Root of Basal Cell Carcinoma by Doug Brunk

Findings from a novel investigation published in the Jan. 5, 2010, edition of Cancer Prevention Research are helping researchers better understand what causes basal cell carcinoma tumors. (Read more.)

3. Rheumatoid Arthritis 5.0 by Mitchel Zoler

Rheumatologists have remade rheumatoid arthritis, a pretty big deal for them if only because it’s “the major systemic rheumatic disease that we as a specialty treat,” said Dr. Michael E. Weinblatt, a Harvard rheumatologist, at the end of a 90-minute session on Sunday afternoon that unveiled a new definition of rheumatoid arthritis to the world. (Read more.)

2. Doctors Attend to Burning Man by Sherry Boschert

Next week more than 40,000 people from around the world will migrate to Black Rock Desert in Nevada to create a week-long community where clothing is optional, illicit drugs are common, and fantastical artwork is everywhere. Dr. Marc Nelson will be one of them at an event called Burning Man. (Read more.)

1. Doctors: Help Them Understand That “It Gets Better” By Mark Lesney

Any growing tolerance of a person’s right to his or her own sexuality that is evidenced in the mainstream culture has yet to impact the Lord of the Flies scenarios that exist for gay, lesbian, bisexual, transgendered, or questioning students in many schools across the country—something that is comically but bitingly portrayed in the Fox hit series “Glee.” (Read more.)

Thanks for following us in 2010. We hope you’ll be back for more in 2011.

— Alicia Ault (on Twitter @aliciaault)

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Video of the Week: When Anti-TNF Fails in RA Patients

Rheumatoid arthritis patients who fail on a first-time trial of tumor necrosis factor inhibitor therapy should change to a biologic with a different mechanism of action, according to Dr. Daniel E. Furst, who is a professor of rheumatology at the University of California, Los Angeles.

If by 12 weeks, you have no response at all, then it’s time to change. If, on the other hand, by 12 weeks you have a little response — just the begining of a change in the DAS [disease activity score], etc. — then it really makes sense to wait another 8-12 weeks before deciding to go to a different mechanism of action.

Read the latest news about rheumatoid arthitis and all things internal medicine at Internal Medicine News.

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Beating the Rheumatoid Arthritis Clock

The sooner top-level rheumatoid arthritis treatment starts, the better a patient’s chances for remission, according to a new analysis reported last week at the annual European Congress of Rheumatology, EULAR, in Rome.

image courtesy Flickr user Jackie Kever

Two years ago, results from the COMET study showed that starting RA patients on a combined regimen of methotrexate and etanercept led to significantly more remissions after 1 year on treatment than methotrexate alone. The new, post-hoc analysis divided the 400+ patients in the study, who began treatment 3-24 months after their RA diagnosis, into two subgroups: patients who began treatment within 4 months after their RA diagnosis, and patients who started treatment beyond 4 months.

The striking results, reported last week by Paul Emery, a rheumatologist at the University of Leeds, U.K., showed that patients begun on the tumor necrosis factor (TNF) inhibitor etanercept plus methotrexate within the first 4 months following diagnosis achieved a 70% remission rate after 1 year compared with a 48% rate in patients started on the same regimen but after the first 4 months passed. This time-dependent effect on remission rates did not appear in patients begun on methotrexate alone. In the methotrexate arms about 1/3 of patients reached remission after a year regardless of when the methotrexate started.

The 70% remission rate in the very-early treatment group jumps out as remarkably good, a “dreamed of” response rate, Prof. Emery said. The findings also reveal a clear window of opportunity. Newly diagnosed RA patients hit early with top-level treatment stand the best chance for their disease to fully resolve, a finding that extends the growing trend in rheumatology to diagnose and treat patients asap.

But the finding also sets up a tension between the potential reward from giving a TNF inhibitor plus methotrexate upfront and early and the potential downside that this strategy will put many patients on an expensive TNF inhibitor who would never need it. After all, a third of the patients in the methotrexate-only arm went into remission without ever seeing a TNF inhibitor. Will rheumatologists now need to decide between taking advantage of a transient opportunity to get the most out of treatment and the risk of giving patients a drug they might never really need?

Not necessarily. COMET ran during 2004-2006, so patients had their RA diagnosed by now obsolete criteria. New RA diagnostic criteria introduced by EULAR and the American College of Rheumatology last October aim to diagnose RA patients much earlier, and in these patients the treatment window of opportunity may be longer.

Second, even if patients start on a TNF inhibitor and methotrexate, another recent report from the Leeds group suggests that once in remission some patients can withdraw from the TNF inhibitor and remain in remission.  And third, hopefully in the near future researchers will find factors that identify the patients who will not optimally respond to  methotrexate alone so that adding a TNF inhibitor will not need to be done universally and in some cases needlessly.

—Mitchel Zoler (on Twitter @mitchelzoler)

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When RA Gets in the Way, and When It Doesn’t

There are people who don’t want to exercise, even though they are physically capable of doing so. Ironically, many people with rheumatoid arthritis want to exercise, but they are unable to do so because of chronic pain.

from flickr user dglider (creative commons)

The physical and psychological benefits of exercise are no secret, but in a study by Dr. Vibeke Strand of Stanford (Calif.) University, 49% of women reported that RA pain prevented them from participating in sports and exercising. Dr. Strand’s study, presented at the annual European Congress of Rheumatology (EULAR) in Rome  included nearly 2,000 women with RA.

Of these women, approximately two-thirds said that they experienced pain on a daily basis, including a majority of those who reported taking pain medication regularly. The study participants also reported that RA interfered with leisure activities and personal relationships, and even contributed to the deterioration of friendships and the end of marriages, Dr. Strand said in an interview.

The complete study data highlight the challenges of assessing and treating pain in patients with RA. The study results were limited by the use of self-reports of RA, but approximately 67% of the women said that they were constantly searching for new forms of pain relief.

Another event at the meeting highlighted how exercise empowers RA patients, including some who are severely disabled. An organization called Biking Against Rheumatism in Europe (BARIE) sponsored a multiday event in which a group of bikers, including individuals with severe RA riding on customized bikes, rode from Brussels to Rome, arriving on the first day of the meeting. Dr Strand’s data suggest that most of them were battling chronic pain. The goal of BARIE is to raise awareness of rheumatism. Ideally, more awareness will lead to more support for research, so more patients can live pain free for better physical and psychological health.

–Heidi Splete (on twitter @hsplete)

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Tocilizumab Approval Causes Buzz

One year after asking the Roche group to submit additional data for its monoclonal antibody tocilizumab, the FDA has approved the biologic agent for the treatment of moderate to severe rheumatoid arthritis (see story).

Although the drug, to be marketed under the name Actemra, is entering a somewhat crowded biologics market—it is joining abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab —it is the first and so far only interleukin-6 (IL-6) receptor inhibitor to be approved for the indication, and clinicians are cautiously optimistic that it will improve the lives of patients who have not responded to therapy with methotrexate alone or in combination with other disease modifying antirheumatic drugs (DMARDS).

 In fact, tocilizumab has been approved specifically for those adult patients who have failed methotrexate and one or more tumor necrosis factor antagonist, according to an announcement released today by the drug’s manufacturer, Roche Holding AG. 

The FDA approval is a much-anticipated development, according to Dr. Larry Greenbaum, a rheumatologist in private practice in Indianapolis. “It’s very exciting. Actually, one of the drug representatives has been stopping by my office for the last year or two, dropping hints about this product, although the company has not been allowed to “detail” the drug before release. And of course, there have been many drug company ads creating a crescendo of drum beats before the official release date,” he said in an interview.

The novelty of tocilizumab lends to the excitement. “There are multiple anti-TNF medications currently, and the reps for those drugs are trying very hard to convince clinicians to choose one medication over another, even though they are probably more similar than different,” Dr. Greenbaum commented. As an IL-6 blocker, tocilizumab IS different, which is why the industry is buzzing, he noted.

The new-drug hype notwithstanding, there are still a number of questions to be answered before clinicians can consider the potential clinical impact of tocilizumab, according to Dr. Greenbaum. “The main questions for me are: Is this medication any safer or more dangerous than the current biologic drugs? Is this medication more or less affordable (or accessible) than the current biologics? Where does this medication belong in the treatment algorithm?

“Undoubtedly, the company is going to try and convince doctors to use this medication immediately after methotrexate failure, but they will first have to convince doctors (and insurers) that this strategy is warranted,” Dr. Greenbaum said.

Of particular concern are the side effects. Biologic agents are powerhouse drugs, and powerhouse drugs often have the potential for causing serious adverse effects. Among the serious tocilizumab-related adverse events that have been reported in pivotal clinical trials include infections that lead to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis. In March 2009, Roche’s Chugai Pharmaceuticals reported that among nearly 5,000 rheumatoid arthritis patients in Japan who had been treated with tocilizumab between April 2008 and February 2009, 15 deaths occurred and the possibility of a link to the drug could not be denied, although the exact causes of the deaths were unknown, according to a press release issued by the company.

Some of the common side effects associated with tocilizumab include upper respiratory infections, including pneumonia, inflammation of the nose and throat, headache, high blood pressure, increased liver enzymes, increased cholesterol levels, neutrophil decreases, and platelet decreases, according to the company.

The drug’s approval comes with a Risk Evaluation and Mitigation Strategy (REMS), which includes a medication guide, communication plan, and timetable for submission of assessments. The drug itself will be available the week of January 18, 2010.

—Diana Mahoney (on Twitter @dmpm1)

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