New drugs for the treatment of both rheumatoid arthritis and osteoarthritis are here or expected to be here shortly, and no one could be happier than some of the patients with these diseases and, of course, the physicians, pharmacists, and other health-care workers who care for them. Also, the paradigm is changing, with nonsteroidal anti-inflammatory drugs losing the dominant place they have had for many years for the treatment of rheumatoid arthritis. This is because they merely relieve symptoms without affecting underlying disease processes, experts told Drug Topics.
"We're treating more aggressively early in the disease," said Fredrick Wolfe, M.D., clinical professor of internal medicine at the University of Kansas and director of the school's Arthritis
Center in Kansas City. "This is a marked change from what we've done before."
This means patients are no longer being told to just stay on NSAIDs for extended periods, while destruction of their intraarticular cartilage goes merrily on.
The key to this new approach is the early use of the so-called DMARDs (disease-modifying antirheumatic drugs), the list of which is getting longer. New research also indicates that the DMARDs should probably be given as combinations, rather than singly, in many patients. Although DMARDs do not cure the disease, they do serve to prevent or reduce joint damage, experts said. There are also many more drugs to choose from in this disease-modifying category, including a new formulation of cyclosporine--Neoral from Novartis--as well as some drugs that have been around for a while, such as the 50-year-old sulfasalazine. DMARDs most commonly used for rheumatoid arthritis include hydroxychloroquine, methotrexate, sulfasalazine, D-penicillamine, azathioprine, and gold compounds. Back to top
There is also a resurrection of the hypothesis that had prompted the fortuitous combination of a sulfa and salicylate half a century ago, which resulted in sulfasalazine. The hypothesis then was that rheumatoid arthritis was caused by an infection, so giving an antibiotic was a logical way to treat it. This idea gained added credence this year when results were announced of studies showing that the antibiotic minocycline HCl, which is sold under several brands and used to treat acne and a variety of other infections, can modify the disease process in patients with rheumatoid arthritis.
A close relative of minocycline--the broad-spectrum antibiotic doxycycline--is also being tested in clinical trials in osteoarthritis patients, to see whether infection plays a role in that condition, too.
There is also considerable excitement about the prospects for approval of drugs that aim at an entirely new target in rheumatoid arthritis--tumor necrosis
factor (TNF). Known to play a major role not only in stirring up trouble within the arthritic joint itself, TNF-alpha also
plays a role in attracting inflammatory cytokines from elsewhere, to make matters worse. Closest to market of the new TNF-alpha blockers is probably Enbrel (Immunex), with favorable results being reported from phase III trials.
There are also some exciting new prospects for the treatment of osteoarthritis of the knee--a common form of arthritis rendering daily tasks, such as walking and climbing stairs, difficult. New on the market to relieve symptoms of this degenerative joint disease are injectable agents aimed at replacing the synnovial fluid in the joint space that deteriorates with arthritis and contributes to the pain of bone rubbing on bone. These two approved drugs are Synvisc (hylan G-F 20, Wyeth-Ayerst) and Hyalgan (sodium hyaluronate, Sanofi). Back to top
Other drugs commonly used to treat patients with both rheumatoid arthritis and osteoarthritis are corticosteroids. Though the agents bring temporary relief from symptoms by reducing inflammation, they continue to present many side effects--especially with long-term use.
Patients also have a new option in NSAIDs, with the recent approval by the Food & Drug Administration of Arthrotec (diclofenac Na 50 mg or 75 mg/misoprostol 200 mcg, Searle). Lee Simon, M.D., associate professor of medicine at Harvard Medical School in Boston, referred to clinical studies showing that the combination pill was just as effective as diclofenac alone but with a reduced potential for GI toxicity. The combination was also shown to be cost-effective, when confined to high-risk patients, who make up a large portion of those taking NSAIDs. These include patients over 60, those with cardiac disease, those taking warfarin or prednisone, and those with a history of ulcers.
The recommended dosage of Arthrotec for osteoarthritis patients is 50 mg t.i.d. For rheumatoid arthritis, the recommended dosage is 50 mg three or four times daily. For patients who are intolerant, the dosage can be reduced to 50 or 75 mg b.i.d, although the company said that the regimen may not be as effective in preventing ulcers. Common side effects, usually transient, include abdominal pain, diarrhea, and stomach upset. The drug will be launched in February. A company spokesman said the price will be set at that time.
In the works, but not yet approved, are members of a newer type of NSAID, selective COX-2 inhibitors. Just like current NSAIDS, these agents exert anti-inflammatory effects by blocking the COX-2 enzyme. But unlike the others, they are not known to inhibit the stomach protective enzyme COX-1. As a result, COX-2 inhibitors may not be associated with the classic NSAID-induced GI disturbances. Phase III trials of this new type of arthritis drug have been conducted by Searle and Merck. Back to top
James O'Dell, M.D., professor of internal medicine and chief of rheumatology at the University of Nebraska, said that some lessons have been learned recently about how to better treat patients with rheumatoid arthritis. "If you treat patients earlier, they do better. This is true of all the disease-modifying therapies that we know of. So someone with rheumatoid arthritis who has persistent symptoms for three months and is not in remission on NSAIDs needs to be on DMARDs."
O'Dell referred to a large study presented at the recent American College of Rheumatology (ACR) meeting in Washington, D.C.--the so-called COBRA trial, showing that "if you treat patients really aggressively at the start, they're going to do better, and if you stop treating them aggressively, they tend to look like the people you didn't treat so aggressively."
In this study, patients with an average disease duration of only four to five months were treated either with a single drug, sulfasalazine, or with three drugs--prednisone, methotrexate, and sulfasalazine. Those on the triple-drug therapy were taken off the methotrexate and prednisone after six months, said O'Dell. "And they found that patients who had taken the three drugs got much better much quicker. They were able to keep their jobs and they had less [joint damage present] on their X-rays even a year and a half later, even though they had stopped taking the other two drugs."
It's not clear how long this "maintenance effect" would last, he said, because "unfortunately some of those patients started to look more like the other patients the longer they went. So we must learn how to maintain the dramatic benefit that they experienced early."
O'Dell also reported at the ACR
meeting how early treatment benefited patients given minocycline. In one study, he randomized 46 patients who had had their disease for less than a year and had not been treated with either DMARDs or steroids, to either minocycline or placebo. Of the minocycline-treated patients, 65% experienced a 50% improvement in their symptoms of joint stiffness, tenderness, and swelling, while 13% of the placebo-treated patients had such a result. The 15 patients who responded favorably to minocycline have now been followed for three years, he said, with five being in complete remission and another five showing 75% or greater improvement in terms of symptoms. Two more patients continued to respond on the drugs but were having troublesome side effects, while three patients had to add DMARDs or prednisone to their minocycline to control their disease. Back to top
Furthermore, when the drug was stopped for periods ranging from two weeks to two years, the patients experienced flares of their disease in all cases. However, 13 of the original group of 15 responded again when they were restarted on minocycline, O'Dell said.
While research is reaffirming that treatment should begin early, there is no confirmation yet as to exactly which combinations of drugs might be best used by an individual patient, or exactly how to maintain the gains that are achieved, noted O'Dell, who is also director of the Rheumatoid Arthritis Investigational Network, a six-state regional clinical study group. He stressed, however, that for best results, care of patients with active disease should be overseen by a rheumatologist experienced in treating patients with various drug combinations, rather than exclusively by primary care physicians.
As a rheumatologist in private practice, Abby Goulder Abelson, M.D., of the University Suburban Health Center in South Euclid, Ohio, an assistant clinical professor of medicine at Case West-ern Reserve University, said that the minocycline trial results were intriguing.
"I am a believer in not waiting long for DMARDs, especially in patients who present early with very high sedimentation rates, and a lot of inflammation," said Abelson. "I don't wait more than two or three months of NSAIDs before initiating DMARDs." She often starts with methotrexate and sometimes with hydroxychloroquine. Abelson finds little difficulty in using methotrexate, "if the patients are closely followed, have frequent blood tests, and if they are not drinking alcohol," she added. Combinations of drugs she uses include methotrexate and azathioprine. "And we're using more cyclosporine than we used to. It seems to be effective in a lot of the refractory patients." Back to top
The role of cyclosporine in treating rheumatoid arthritis was spelled out in some detail by David Yocum, M.D., professor of medicine in the division of rheumatology at the University of Arizona, at the recent ACR meeting. The newest version of cyclosporine, which was approved this year, is available under the brand name Neoral. He said that because the new formulation is a microemulsion, it is better absorbed than the standard Sandimmune (cyclosporine, Sandoz). He added that the new product produces a nonresponse rate of only about 5%, compared with 25% with standard cyclosporine.
Yocum noted that patients who are experiencing absorption problems with standard cyclosporine may fare better if switched to Neoral. As far as dosing goes, he said, it's better to dose the new lipophilic cyclosporine on the basis of body weight than on the basis of actual weight, because in very heavy patients the drug may be stored in adipose tissue causing a potential for drug toxicity. Distribution of the drug, Yocum added, "is largely extravascular, and metabolism is through the liver."
Studies show that, overall, about a third of the patients will respond to Neoral long term. Although the drug's role in early disease has not yet been established, at least one trial shows that earlier is better in terms of maintaining patients longer. But the real benefit of cyclosporine may come from using it in combination with methotrexate. Back to top
Yocum explained that the two drugs act differently in affecting the body's various immune cells. The theory behind using the two agents together "was that methotrexate primarily affects macrophages and monocytes, and inhibits IL-1, while cyclosporine inhibits Il-2 and T cells." This theory has also been supported by animal studies and one human study, he said.
Combining cyclosporine and methotrexate also appears to be synergistic, Yocum declared. This provides a new treatment for those patients who are "incomplete methotrexate responders."
The human study showed that the total area under the curve (AUC) for methotrexate is the same if given with or without cyclosporine. However, if given with cyclosporine, the parent drug methotrexate is increased about 30% and the major metabolite is reduced by 80%. "To be cynical, one might say cyclosporine just slowed down metabolism [of methotrexate]. However, by 24 hours, all drug has been cleared, and no increased side effects were seen in patients on the combination," said Yocum. "It's unclear whether this just means this is an expensive way to increase your methotrexate dose, although I think there is some truth that this is a biologic reaction."
Yocum said that theoretically there is some worry that using these two drugs together could potentially cause lymphoma. "But after 18 months, we found no untoward effect on immunological markers." Other studies, he said, are looking at antimalarials and gold compounds in conjunction with cyclosporine. The main point, he added, is that cyclosporine differentially affects T cells and Interleukin-2, so "it may be an excellent drug to use with other compounds."
Another investigational immunosuppressive drug, sirolimus (Rapamune, Wyeth-Ayerst), also appears to be synergistic with cyclosporine, although studies so far are in transplant models, not in arthritis, said Yocum.
The main reasons for discontinuing cyclosporine are its gastrointestinal effects, which can present as simply an "uncomfortable feeling," he said. Most serious side effects involve the kidney, with anywhere from 20% to 50% of patients in clinical trials showing an elevation of serum creatinine. The lab finding is accompanied by vasoconstriction in the glomerular arterioles of the kidney and a reduced kidney blood flow and glomerular filtration rate. Back to top
The way to avoid bad effects on the kidney, Yocum said, is observation of "the golden rule. The golden rule of cyclosporine therapy is to maintain the patient's serum creatinine at less than 30% above his or her baseline. If you follow the golden rule, the cumulative rate of reversal of effects on the kidney is about 50% at six months, and at 21 months, it is 100%. The higher you push the creatinine, the longer it will take for the creatinine to come down to baseline after you discontinue the drug." When the creatinine rises 30% above baseline levels, the effects on the kidney may not be reversible, and structural renal changes may remain.
Another possible side effect that occurs with this drug is hypertension. Studies have shown an approximate 10% to 15% elevation in blood pressure, with the risk being greater in those over age 55. The risk of sustained hypertension after stopping the drug is probably no more than about 10% in those patients who did not have hypertension to begin with, said Yocum. Most at risk, he said, are the elderly; patients with a reduced glomerular filtration rate; patients receiving concurrent nephrotoxins, "although NSAIDS are hard to avoid"; and patients treated with maintenance doses of more than 5 mg/kg/day, or in the case of Neoral, more than 4 mg/kg/day. Also at risk are "patients who develop high cyclosporine levels or patients in whom plasma creatinine rises significantly."
As for the risk for lymphoma in rheumatoid arthritis patients, Yocum said, worldwide data involving some 25,000 patients treated with cyclosporine show no increase at present, "although I think only time will tell if there is an increase or not."
One disturbing side effect in women, he said, may be an unwanted growth of hair. Tremor is another side effect, "although we see little at low doses." Patients may also report other side effects such as paresthesias or dyspepsia.
There are also drug interactions to watch out for, since calcium-channel blockers, for instance, can increase blood levels of cyclosporine.
Yocum said that, overall, with cyclosporine used as a single agent, "you're looking at a 30% to 40% response rate," but that combination therapy should increase this. Back to top
TNF-alpha drugs emerging
While the treatment of rheumatoid arthritis has been greatly enhanced by the use of DMARDs, the realization that these agents themselves are not curative has spurred the search for additional ammunition with which to attack the disease, such as TNF-alpha.
"Tumor necrosis factor alpha plays a central role in rheumatoid arthritis," said Peter Lipsky, M.D., of the University of Texas Southwest Medical School in Dallas, during the ACR meeting. "We know TNF-a has a variety of pro-inflammatory activities, including the production of additional pro-inflammatory cytokines and pro-inflammatory mediators."
"Emerging data suggest that as treatment, along with DMARD therapy, TNF-alpha inhibitors may be able to blunt the symptoms and signs of the disease over a period of at least 40 weeks, so it makes a significant difference in the patients' capacity to function," said Lipsky.
Indeed, the favorable results of phase III trials of Immunex's TNF-alpha blocker Enbrel have convinced the company to go ahead with a New Drug Application early this year. If approved, this would be the first of an entirely new class of drugs for the treatment of rheumatoid arthritis. Enbrel works by blocking the natural TNF receptor from attracting inflammatory cytokines to the affected joints. Back to top
"We are really hopeful that it will be approved," Michael Kleinberg, Pharm.D., v.p. of professional services for the Immunex Corp., told Drug Topics. "There are a number of drugs being looked at that involve various aspects of inflammation," he noted. "The whole science is really centering around inflammation cascades, and we happen to think that the soluble receptor that binds with TNF is one of the better targets for drug therapy."
Although the trials so far have involved patients with advanced disease who had failed other therapies, Kleinberg believes that additional trials should show that Enbrel can be used earlier in the disease process. The product comes as a lyophyllized powder, which when reconstituted is given by subcutaneous injection. "We see the pharmacist as being very active in terms of helping patients. I think we will see the pharmacist ... helping in the reconstitution phase and helping draw the medication up into the syringe, if required," he said.
Kleinberg, who also heads the Washington State Board of Pharmacy, said that he sees no problem with patients injecting themselves, because it will be similar to what diabetics do all the time with their insulin injections. He added that Enbrel has also been shown to be very well tolerated in the clinical trials so far.
At the ACR meeting, data from the drug's double-blind, placebo-controlled, randomized trial in 234 patients were released. They showed that patients receiving a 25-mg dose of Enbrel had a 71% reduction in their tender joint counts, compared with only 6% of the placebo-treated patients. All the patients in the study had previously failed on DMARDs. Lower doses were also effective but in fewer proportions of patients. Back to top
Something new for OA, too
There are approximately 16 million Americans with osteoarthritis, according to the Arthritis Foundation. The only ultimate cure for patients with a badly deteriorated hip or knee may be joint replacement. But, meanwhile, there are two similar agents--hylan G-F 20 and Na hyaluronate--that can stave off the time when that might be necessary, or perhaps prevent the need. Both are designed to replace the hyaluronic acid normally present in the knee joint, which protects the cartilage cushion capping the ends of bones from deteriorating and allowing the bones to scrape against each other.
Lisa Gottlieb, R.Ph., manager of product information services for Sanofi Pharmaceuticals Inc., described hyaluronate (Hyalgan) as "a viscous solution of a purified natural hyaluronate of high molecular weight derived from rooster combs." It has been evaluated clinically in comparison with intra-articular saline and with oral naproxen, in a 26-week, double-blind, randomized, multicenter U.S. trial of 495 patients with moderate to severe pain due to osteoarthritis of the knee.
In the study, one set of patients received five weekly intra-articular injections of hyaluronate, 2 ml, and placebo naproxen. Another group received only naproxen, 500 mg b.i.d. The control group was given five intra-articular saline injections and placebo naproxen. All patients got subcutaneous lidocaine injections and could take up to 4 gm per day of acetaminophen. The results? "Pain relief provided by Hyalgan was comparable to that obtained with naproxen therapy, and significantly greater than with intra-articular saline," said Gottlieb. Back to top
Charles Nicol, M.D., senior medical director of Sanofi, said that the typical course of therapy is five injections, with a cost of about $100 an injection, which he said would be similar to a course of intra-articular steroid therapy. He said the principal side effect has been pain at the injection site, which can be overcome with reassurance and perhaps the use of acetaminophen. While the drug is now indicated only for use in the knee, studies are ongoing to see how effective it is in the shoulder and hip, he said. He also said that there appears to be no need to test patients for allergy to avian proteins because this product comes from roosters. He said the product has been used elsewhere in the world for about 10 years, with no reports of anaphylaxis occurring after the injections. He added that studies have been conducted in patients getting the injections over a period of six months only, so there are no specific recommendations about taking a second course of injections.
As for hylan, the other hyaluronic acid replacement therapy, Charles Weiss, M.D., chairman of the department of orthopedic and rehabilitative medicine at the Mount Sinai School of Medicine in Miami, said, "In clinical use, a course of treatment consisting of three injections has provided pain relief in some patients for up to six months or more."
Wayne Potashner, M.D., a rheumatologist in Toronto, Ontario, who took part in a Canadian multicenter trial of hylan (Synvisc), said that he personally has injected 650 knees over a four-and-a-half-year period. "What we found was that, across all classes of osteoarthritis of the knee, there was a 77% response rate after the first injection, and 86% with the second set of the injections."
Potashner told Drug Topics that "basically, there are three sets of patients this treatment is good for.... Young people with early osteoarthritis who want to get on with their lives and are not ready for surgery; people who have changes on X-ray, but don't want to be on NSAIDs; and those with severe osteoarthritis who for one reason or another can't have knee replacements." He added that after three injections some of his patients don't return for more for another 18 months, and that he has found that repeated injections still work. Also, such patients use NSAIDs less, he said.
Potashner noted that he also used the treatment in a limited number of patients with osteoarthritis of the shoulder, hip, and ankle. "The thing I'd like to get across is that this is a treatment with few side effects and excellent efficacy, and it will help people we previously haven't been able to do much for." Back to top
Steroids and side effects
Corticosteroids are still commonly used to prevent the pain and inflammation of both kinds of arthritis, and they are known to make patients feel both better, in terms of their disease, and worse, because of the side effects. One side effect that rheumatologist Goulder Abelson of South Euclid, Ohio, would like everyone to pay far more attention to is the problem of osteoporosis in arthritis patients, and the need to treat this proactively.
"Patients on chronic steroid therapy get accelerated osteoporosis, and they can also get a secondary hyperparathyroidism," she warned. "The gold standard for treating osteoporosis is hormone replacement therapy," she noted, although some women may now wish to switch to the newly approved raloxifene, which has been shown to not have deleterious effects on the breast or uterus. She said that perimenopausal women can take an estrogenic compound around the time of menopause to alleviate vasomotor symptoms and then switch to a bisphosphonate such as Fosamax (alendronate sodium, Merck) or etidronate, or they may wish to go on combination therapy involving a bisphosphonate and an estrogen. Nasal calcitonin is another option for this group of women. Back to top
Based in Ohio, the author has extensive experience covering national and international medical and pharmaceutical meetings and is a clinical contributor to many journals.
WHY NEW DRUGS ARE NEEDED:
A PATIENT SPEAKS ...
Michelle Conti, 38, has had rheumatoid arthritis for about 12 years. She earlier had to drop out of medical school because of this but is now poised to graduate, as a physician's assistant, next June. "My symptoms started in 1984, when my left knee swelled," she explained. "They put me on nonsteroidals from the very beginning--and crutches and exercises. At one point, the orthopedic surgeon noticed my fingers were different colors, and he sent me to a rheumatologist.
"It took about a year to get the specific diagnosis. During that time, I started getting stiff all over, and my joints started aching. I was started on Motrin at a maximum dose, and this went on for four or five months, and I started getting sicker and sicker, losing more weight, and my fingers swelled. I was started on prednisone and Plaquenil as well as an NSAID. With the prednisone, I felt much better, although I felt the side effects right away. I turned a blue-black color and had to discontinue the Plaquenil.
"Later, I was put on injectable gold, and I had to abandon that because I got rectal bleeding, which is not a real common side effect. With oral gold, I developed diarrhea, so I was put in the hospital and begun on methotrexate. That was in the summer of '96. I did pretty well on that, but then I developed sores all over my mouth, and so they tried injectable methotrexate, but because of the NSAIDs and prednisone, I had a lot of GI bleeding, and I started to use higher doses of steroids to control flare.
"I was then started on Imuran and did well for a couple of years, but that was discontinued because it was no longer effective, and this whole time I'd also been on the prednisone and the nonsteroidals. Then I was put on Cytoxan, which worked, but then I developed hemorrhagic cystitis, even though I was religious about the fluids. I also tried sulfasalazine somewhere in there.
"My options then were Leukeran or dapsone, and I was told if you get leukemia from the Leukeran, there's no treatment for it. With the dapsone you've got methemoglobinemia, and if that happens, you stop the drug. And if it's really bad, you use methylene blue, and it goes away, so I opted for the dapsone. I would be ready to consider TNF drugs. Considering what I'm already on, it sounds a little safer. Knowing what I know now, I can't say I would have made my choices any differently, although I would like to get off the steroids." Back to top
WHY NEW DRUGS ARE NEEDED:
A PHARMACIST SPEAKS ...
Keith Caryer, R.Ph., M.S., a pharmacist at the Cedar Fairmount Pharmacy in Cleveland Heights, Ohio, has a lot of contact with people with arthritis. "However, in the case of about half of my patients who are on hydroxychloroquine or methotrexate, I deliver the drug to them. This tells me that these people do not get around well. Their arthritis is crippling to them, and they live in constant pain. The other indication that they are not doing well is that there is a constant introduction of old drugs under a new name for topical application. That's an indication that people are seeking more relief, or better relief, than they're getting with their current therapy," said Caryer.
"I don't know how many of my patients are on prednisone because it has so many uses. Steroids are wonderful drugs, but they're two-edged swords because people can easily become conditioned to them. Also there's the potential to affect glucose metabolism, fat distribution, and the immune system, decreasing the patient's ability to fight off infection. Steroids also increase acid production, and because the patients are typically also using nonsteroidals, they have decreased capacity to protect themselves from their own acid production.
"There are drugs that help some people, but the miracle drug that everybody wants that will arrest or reverse the disease process--we don't have a good handle on this yet." Back to top
R.Ph.'S VIEW ...
Helen Lentz, R.Ph., is pharmacist-manager at the Rite Aid Pharmacy in Cleveland Heights, Ohio. "Most of my patients are on single agents for rheumatoid arthritis--I have very few combination people," she related. "It's NSAIDs, usually, or Plaquenil, usually either/ or. Many are also on steroids, usually when they have a flare-up.
"A lot of people want to take pills that are 'natural.' They're using the glucosamines and the chondroitin combinations. I've had people say they stopped taking NSAIDs. We also sell a lot of creams for arthritis. Some people are content to use these or they may take aspirin or Advil, but as far as going to the doctor for an actual prescription, they don't like to do that." Back to top