Arthritis Drugs & New Medications-2001 Meeting (cont.)

Dr. Shiel's Perspective: This is a welcome addition to treatment options, which have been sorely lacking for these diseases.

Enbrel-treated patients were able to mount a normal immune response to Pneumococcal vaccine.

Dr. Shiel's Perspective: This is significant in that it demonstrates that while TNF-blocking could theoretically increase the infection rate by impeding the immune system, at least the antibody-producing branch of the immune system is functional.

Two papers documented the effectiveness and safety of Enbrel in the treatment of ankylosing spondylitis in children (juvenile ankylosing spondylitis).

Dr. Shiel's Perspective: These are important papers that will open up options of treatment for this rare disease of children and even children under the age of 4 years, according to one of the studies.

Enbrel was documented to be effective and safe in treating juvenile rheumatoid arthritis in children under the age of 4 years.

Dr. Shiel's Perspective: Enbrel is already approved for use in children. This verifies its potential in the very young.

Two papers documented the effectiveness and safety of Enbrel in the treatment of ankylosing spondylitis in children (juvenile ankylosing spondylitis).

Dr. Shiel's Perspective: These are important papers that will open up options of treatment for this rare disease of children and even children under the age of 4 years, according to one of the studies.

ARAVA (leflunomide)

Arava reduces inflammation by suppressing the immune cells responsible for the inflammation. It does this by preventing the formation of DNA and RNA in the immune cells by inhibiting an enzyme (dihydroorotate dehydrogenase) that is necessary for the production of a critical component of DNA and RNA, pyrimidine (a nucleic acid).

Arava plus methotrexate was reported as helpful and safe in patients with rheumatoid arthritis who had failed treatment with methotrexate alone. Elevations in liver function test were reversible with either a dose reduction or discontinuation of Arava.

Dr. Shiel's Perspective: This is a combination that I have not yet used. Both drugs have similar potential side effects in the liver and bone marrow.

Remicade is frequently given together with weekly methotrexate as this has previously been shown to be helpful in preventing immune reactions to the Remicade. At this meeting, papers were presented that demonstrated the safety and effectiveness of Arava in combination with Remicade as an alternative to the methotrexate/Remicade combination in the treatment of rheumatoid arthritis.

Dr. Shiel's Perspective: I have already been using this combination effectively in my practice based on preliminary reports already published.

Arava was documented to be as safe after 2 years as in previously published studies of 1 year of use in patients with rheumatoid arthritis.

Arava's main side effects involve liver inflammation, skin rash, diarrhea, and reversible hair loss. Dr. Shiel's Perspective: These side effects all appear to be relatively uncommon and seem to usually improve or resolve with adjustments of the dosage of the drug.

Arava was shown to be well tolerated and effective in treating children with rheumatoid arthritis who had failed or were intolerant of methotrexate.

Dr. Shiel's Perspective: This appears to be an important alternative it appears in treating juvenile rheumatoid arthritis.

High doses of Arava were successful in treating 30% of lupus patients with resistant arthritis.

Dr. Shiel's Perspective: Arava is a drug that is used to treat inflammatory arthritis, such as rheumatoid arthritis. The doses used in this study were double the recommended doses. I won't be using this one until many follow-up studies are performed that verify safety and effectiveness.

Arava was reported as beneficial and well tolerated as a treatment for psoriatic arthritis in a study reported from Italy. Another study from Illinois demonstrated the effectiveness of Arava in treating both psoriasis and psoriatic arthritis.

Dr. Shiel's Perspective: These are preliminary studies with a small number of patients (six and twelve). More studies are needed to verify these encouraging results.

KINERET (anakinra)

This is the first in a new drug class that has just become commercially available for the treatment of moderate to severe rheumatoid arthritis, in patients 18 years of age or older, who have failed treatment with other disease-modifying drugs. It works by blocking the action of a chemical, interleukin-1, which is important in promoting inflammation. Kineret's safety and effectiveness has previously been documented in studies of over 1,300 patients with rheumatoid arthritis.

Kineret was shown to improve the functional status of patients with rheumatoid arthritis. In another study, Kineret was demonstrated to significantly improve the number of productive days at work and domestic home activity in patients with rheumatoid arthritis.

Dr. Shiel's Perspective: These are important because, after all, these are critical measures of successful treatment.

Kineret was found to be safe in patients when used in combination with Enbrel (see above). The safety of Kineret in over 1,100 patients was demonstrated as being similar to that of a placebo.

Dr. Shiel's Perspective: A combination therapy using more than one antirheumatic drug is commonly necessary in the treatment of certain patients with rheumatoid arthritis. This combination awaits further studies of Kineret before it is used commercially. Low white blood cell counts have previously been reported when combining Kineret with TNF-blocking drugs, such as Enbrel and Remicade. Kineret was also reported to reduce the inflammation of joints when used in combination with other arthritis drugs, such as indocin and methotrexate, but this was in rats. This drug appears relatively safe, but previous reports showed a small increase in infections as compared to the placebo. This drug must be injected into the skin daily. Local skin reactions (usually mild redness and irritation) at the site of the injections is the most common adverse reaction with the drug.

Kineret decreased signs of inflammatory arthritis in rats.

Dr. Shiel's Perspective: Well, this actually was a significant study because it demonstrated the beneficial effects of Kineret in reducing inflammation in the joints when used in combination with other arthritis medications, such as methotrexate.

The rate of side effects of Kineret was only slightly increased in regard to serious infections in comparison with the placebo.

Dr. Shiel's Perspective: I would like to see further side effect studies with this treatment. Preliminarily, these results are very encouraging.

ADALIMUMAB

This is a new drug that is not commercially available. Adalimumab (D2E7) is the first fully human, monoclonal antibody in development. Adalimumab is an investigational agent designed to block the activity of tumor necrosis factor alpha (TNF-a), which contributes to the inflammation in autoimmune diseases, such as rheumatoid arthritis. This drug, which is given by subcutaneous injection every 2 weeks, was effective in combination with methotrexate and seems to be well tolerated other than occasional injection site reactions. It is not yet commercially available, but is worth keeping an eye on.

Dr. Shiel's Perspective: Well, here comes a new kid on the block. It will be important to watch for further research on this drug. It may well be an effective addition to our current treatments. Injecting only every 2 weeks would be relatively convenient.

VALDECOXIB

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is being studied for use in the treatment of rheumatoid arthritis. It is not yet commercially available. Prostaglandins are chemicals that are important contributors to the inflammation of arthritis, which causes pain, fever, swelling, and tenderness. Valdecoxib blocks the enzyme that makes prostaglandins (specifically, cyclooxygenase 2 or Cox-2), thereby resulting in lower concentrations of prostaglandins. As a consequence, inflammation and its accompanying pain, fever, swelling, and tenderness are reduced. Cox-2 Inhibitors differ from traditional NSAIDs in that they cause less inflammation and ulceration of the stomach and intestine and do not interfere with the clotting of blood.

Valdecoxib was superior to the placebo and similar to naproxen (at 500mg twice daily) in effectiveness. At the lower doses, it showed less stomach irritation than Naprosyn.

Dr. Shiel's Perspective: This would be a welcome addition to Celebrex, which is the Cox-2 NSAID currently available for the treatment of rheumatoid arthritis.

Valdecoxib was shown to be beneficial in treating osteoarthritis of the hip.

Dr. Shiel's Perspective: This drug may be an additional Cox-2 on the menu in the near future.

ETORICOXIB

Etoricoxib is another Cox-2 NSAID that is being investigated for the treatment of rheumatoid arthritis (see Valdecoxib above). Previous studies have demonstrated this drug's effectiveness in relieving the signs and symptoms of joint inflammation.

Fewer patients treated with etoricoxib had to discontinue the medication because of gastrointestinal complications as compared with the traditional NSAIDs, Voltaren, and Naprosyn.

Dr. Shiel's Perspective: This is an example of a safety study that must be performed before a drug is approved to demonstrate its value. Because it is billed as a Cox-2 inhibitor, etoricoxib should, and apparently does, have advantages with regard to the stomach and intestines.

The experimental drug, Etoricoxib, was shown to be effective in the treatment of osteoarthritis of the knee and hip in over 200 patients.

Dr. Shiel's Perspective: This drug also may be an additional Cox-2 on the menu in the near future.

Fewer patients treated with etoricoxib had to discontinue the medication because of gastrointestinal complications as compared with the traditional NSAIDs, Voltaren, and Naprosyn.

Dr. Shiel's Perspective: This is an example of a safety study that must be performed before a drug is approved to demonstrate its value. Because it is billed as a Cox-2 inhibitor, etoricoxib should, and apparently does, have advantages with regard to the stomach and intestines.

GLUCOSAMINE

Glucosamine is a food supplement that is being used to treat the symptoms of osteoarthritis.

Glucosamine (in a radioactive form that could be identified in tissues) taken by mouth was found to be incorporated into the cartilage of Beagle dogs.

Dr. Shiel's Perspective: This study implies that glucosamine supplements taken by mouth actually can become bioavailable to the cartilage of the joints. Perhaps this will be shown to not only provide some relief of symptoms (already reported in some patients), but it may also be shown in future studies to protect the joints affected by osteoarthritis (being looked into at the NIH).

COMPLEMENTARY & ALTERNATIVE MEDICINES

Complementary and alternative medicines are being used by 33% of osteoarthritis patients. It was also shown that these patients seem to be more cautious about their health and seek specialists' care more commonly.

Dr. Shiel's Perspective: As a practicing rheumatologist for two decades, this is not really news. I frankly believe that this study grossly underestimates the number of persons using complementary and alternative medicines. It does, however, highlight the need for doctor-patient communication with regard to all manners of treatment.

PLAQUENIL (hydroxychloroquine)

Plaquenil is commonly used to treat rheumatoid arthritis and systemic lupus erythematosus.

Plaquenil protects against both heart and kidney damage in lupus patients. Another paper also found protection for nervous system damage.

Dr. Shiel's Perspective: Earlier studies had suggested this protective effect years ago. I tend to favor long-term usage of Plaquenil for such preventative purposes.

ALEFACEPT

Alefacept is an experimental drug that is not commercially available. Alefacept was given intravenously weekly for 12 weeks to 11 patients with psoriatic arthritis. It was found to improve joint symptoms and reduce the psoriasis.

Dr. Shiel's Perspective: This is a very preliminary study. I feel its primary interest lies in the fact that psoriasis and psoriatic arthritis are both significantly affected by T cell action. This drug blocks T cell activation and this likely explains its effects. While this report is encouraging, more studies will be required to verify the drug's safety and effectiveness of treatment in larger numbers of patients.

PROZAC

At this meeting, Prozac (fluoxetine) was demonstrated to be effective in relieving the symptoms of fibromyalgia in a study from the University of Cincinnati Medical Center. It seemed to significantly help the pain and fatigue, as well as associated depression. The patients studied were all female and were 18 years of age or older.

Dr. Shiel's Perspective: In speaking with the presenter of this paper, she told me that on average patients seemed to require higher than the starting doses of Prozac for best results. She adjusted up the doses at 2 week intervals. Prozac has been reported to be beneficial in the past when taken together with Elavil. This study documents that some patients will find Prozac helpful if taken alone.

ULTRACET

Ulracet was effective and well tolerated in relieving the pain symptoms of fibromyalgia. 313 patients were studied and 94% were female.

Dr. Shiel's Perspective: I am not surprised by this study, which was performed by one of the national experts in fibromyalgia from Oregon. I have been using Ultram for some time and finding it helpful for many, but not all, patients with fibromyalgia. Ultracet is a combination pill that contains both the main ingredient in Ultram and acetaminophen (Tylenol).

COLCHICINE INTRAVENOUSLY

21 deaths from intravenous (given in the vein) colchicine were reported. The causes of death included bone marrow suppression and kidney failure.

Dr. Shiel's Perspective: Colchicine is commonly used to treat both gout and pseudogout. Although this drug is typically given by mouth, occasionally there is no other method of administration in certain patients except to give it by vein (intravenously). This study strongly emphasizes that when it used in this manner, colchicine can be dangerous if the doses exceed the maximum recommended cumulative dose of treatment of 4 milligrams. The doses must also be reduced in patients with kidney or liver dysfunction and in the elderly.

CYTOXAN (cyclophosphamide)

Lung scarring (pulmonary fibrosis) did not progress in most patients with systemic sclerosis, even without cyclophosphamide (Cytoxan), over 6 years.

Dr. Shiel's Perspective: Lung scarring conditions can seriously damage the lung. Although Cytoxan can improve many lung scarring conditions, it is now difficult to recommend this potentially toxic drug for the scarring form of scleroderma lung (pulmonary fibrosis). This form of lung disease must be distinguished from inflammation of the lungs' tiny air sacs (alveolitis), as in the next report below.

The inflammation of the lungs' tiny air sacs (alveolitis) stabilized or improved in scleroderma patients treated with cyclophosphamide (Cytoxan) and prednisone.

Dr. Shiel's Perspective: This form of lung disease (as compared to the one described in the report above) actually did respond to Cytoxan. The key element seems to be inflammation. If inflammation is present in the lungs, it may be helped by Cytoxan treatments (typically given as a monthly intravenous infusion). The exact form of lung disease requires a lung biopsy for a precise diagnosis.

For patients with Wegener's Granulomatosis, cytoxan (cyclophosphamide) that is taken by mouth with prednisone until the condition is in remission and then switched to methotrexate for 2 years and tapered off was effective and less toxic than the traditional long-term Cytoxan treatment.

Dr. Shiel's Perspective: This was an important paper presented at this meeting. Methotrexate has recently been introduced as a drug for Cytoxan treatment failures. I have several patients doing very well on it for this purpose in my practice. The significance of this paper is twofold. First, while Cytoxan is very effective, it is also toxic. It now appears that Cytoxan will not be necessary in order to maintain long-term remission in Wegener's Granulomatosis and that doctors can convert to the less toxic methotrexate for maintenance. Secondly, the report also demonstrates that methotrexate can eventually be tapered off entirely after 2 years. This is good news for patients with Wegener's granulomatosis.

Churg-Strauss Syndrome patients did equally well if treated with Cytoxan (cyclophosphamide) for 6 or for 12 months.

Dr. Shiel's Perspective: This study suggests that doctors might now be able to recommend a shorter (and, therefore, less toxic) course of Cytoxan for patients with Churg-Strauss Syndrome.

VIAGRA

Viagra (sildenafil) seemed to help function in scleroderma patients with severe pulmonary hypertension (elevated blood pressure in the artery to the lungs).

Dr. Shiel's Perspective: Because Viagra has an effect on the smooth muscle of the blood vessels, it was tried in these very ill patients who had failed the traditional prostacyclin intravenous infusions. Although Viagra did show favorable results, these are very small preliminary studies. Incidentally, it might be expected that there would be some benefit on the Raynaud's phenomenon in patients treated with this drug, and that is exactly what the researchers saw in all patients. Further research studies are now needed to really determine the exact role and safety of Viagra in patients with scleroderma.

ERYTHROMYCIN

Erythromycin helped the stomach involvement in scleroderma patients more effectively than the bowel muscle-stimulator drug, metoclopramide.

Dr. Shiel's Perspective: Stomach and bowel muscles can become weakened as a result of scleroderma, thereby resulting in loss of normal function of the bowels. This is a serious condition. In the past, doctors have used bowel muscle-stimulating drugs, such as metoclopramide. Doctors have also used antibiotics (I use tetracycline or erythromycin). The reason for the antibiotics is that the bowel of scleroderma patients can become overgrown with bacteria, which is associated with slowing the bowel function. The antibiotics seem to improve this condition. This study is a head-to-head comparison of the two options. It is encouraging to see that common antibiotics can be beneficial in this condition.

TRENTAL (pentoxifylline)

Mouth and genital ulcers in patients with Behcet's disease healed and were reported as less frequent in 9 or 12 patients who were treated with Trental (pentoxifylline).

Dr. Shiel's Perspective: Trental also seemed to maintain the healed ulcers for up to the 29 months of the study. The effectiveness of Trental, the researchers said, seemed to be enhanced by the combination with colchicine in some patients. I felt this paper was significant because, to date, colchicine has been the mainstay of treatment of these often terribly painful sores. Now, it appears that we have other options.

LAMIVUDINE

Treatment of polyarteritis nodosa (PAN) that is associated with Hepatitis B with the anti-virus drug lamivudine, along with steroids and plasma exchange (plasmapheresis), can be safe and effective.

Dr. Shiel's Perspective: Traditionally, PAN that is not associated with hepatitis virus infection is treated with high doses of steroids and Cytoxan (cyclophosphamide). Cytoxan can suppress the immune system. Thus, if a patient's PAN is associated with hepatitis infection, the virus infection could worsen with Cytoxan. These researchers reported that removing immune factors in the blood with plasmapheresis combined with antivirus drug (lamivudine) can be beneficial in the situation of Hepatitis B-related PAN. This is very helpful information for doctors and those patients affected by this condition.

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Last Editorial Review: 12/3/2001