Until recently, there was little data about risk factors for acute urinary retention (AUR). Men with enlarged prostates seem to get it more, but that’s about all that was certain about this problem. Now, a new study published in the “Journal of Urology” sheds light on who’s most at risk for this painful condition.

Over 6,000 men from a long-term health study completed questionnaires about AUR and lower urinary tract symptoms. These men also filled out general health questionnaires every other year.

Overall, four to five men per 1,000 had acute urinary retention episodes each year during this two-year study. Chances of AUR increased with age, severity of urinary symptoms, and diagnosis of benign prostatic hyperplasia (BPH). Men with BPH who also had high symptom scores were nine times more likely to have an AUR episode than men without severe symptoms or benign prostatic hyperplasia.

About two-thirds of the men with AUR episodes had either high symptom scores or BPH, but about 20 percent of episodes occurred in “low-risk” men with no urinary problems or benign prostatic hyperplasia.

The urinary tract symptoms that made up the scale are:

Sensation of incomplete bladder emptying,
Having to void again after less than two hours,
Stopping and starting several times during voiding,
Difficulty postponing voiding,
Weak urinary stream,
Having to push or strain to begin voiding, and
Typically got up three times/night or more to void during the past month.

Having one of these symptoms more than 25 percent of the time doubled or tripled the risk for acute urinary retention, as did worsening of symptoms over a two-year period. Symptoms of urinary irritation or obstruction (incomplete emptying, urinary frequency, weak urine stream) particularly increased risk for AUR. Men taking calcium blockers, beta-blockers, or antiarrhythmic drugs were also at increased risk.

This research confirms that lower urinary tract symptoms are an important risk factor for AUR, whether measured by severity or increased frequency — a fact that has been inconclusively studied in the past. The study also confirms that acute urinary retention risk increases with age and presence of benign prostatic hyperplasia.

Results from a Phase I human study of a new treatment option for benign prostatic hyerplasia (BPH) helps men overcome problems associated with an enlarged prostate gland without the need for surgery.

BPH accounts for a variety of urinary difficulties in men over the age of 50. These symptoms typically include a need to pass urine more frequently (especially at night), an urgent need to urinate, weak or interrupted urine flow, a feeling that the bladder is not completely empty, and a delay or hesitation at the onset of urination. It is estimated that 50 percent of men over age 50 suffer from BPH.

Produced by Celsion Corporation, this exciting new therapy uses two mechanisms to overcome the problem of an enlarged prostate. First, a microwave balloon catheter system shrinks the prostate through the delivery of microwave heating. Second, simultaneous expansion of the balloon catheter compresses the walls of the urethra, enlarging the urinary opening.

Since the system is designed to relieve obstruction, it concomitantly relieves uncomfortable urinary symptoms. The procedure can be performed on a one-time, outpatient basis.

The results of the Phase I trial, conducted by researchers at the Montefiore Medical Center in New York, are reportedly encouraging. Principal investigator Dr. Arnold Melman stated that “(The) preliminary results suggest that the system, when fully tested and approved, could provide immediate symptomatic relief.” He added, “If Phase II studies are successful, I believe Celsion’s system should encourage a greater number of men with BPH to seek treatment, particularly those who suffer from milder forms of the condition.”

The company is in the midst of seeking approval from the U.S. Food and Drug Administration (FDA) for multi-site Phase II clinical studies. The studies are required to determine the safety and effectiveness of the system in benign prostatic hyperplasia patients. Pending FDA approval, Celsion plans to start Phase II studies in the summer of 1999. If the results obtained are positive, the company will then apply for premarket approval from the FDA to market the system in the United States.

Several studies in the past year have reported racial variations in the incidence of benign prostatic hyperplasia (BPH). Some have suggested that African-American men are more likely to get this condition than white Americans. Others report no differences. A new study looked at different definitions of race and BPH to try to sort it all out.

Researchers from the Harvard Medical School and Brigham and Women’s Hospital, both in Boston, examined data from the Health Professionals Follow-Up Study, a long-term study of more than 50,000 male healthcare professionals. The men were aged 40 to 70 when the study began in 1986, and have completed questionnaires and physical examinations every other year since.

Of the 31,775 men in this study, 3345 were defined as having benign prostatic hyperplasia, based on symptom reports, surgery for the condition, or diagnosis from a rectal exam.

After accounting for age, alcohol intake, smoking, weight, and other factors that affect BPH, the researchers found that black and Asian men were no more or less likely to develop benign prostatic hyperplasia than white men. They were, however, less likely to have surgery for it. The researchers also measured a number of hormones related to prostate symptoms, and again found no racial differences.

When Caucasians were split into groups, those of southern European origin were slightly more likely to have a variety of prostate problems, including BPH, than other white men, and those of Scandinavian origin were slightly less likely.

In the February issue of the Journal of Urology, the researchers explain that they used three different ways of classifying race and ethnicity to analyze the data, and the results were similar each time. They also used different combinations of benign prostatic hyperplasia symptoms, and again the results were the same.

The men in this study were well-educated professionals, the researchers point out, so they may not represent the general population of American men in health behaviors — diet, lifestyle and other factors that influence BPH. On the other hand, none of the factors measured in the study, including diet, obesity, lifestyle, vasectomy, blood pressure, or heart disease, accounted for the racial differences.

The researchers conclude that the “common contention” that black men are at higher risk, and Asian men at lower risk, than whites was not supported. They recommend further study of differences among different Caucasian groups.

Questions and Answers:

1. Do you know why mortality rates for elderly asthma patients have been rising more rapidly than for younger patients?

No one really knows, but there are several possibilities. When elderly people developed asthma, it used to be diagnosed as emphysema or bronchitis, but now we know that asthma can occur at any age. So it may not be a real increase in incidence, but simply better recognition. Second, as the population has aged in the last several decades, many diseases occur more commonly than they did years ago. We didn’t use to see many 80-year-olds with asthma because there weren’t many 80-year-olds around. When an elderly asthmatic dies, it’s not necessarily from the asthma. There may also be other factors that we don’t know about yet — ambient air quality, second-hand smoke. But I think better recognition is the most important factor.

2. Does asthma tend to be more severe in the elderly due to aging factors?

Again, this is not really known. My guess is that it’s because as people get older, lung function deteriorates. When you put asthma on top of that, patients do get much more symptomatic. Some, but not all, asthmatics get worse and worse over the years because of an excessive decline in lung function. If you live long enough, it’s going to lead to very severe disease. Research is just now being conducted to find out why and how often this happens. In part, it’s aging factors, and partly the chronicity of the asthma itself in some patients.

3. What complications of asthma are specific to elderly patients?

Elderly patients are more likely to develop problems tolerating their drugs, and interactions with other medications. Beyond that, I can’t really say that there are any complications specific to the elderly asthmatic.

4. What is the advantage of the shift to using long-term treatment strategies, especially with regard to the elderly?

Overall, there is much more emphasis on preventive therapy in asthma. Inhaled corticosteroids are anti-inflammatory in the lungs, and can prevent flare-ups, exacerbations and worsening of lung function. This leads to less utilization of the health-care system, fewer emergency-room visits, hospitalizations and so forth. Elderly people don’t perceive their symptoms as well, especially breathing problems, and are more likely to delay going to the hospital until symptoms are severe because they’re reluctant to complain, so anything we can do to prevent worsening of the disease would be advantageous, as it would in any patient with any disease.

5. Can people develop asthma at any age, or is the asthma seen in elderly patients really the continuation of a previous chronic condition?

I’ve seen patients in their 70s, 80s — even a 90-year-old I saw recently — develop asthma for the first time. It’s not known what causes this, but the leading theory is that it’s a viral respiratory disease that just goes haywire. What’s thought is that the inflammation from the acute infection for some reason stays in the lungs and worsens, and this eventually leads to some of the changes of asthma. Which viruses or other organisms are responsible is unclear. Some investigators think it may be a latent virus that’s been dormant in the body for years, even since childhood, until something, perhaps another respiratory virus or some kind of stress to the immune system, triggers a flare-up — as in shingles from chicken pox or fever blisters from the herpes virus. I wish I had more definitive answers, but this is all just conjecture at this point. What’s certain is that much research remains to be done in this field.

Improved knowledge of how asthma operates as an inflammatory disease has led to a major change in the way medications are used to relieve bronchospasm and remove mucous. Doctors are moving away from an emphasis on relatively short-acting agents to using long-term strategies with inhaled corticosteroids to prevent and eradicate airway inflammation.

Elderly asthmatic patients are prone to the same factors that worsen asthma in younger sufferers: viral respiratory infections, paint and household cleaning product fumes, cold air, exposure to smoke, etc. The pharmacological management of asthma does not differ very much in the elderly from what is used at any age, except in three ways: the elderly are likely to experience significant side effects from medications; they are more likely to develop drug interactions with other medications they may be required to take; and they are more likely to rely on medications over many years.

Because of these factors, another problem arises: elderly patients are less likely to take their medications regularly — or at all — either because of the side effects, or because they simply don’t want to admit to being ill. Furthermore, while some elderly asthmatic patients have only mild and occasional symptoms of wheezing and cough, most have almost continual symptoms. Doctors have been investigating ways to tailor medications to these individual needs.

The two main types of drugs used to treat asthma are bronchodilators, which are used as short-term treatment (a matter of minutes or hours) for symptoms such as wheezing, and anti-inflammatory agents which stop inflammation and are used primarily for prevention. Treatment with either of these classes of drugs has pros and cons that doctors need to weigh when prescribing medications for their elderly patients.

Beta2-adrenergic agents

Taking a beta2-adrenergic agent is the most effective way to open up obstructed airways in a hurry. It works by activating beta2 receptors in the lungs (found on the airway smooth muscle cells or inflammatory cells) resulting in the relaxation of bronchial smooth muscle. Inhaled types are commonly prescribed, including albuterol, bitolterol, salbutamol and terbutaline, to name a few. Long-acting, effective oral treatment, such as bambuterol, is available only in certain countries. So far, there seems to be no particular advantage in taking the oral forms; since the inhaled forms have fewer side effects, they are preferred.

Concerns have been raised recently about the possible effects of long-term use of beta2-adrenergic (also called beta-agonist) drugs, and about the association of their excessive use with high asthma death rates. A Saskatchewan study discovered this latter link, but the key word here is “excessive” — that is, exceeding the recommended dosage is dangerous, possibly because the beta2 receptors become desensitized with excessive use. The additional effect of aging on beta2 receptor responsiveness may also be a factor in long-term beta-agonist use. Some, but not all, investigators have found decreased responsiveness to these agents with advanced age.

Common side effects of these drugs include racing heart (tachycardia), a drop in serum potassium (which can increase cardiac problems) and tremor, all of which cause special problems for elderly patients. In addition, the elderly sometimes have trouble using metered dose inhalers and spacers — such cases make getting the right dose problematic. Instead, for acute asthma attacks, beta2-agonist drugs can be inhaled in wet nebulizer form.

Anticholinergic drugs

Drugs like ipratropium bromide or oxitropium bromide act as bronchodilators by working on different receptors than the beta-agonists. However, because ipratropium bromide is not as rapidly effective a bronchodilator as beta2-agonists, it is not a first-line agent for acute symptoms. It is generally used when side effects prohibit taking beta2-agonists, or when additive therapy is needed for severe, persistent symptoms.

Methylxanthines

The most prescribed oral methylxanthine is theophylline, which is no longer used as first-line asthma therapy. It has a limited scope of action which, in some cases, makes it useful as add-on therapy, especially if patients are not getting good asthma control despite maximum use of anti-inflammatory agents and inhaled bronchodilators. Side effects at lower blood levels include nausea and upset stomach; higher blood levels can produce life-threatening seizures and cardiac arrhythmias, which occur many times more frequently in the elderly than in younger patients.

Corticosteroids

As anti-inflammatory drugs, corticosteroids are extremely effective in the prevention and treatment of asthmatic symptoms. In their inhaled form, they can reduce or eliminate the need for brochodilators and oral corticosteroids. Unfortunately, many elderly patients require oral corticosteroids (prednisone is most common in North America) to control symptoms without interrupting their normal levels of activity. Corticosteroids have numerous side effects when taken in their oral form, including insomnia, emotional disturbances, diabetes mellitus and cataracts. For elderly patients, the risk of rib and vertebral fractures rises dramatically, and osteoporosis is a serious problem that requires aggressive, early preventive treatment using calcium supplements and exercise.

Asthma treatment in the elderly is challenging, especially when complications such as those that can occur with oral corticosteroids become severe and life-threatening. But effective treatment is available. Many studies are currently underway to increase our understanding of asthma — all the better to develop successful drug treatment strategies for the elderly.

Questions and Answers

1. Are oral corticosteroids not effective enough in treating asthma?

The problem is not the effectiveness of corticosteroids. Patients respond to corticosteroids, but because of the toxic effects of the drug, we’re always looking for what we call a corticosteroid-sparing effect. We want to reduce the use of steroids through alternative medication, but it’s not a question of one drug being better than the other.

2. Are you concerned about dependency on corticosteroids, or about other side effects?

Corticosteroids are not like cocaine, which creates a physical dependency. We’re much more concerned about toxicity, particularly in children. Steroids stunt growth, can cause cataracts, high blood pressure, hair all over your body, and can induce a diabetic-like state. But the major concerns are that it stunts growth and weakens bones. Some patients can fracture their ankle just stepping off a curb.

3. What is IgE and why do some people have more of it than others?

Immunoglobulin E or IgE is the allergic antibody, discovered in Denver in the 50s. Clearly, it’s one of the major causes of allergy-induced problems, whether it’s rhinitis (people who have ragweed allergy or hay fever), skin disease such as eczema, or in some cases, asthma. A high percentage of asthmatics manifest this allergic reaction, particularly children. In most cases of asthma it’s the allergy to whatever is in the environment that triggers the allergic response, which in this case targets the airways.

3. Is asthma caused by IgE reactions to allergens harder or easier to treat than non-allergic asthma?

It depends. Some people have what’s called exercise-induced asthma, and they can take a bronchodilator just before they exercise and they’ll be fine. Others have aspirin-sensitive asthma, and as long as they avoid anything containing aspirin, they’ll be fine. It’s not that one is easier or harder to treat. It’s just that one has to identify and then target different mediators and causes with different drugs in the various types of asthma.

4. What is inflammation?

Let’s say that you’re allergic to dogs. Your family has a history of allergy, because there’s a big genetic component to it. You encounter a dog, and inadvertently inhale some of the dog dander. What happens is: the IgE binds to mast cells, which are a type of cell that is present throughout the body’s airways. The allergen also binds to the IgE. The mast cells then degranulate and release a lot of mediators. Other cells, such as lymphocytes (white blood cells), also get activated. This activation process calls in a lot of inflammatory cells. In the case of asthma and other allergic reactions, a major cell that’s called in is the eosinophil. The eosinophils accumulate around the airway, probably releasing their own mediators that break down the epithelium (lining) of the airways. That leads to altered control of some of the nervous functions of the airways. You get smooth muscle hypertrophy (swelling), and contraction and constriction of the airways.

4. Are immune globulin injections as effective in treating asthma as corticosteroids?

One has to think of the therapy of asthma. There are controllers of asthma and there are relievers of asthma. The relievers of asthma are those drugs that go straight to the airway such as beta-agonists — ventolin, for example — where they act to relieve bronchoconstriction. You take the inhaler, and within seconds you get relief. But if you’re looking for a more prolonged effect to keep inflammation down, you need something that’s going to work to keep those inflammatory cells from coming in. The first line therapy is drugs such as cromolyn and nedocromil, which are weak drugs. They may be okay, however, taken as a prophylactic by people with mild asthma. The really effective anti-inflammatory that is available today is corticosteroid; nothing can beat it. But if you take these drugs by mouth, the toxicity is great, particularly if you take it on a continuing basis. Hence the big push to taking steroids by inhalation. The next step after cromolyn or nedocromil is now inhaled corticosteroids. The toxicity is clearly much lower than when taken by mouth, because they act locally with as little systemic absorption as you can get away with. But some patients continue to have inflammatory changes and asthmatic symptoms, so they need oral corticosteroids. And once you’re on oral corticosteroids as a requirement for control, you start to look at experimental therapies for inflammatory control, because you just want to get the patient off the steroids if you can. A lot of what has been tried has followed from the rheumatoid arthritis literature. Arthritis is also an inflammatory disease, and it’s been treated using things like methotrexate, gold and chloroquin. All of these anti-inflammatory drugs have been tried with asthma, without any great success. Also, some of these drugs are themselves quite toxic: methotrexate, for example, is an anti-cancer drug. We were looking for something that had an anti-inflammatory effect without the toxicity, and we were pleasantly surprised to find that gamma globulin (IgG) has that effect. We were able to significantly reduce the need for steroids without losing control of the disease.

Editorial:

This is an experimental therapy. Double-blind, placebo-controlled studies need to be done to determine the efficacy of gamma globulin, and pilot studies have already been done which have supported its efficacy. It’s also a very costly therapy, and that fact is likely to limit its use. But we’re talking about using this therapy in the very small subset of asthmatic patients whose asthma cannot be controlled using conventional methods. Probably no more than one in 100 to one in 500 asthmatics really have severe steroid-dependent asthma. Of course, when you consider that there are 16 million asthmatics in the United States, that’s still a pretty large number of people who stand to benefit.

Glossary:

Immune globulin E (IgE): An antibody that generally makes up only 0.01% or less of the total immune globulin armoury in human blood, but which frequently appears at higher concentrations in allergic people. This antibody is implicated in reactions such as ragweed and hay fever allergies, most food and contact allergies, and allergy-related asthma.

Immune globulin G (IgG): Also known as gamma globulin, this is the most common of the immune globulins, accounting for approximately 80% of all those present in human blood. It is frequently given by injection to boost the immune system prior to possible exposure to infectious diseases (ie. before a visit to the tropics).

Degranulation: The release by cells of lysosomes (small, self-contained bundles of enzymes that normally remove and digest unwanted or deteriorated components of the cell). Once released, the lysosomes turn their attention to foreign material such as bacteria, and stimulate a cascade of immunological reaction.

Eosinophil: A mobile, antiparasitic white blood cell that hunts and kills foreign bacteria. Vital components of the body’s immune system, eosinophils are attracted to the scene of inflammation, where they can aggravate a hypersensitive reaction such as an asthmatic attack caused by allergy.

Immunologists are increasingly coming to view asthma in terms of inflammatory disease. That means that asthma results from a condition known as airway hyperresponsiveness, which involves inflammation prompted partly by the body’s own antibodies, specifically the antibody known as immunoglobulin E (IgE). That inflammation in turn stimulates the production of aggravating substances that cause muscles in the bronchial tract to contract and spasm. “Sensitized” lymphocytes (white blood cells formed in the lymphatic system) are also found in the bronchial fluid of asthmatics, further inflaming the cells of the airway. This is part of an extremely complex inflammatory process involving numerous types of cells and different chains of events, of which the end result is bronchial constriction and reduced air flow.

Corticosteroids are the most effective anti-inflammatory treatment for airway hyperresponsiveness, and are considered safe for use in the inhaled form. But when these fail, it sometimes becomes necessary for physicians to prescribe oral corticosteroids, which have a steroidal effect on the entire system. These drugs can suppress growth in children, cause weight gain, hypertension, cataracts, osteoporosis and even spontaneous bone fractures, and most specialists would use them only in the most extreme and intractable cases of asthma. Naturally, the discovery of a safe and effective anti-inflammatory agent that allowed patients to avoid or limit prolonged use of oral corticosteroids would be a welcome development. Treatments such as methotrexate, dapsone and even gold have shown some benefits, but none has been consistent enough to eliminate the need for systemic corticosteroid use.

As far back as the 1950s, it was noted that monthly injections of immunoglobulin reduced the rate of infections, particularly respiratory infections, in people with gamma globulin deficiency (an immune disease). Intravenous immune globulin (IVIG) has since shown signs of being a potent anti-inflammatory agent in patients with various conditions such as juvenile rheumatoid arthritis. It has the proven capacity to reduce fever and other more sophisticated measurements of inflammation such as levels of C reactive proteins (which are produced in the so-called acute phase response to inflammatory illness or injury). Moreover, IVIG may mimic some of the effects of immunotherapy with known allergens, blocking and neutralizing them before they can get to the IgE bound up in cells and start an allergic reaction. Finally, antibodies found in intravenous immune globulin would seem to limit the production of IgE in the first place. There is known to be a strong link between asthma and allergy, and allergic reactions in the airway are an important factor in many asthmatic attacks. For all of these reasons, IVIG seems a strong possible alternative to systemic corticosteroids.

To test the effectiveness of intravenous immune globulin therapy in asthma, researchers recruited eight steroid-dependent asthmatic children aged from six to 17. Every four weeks, the patients were given 2 g of intravenous immune globulin for each kilogram of body weight. The treatment continued for six months. To assess results, doctors compared symptoms of coughing, wheezing, shortness of breath and chest discomfort before and after IVIG, as well as any changes in medication, and the frequency with which the patients were forced to use beta-agonists to control episodes of exacerbated asthma. Since 40% to 85% of asthmatics tend to test positive for reactions to various common airborne allergens, researchers also carried out some skin-prick tests.

Steroid use among the children declined greatly from an average 154 mg per month before treatment to only 49 mg/month after IVIG. Likewise, use of beta-agonists was halved during IVIG treatment, reflecting the fact that asthmatic symptoms were greatly reduced. Evaluating the severity of six different symptoms such as coughing and nocturnal wheezing on a scale from 0 (no symptoms) to 4 (incapacitating symptoms), average monthly scores decreased from 32 before intravenous immune globulin to 17 after one month of treatment, and remained in the 16 to 18 range as long as therapy was continued.

Confirming the known link between allergy and asthma, seven of eight children had skin reaction to one or more needle-prick tests of common allergens, giving a total of 30 positive reactions before intravenous immune globulin injections began. Following IVIG therapy, only one of those reactions worsened, while two remained unchanged and 27 improved. The average decrease in sensitivity to allergens was a striking hundred-fold. All of these gains were lost when the intravenous immune globulin treatment was suspended for six months, yet when five of the patients restarted intravenous immune globulin therapy six months later their asthma symptoms and steroid requirements once again stabilized and their overall improvement, in fact, surpassed that of the first therapy period.

Perhaps the most notable result was that the average annual cost of hospitalization in the five children who continued with intravenous immune globulin went from over $40,000 to under $3,000. That is a significant change, especially when one bears in mind that asthma is the leading cause of emergency room visits and hospital internment in children. A similar dramatic improvement was seen in three adult patients suffering from a chronic disfiguring skin disease known as atopic dermatitis. Sensitivity to allergens was found to have declined on average thirty-fold, and symptoms of itching, scaling and discolouration retreated rapidly.

More research is needed to learn about the applications of this therapy in a whole range of diseases with both inflammatory and immune components. It remains to be seen what is an optimum dose and what are the limits of intravenous immune globulin. But it is clear that it offers hope to sufferers of many debilitating conditions and may help to free many patients from dangerous steroid dependency.

Behavioral disturbances in the elderly are probably the most important facet of dementia prompting institutionalization. The referral for pharmacologic intervention is often the result of the need for management of mood and behavior. Symptoms tend to be superficially described as “agitated,” “combative,” “depressed,” “acting out,” “inappropriately accusing,” etc., by spouses, family members, and caregivers.

Dementia may be the most common cause of anxiety in the elderly, with an increased risk of anxiety seen in patients initially transferred to a long-term care facility from the hospital or from home. Trauma or a stressful event may induce an acute, short-lived, situational anxiety. Anxiety disorders (also known as anxiety and phobic neuroses) are classified as phobic disorders, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and panic disorder (Table 1).

Attempts at alleviating anxiety in the elderly, and especially in those with dementia, should be attempted through nonpharmacologic intervention whenever possible. This may include providing a more structured environment with consistent routines, simplifying everyday tasks, avoiding over- or understimulation in the environment, providing soothing background music, and providing support to caregivers. Testing for adequate hearing and vision is also essential. Supportive psychotherapy, behavioral therapy, biofeedback, relaxation therapy, and paced exercise therapy may be used as nonpharmacologic and adjunctive therapy where appropriate.

Reversible etiologies of anxiety related to adverse drug effects and concomitant medical disorders should not be overlooked. When possible, eliminating medications known to contribute to or induce anxiety and treating medical conditions that may cause anxiety or similar symptoms (Table 2) may help avoid unnecessary intervention with an anxiolytic. For example, eliminating anxiety and agitation secondary to depression with the use of an antidepressant may be sufficient.

Benzodiazepines are often prescribed for elderly dementia patients with behavioral disorders because of a prescriber preference over the antipsychotics that carry a liability of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Extrapyramidal reactions are more common in the elderly, with up to 50% of patients developing these reactions after age 60; incidence may be more common in dementia patients. The prevalence rate of tardive dyskinesia in the elderly may be as high as 40%; elderly women are especially at risk. Up to 20% of older adults take benzodiazepines, and their use is more common among women than men. Benzodiazepines are useful in treating general anxiety disorders, panic disorders, and depression, as an adjunct to antidepressants. They are also indicated in insomnia, on a short-term basis. In addition, they are useful for preprocedure/preoperative sedation (e.g., dental procedures, MRI screenings) and in cases of status epilepticus.

New Therapeutic Advances

Recently, many new agents to treat rheumatoid arthritis have been developed or are under investigation. Traditional antirheumatic drugs suppress the inflammatory response and slow the process of joint destruction. Yet the mechanisms of action for these drugs are nonspecific. Newer drugs have been designed to target the inflammatory process and specific components in the inflammatory cascade. The newer biotechnology agents have been designed to target components of the immune system involved in inflammation, while preserving the integrity of the immune system to fight off infection. Another relatively new approach is the use of combination therapy with various DMARDs in the hope that combining drugs with different mechanisms of action will provide added benefit.

Cox Inhibitors: The variation in GI side effect profiles of NSAIDs may be due to the COX selectivity of individual drugs. COX serves as the rate-limiting enzyme in prostaglandin production. Inhibiting this enzyme decreases prostaglandin-induced initiation and maintenance of inflammatory responses. Two isoforms of COX have been identified (COX-1 and COX-2).27 COX-1 is beneficial in helping to maintain normal cellular physiologic processes in the GI tract, kidneys, and blood. In the gut, COX-1 stimulates the secretion of bicarbonate and mucus, and reduces stomach acid secretion. All of these actions are protective for the lining of the stomach against irritants. COX-2 is involved in selectively activating pro-inflammatory cytokines and does not have a gastroprotective effect. Therefore, the ideal agent would selectively inhibit COX-2 to reduce the inflammatory response but also maintain the GI and renal protective nature of COX-1.29 NSAIDs have been developed to be COX-2 selective, or combined with synthetic prostaglandins to minimize GI intolerance. Of the NSAIDs on the market, etodolac (Lodine) and nabumetone (Relafen) are the most selective agents for COX-2 and have the lowest incidence of GI and renal side effects. Piroxicam (Feldene), indomethacin (Indocin), naproxen (Naprosyn), and sulindac (Clinoril) have a greater affinity for inhibiting COX-1 and therefore an increased risk of GI and renal problems. Flurbiprofen (Ansaid), ibuprofen (Motrin), meclofenamate sodium (Meclomen), and diclofenac (Voltaren) show equal affinity for COX-1 and COX-2 inhibition. While the clinical relevance of COX-2-selective NSAIDs is unclear, these agents may prove beneficial in patients requiring long-term NSAID therapy who are predisposed to developing adverse GI effects. COX-2 selective agents would inhibit the inflammatory response but maintain the GI protective properties of COX-1. Studies using one of the first COX-2 inhibitors, meloxicam, demonstrated that selectively inhibiting COX-2 improved GI tolerability while maintaining therapeutic effectiveness. An FDA advisory panel has recommended approval of Celecoxib (Celebra), which in Phase III trials shows promising results for pain reduction and joint swelling. In a clinical trial enrolling 300 patients with active RA, celecoxib was administered to patients experiencing an acute flare. Patients given either 200 mg BID or 400 mg BID had a statistically significant improvement. Patient global assessment scores, duration of morning stiffness, and number of painful or tender joints all improved compared to placebo. A COX-2 inhibitor by the name of Vioxx will be undergoing clinical trials in late 1998. Preliminary research shows a significant improvement in preventing GI mucosal damage when compared to aspirin and ibuprofen.

Biotechnology: Biotechnology is playing an increasing role in the development of novel approaches to manage rheumatoid arthritis. Molecular technology has permitted the identification of specific cell components and cell surface markers that contribute to the immune-mediated response in rheumatoid arthritis. Although the etiology of rheumatoid arthritis remains unknown, this increased understanding of the pathogenesis provides opportunities to target the immune system with specific therapies. Several biologic agents developed for the treatment of rheumatoid arthritis include monoclonal antibodies, recombinant interleukin-1 receptor antagonists, and recombinant soluble tumor necrosis factor receptor.

The role of cytokines in rheumatoid arthritis is a concept that has been explored for many years. Identifying a T-cell mediated immune response was the first step in targeting the inflammatory response in rheumatoid arthritis. The concept of activated T-cells both initiating rheumatoid synovitis and maintaining chronic RA has focused new attention on specific pro-inflammatory cytokines such as IL-1 and TNF-a. These cytokines are believed to be directly responsible for the clinical manifestations of rheumatoid arthritis, and therapies are being developed to specifically target these areas.

Monoclonal Antibodies: Monoclonal antibodies (MAbs) have been developed to bind to receptors on the surface of T-cells, thus interfering with their function or making the T-cells unavailable for binding. By binding to T-cells, MAbs disable the autoimmune response involved in inflammation and tissue destruction. This may slow the disease progression. Some trials of monoclonal antibodies (MAbs) have shown a resultant reversible depletion of T-cells that would prevent the patient from mounting a T-cell mediated immune response. IDEC Pharmaceuticals and SmithKline Beecham have partnered to develop a chimeric combination of human and monkey antibodies. This agent has proven to be less allergenic than previous products made with mouse antibody. Phase II trial results indicate an improvement >20% by American College of Rheumatology criteria in 42%–47% of patients receiving therapy with 40 mg and 80 mg, respectively. Dosages of 140 mg were also evaluated but had to be discontinued due to the development of rash. No other adverse effects were reported, and rash was not observed in patients receiving the lower dosages. Patients receiving this therapy sustained benefit for 2–3 months following discontinuation before arthritis symptoms worsened.
Other MAbs are being developed, such as an antibody that would be coupled with a cytotoxin that, when taken up into the target cell, would cause cell destruction and decrease the immune response. No agents are currently available using these techniques.

Cytokines: Tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) are two proinflammatory cytokines that appear to be dominant in the inflammatory response in rheumatoid arthritis. In patients with rheumatoid arthritis, there is an imbalance between proinflammatory and anti-inflammatory mediators, which may or may not be cytokines. This leads to increased activity of the proinflammatory components (TNF-a and IL-1) and inflammation at the site. By providing exogenous inhibitors such as antagonists or antibodies or soluble receptors, one may achieve an anti-inflammatory state within the joint. When administered over 6 months to patients with rheumatoid arthritis, IL-1 receptor antagonists have been shown to decrease C-reactive protein, as well as improve responses based on American College of Rheumatology clinical response criteria. Monoclonal antibodies to TNF provided the first evidence that TNF inhibitors may be useful agents in treating rheumatoid arthritis. Both open-label and double-blind, placebo controlled trials using MAbs to TNF have demonstrated significant decreases in CRP levels and number of swollen joints. Agents used to inhibit the activity of TNF-a and IL-1 have only been used as monotherapy. Combination biologics is in its infancy at this time.

TNF Receptors: The identification and isolation of soluble TNF receptors (sTNFRs) is also being pursued. sTNFRs are a naturally occurring counter-regulation mechanism to the activity of TNF. Levels of soluble receptors are elevated in both plasma and synovial fluid samples of rheumatoid arthritis patients and patients with other autoimmune and inflammatory conditions. A recombinant human TNFR fusion protein (TNFR:Fc) has been developed by Immunex to neutralize TNF. Etanercept (Enbrel) is a product of recombinant DNA technology in which the extracellular portion of two TNF receptors is linked to the Fc fragment of human IgG1 molecules and then expressed in mammalian cells. The product acts as a noncompetitive inhibitor of TNF, preventing binding of TNF to the cell surface receptor, thus reducing TNF activity.
Both Phase II and Phase III clinical trials have been conducted using etanercept. Etanercept was administered as 10–25 mg SC twice weekly. Subjects had active RA and had failed to respond to therapy with DMARDs at least once. Results show a statistically significant reduction in disease activity, which was determined using clinical endpoints (American College of Rheumatology clinical response criteria); biological markers (CRP, ESR); and quality of life assessments (health assessment questionnaire, visual analog pain scale). Clinical improvement was seen in these areas within 2 weeks of initiating therapy. Treatment was generally well tolerated, with the most common side effect reported as redness and discomfort at the injection site. There appeared to be an increased incidence of upper respiratory tract infections in patients receiving etanercept; however, this difference was not significant when the data was analyzed over time.

Soluble cytokine receptors such as etanercept may have a therapeutic advantage over other TNF agents since immunogenicity does not appear to be an issue. Nonhuman or chimeric MAb therapy often stimulates the production of antibodies which deactivate the therapeutic agent, limiting long-term use or inducing allergic reactions. In the previously mentioned Phase II and III studies involving etanercept, neutralizing antibodies were not detected. The information gathered on etanercept is promising in its therapeutic applications in rheumatoid arthritis. At press time etanercept was recommended for approval by the FDA arthritis advisory committee as a mono agent or in combination for the treatment of active rheumatoid arthritis.

Immunosuppression: Suppressing the immune response to a particular antigen can be induced by oral administration of certain antigens. This may be beneficial in treating rheumatoid arthritis since oral administration of antigens including collagen have been shown to be effective in blocking the induction of, or ameliorating, established disease. Proposed mechanisms of action include induction of anti-inflammatory cytokines (i.e., IL-4 and IL-10) and the stimulation of growth factor at the site of joint injury. Several studies have investigated oral collagen. Patients given chicken type II collagen showed statistically significant improvements in the number of swollen or tender joints while patients receiving bovine type II collagen showed only minor clinical response. More controlled trials are needed to evaluate the efficacy of orally administered type II collagen in treating rheumatoid arthritis.
Immunosuppressive agents are another growing area of development in treatments for rheumatoid arthritis. Leflunomide (Arava) is an isoxazole derivative similar to methotrexate. Current studies with the drug are focused on treating autoimmune diseases such as rheumatoid arthritis. The mechanism of action of leflunomide is not completely known; however, it is believed to interfere with T-cell proliferation, which then inhibits synthesis of pyrimidines. This decrease in pyrimidine synthesis leads to a reduced number of proinflammatory cytokines within the body. The mild anti-inflammatory effect seen with leflunomide may be attributed to this activity.
Leflunomide dosing is one 100 mg tablet daily for three days, followed by a maintenance dose of one 20 mg tablet each day. Data on the use of leflunomide in patients with RA are promising. Both Phase II and Phase III double-blind, placebo-controlled, clinical trials showed statistically significant improvement versus placebo. Patients receiving leflunomide had a decreased number of tender or painful joints, improved global patient assessment scores, and improved clinical response criteria. Clinically significant results were seen after 1 month of therapy and benefit was retained for up to 18 months. Side effects associated with leflunomide include diarrhea, reversible alopecia, and hypertension. Six percent of patients discontinued therapy due to these side effects. Leflunomide has now been approved by the FDA for the treatment of inflammatory arthritis. This new agent will provide yet another approach to treat RA and add to possible combination therapies with other DMARDs.

Combination Therapy: By combining several drugs with different mechanisms of action, a greater benefit may be achieved than if the same drugs were used independently. It may also be possible to use lower doses of the medications, therefore minimizing the toxicities associated with each drug. Combinations of DMARDs that have been evaluated in the literature include MTX and HCQ; MTX, AZA, and HCQ; MTX and gold; MTX and cyclosporin A; MTX and SSZ; MTX, SSZ, and HCQ; HCQ and cyclosporin A; and MTX and DP. Studies indicate that the combination of antimalarials and DP shows antagonism within the body. While the effectiveness of combination therapy is difficult to evaluate, these therapies have provided relief when other medications used alone failed to do so.

Rheumatoid arthritis: Conclusion

New therapies and modifications on old therapies are constantly being explored in order to improve the treatment of rheumatoid arthritis. As more is learned about the disease process and the pathophysiology behind it, improved, targeted therapies can be developed. While there is no cure yet for rheumatoid arthritis, the future is promising for finding the treatments necessary to control and suppress the disease, enabling rheumatoid arthritis patients to continue to work and more comfortably perform their daily activities.

Nonsteroidal Anti-inflammatory Drugs

OTC NSAIDs are indicated for self-treatment of pain rather than inflammation, and the dosing guidelines on the package should not be exceeded unless the patient is instructed to do so by a physician. Patients taking OTC products should be closely monitored for effectiveness of therapy and the development of toxicities. NSAIDs are the initial drug treatment of choice for rheumatoid arthritis since they work to reduce joint pain and swelling, and improve function. While their analgesic and anti-inflammatory properties provide benefit, NSAIDs do not alter the course of rheumatoid arthritis or prevent joint destruction. Their mechanism of action is related to the inhibition of prostaglandin (PG) synthesis. Cyclooxygenase (COX) serves as the rate-limiting enzyme in PG production. Inhibition of this enzyme decreases PG-induced initiation and maintenance of inflammatory responses. There is no significant clinical difference in efficacy among the NSAIDs, although patient response to individual agents varies greatly. The choice of NSAIDs should be based on cost, duration of action, and patient tolerability and acceptance. While the analgesic effect of NSAIDs is quick in onset, the anti-inflammatory effect may not be complete for 4–6 weeks. If a patient fails therapy with a particular NSAID at the recommended dosage, another NSAID from another chemical class should be tried. The side effects of NSAIDs should be considered in patients who are elderly, have comorbid disease states (hypertension, diabetes, congestive heart failure, renal failure, peptic ulcer disease), or may be taking concurrent medications (e.g., diuretics) that may reduce renal blood flow. The primary adverse effect of NSAIDs is a tendency to cause bleeding and ulcerations in the stomach. A strategy to manage this condition is to prescribe misoprostol (Cytotec) concurrently for patients to take with their NSAIDs. Since misoprostol is a synthetic prostaglandin, it both prevents and heals NSAID-induced ulcers. A fixed combination product of diclofenac and misoprostol is available commercially. This product has been designed for patients who are at increased risk of developing gastric or duodenal ulcers from NSAID therapy. Patients receiving this fixed combination therapy had a reported gastric ulcer rate of 3%–4%, compared to 11% with diclofenac alone. Combination products of misoprostol and other NSAIDs are also being developed.

Corticosteroids: Corticosteroids have been proven to rapidly and effectively reduce inflammation and relieve symptoms in patients with rheumatoid arthritis. However, the development of adverse effects with corticosteroids, when taken for extended periods of time and at higher doses, limits their use. Intra-articular injections of steroids are generally safe and effective when administered appropriately, and can provide patients with immediate relief. Injections directly into the joint may also allow the patient to regain more range of motion in joints that have become stiff and inflamed. Low-dose oral corticosteroids (10 mg of prednisone daily or the equivalent) are beneficial for patients during the following situations: acute flares, special life events, the period of therapy after a DMARD has been initiated but not yet reached full effect, or when unacceptable discomfort or functional limitations persist despite full-dose NSAID and/or DMARD therapy.

The patient should be closely monitored for the development of side effects such as adrenal suppression, Cushing’s syndrome, osteoporosis, glaucoma, cataracts, gastritis, and hypertension. In patients receiving steroids for only 1–2 weeks, the corticosteroid need not be tapered since adrenal suppression is minimal over such a short period of time. However, in patients receiving doses of corticosteroids for greater than one month, tapering should occur gradually and be proportional to the length of time that the patient was on corticosteroids. Slow tapering of glucocorticoids allows the body to resume its natural production of cortisol, which becomes suppressed when patients take exogenous sources of steroid. It may be necessary to decrease the dose of corticosteroid by 1 mg every 1–2 weeks if the patient experiences symptoms of rheumatoid arthritis or has other complaints. A goal of any corticosteroid therapy should be to limit the use of the corticosteroid and avoid long-term therapy if possible.

Disease-Modifying Antirheumatic Drugs: Since active disease leads to irreversible joint and bone damage, it is important to start patients on DMARD therapy as soon as possible. Initiation of DMARD therapy is crucial in the management of rheumatoid arthritis. For a patient with a confirmed diagnosis, therapy should not be delayed beyond three months if, despite full-dose NSAID therapy, he or she has continued joint pain, significant morning stiffness or fatigue, active synovitis, or persistent elevation in ESR. The goal is to intervene before joints become damaged. While NSAIDs and corticosteroids alleviate symptoms, joint damage can still occur during their use, and the disease will progress. Disease-modifying agents such as hydroxychloroquine (HCQ), sulfasalazine (SSZ), methotrexate (MTX), gold salts, d-penicillamine (DP), and azathioprine (AZA) are intended to reduce or prevent joint damage, preserve joint integrity and function, maintain patient productivity and reduce total healthcare costs of patients with rheumatoid arthritis.

DMARDs as a class have a relatively slow onset of effect (1–6 months) and each patient will respond differently to various agents. Each DMARD also has its own unique toxicities which require close monitoring in order to avoid adverse events (Table 2). Patients must be educated about the potential risks versus benefits before initiating therapy.

The best initial DMARD for treatment of rheumatoid arthritis has not been established. SSZ or HCQ is usually selected for patients with mild disease. Both are available generically and have convenient dosing schedules and favorable safety profiles. HCQ therapy requires no additional laboratory monitoring, although patients should receive eye exams every 6–12 months to detect the development of reversible retinal toxicity (i.e., decreased night vision, loss of peripheral vision). SSZ requires that patients have routine CBCs to detect possible development of blood dyscrasias. The onset of action of these therapies should be apparent within 1–6 months; if no response is seen after this time, a change in therapy is warranted.

Methotrexate is the drug of choice in patients who have a more severe form of the disease (for example, erosions or extra-articular manifestations). Low-dose, once-weekly therapy has become a mainstay of treatment because MTX is relatively inexpensive; the cost of monitoring for toxicity is less than that of monitoring with use of gold, penicillamine or immunosuppressive agents; and there is a high rate of clinical response. The onset of action is generally within several weeks of initiating therapy, and patients are likely to still be on treatment after 5 years. Other DMARDs do not have such a quick onset of effect or long-term patient tolerability.

Methotrexate therapy is usually initiated at 7.5 mg/week. This dosage may be either increased or decreased depending on efficacy or development of toxicity. The usual dose is from 7.5–15 mg/week. To aid patients in appropriately taking MTX therapy, specially designed dose packs are available. Each dose pack contains one month’s worth of MTX therapy. The tablets are grouped by weekly doses and clearly marked to improve patient adherence. All of the dose packs contain 2.5 mg MTX tablets but are available in different weekly doses.
Prior to beginning MTX therapy, it is necessary to perform baseline laboratory work. A CBC with differential, platelet count, liver function tests, hepatitis B and C studies, serum creatinine and chest x-ray should be obtained. Subsequently, every 1–2 months CBC with platelet count, AST, and albumin should be evaluated. These tests, along with routine chest x-rays, help to monitor for thrombocytopenia, leukopenia, anemia, renal insufficiency, liver fibrosis, and pulmonary changes that are associated with MTX therapy. Side effects such as nausea, vomiting, diarrhea, and stomatitis may develop. These side effects may be minimized with the administration of folic acid 1 mg/day. Concurrent administration of folic acid decreases the incidence of side effects by 50% without decreasing the clinical efficacy of MTX.20 It is also possible to split the MTX dose over 24 hours instead of taking all of the tablets at once, or administer MTX subcutaneously or intramuscularly should GI discomfort continue.

Contraindications and drug interactions are also considerations when initiating MTX therapy. Since it is highly teratogenic, MTX should not be given to pregnant or lactating females. Patients who are known alcoholics or have alcohol-associated liver disease should not receive MTX since hepatic fibrosis may develop. Methotrexate should also not be used in patients who are immunocompromised, are known to be nonadherent with therapy, or have existing blood dyscrasias. Patients should be educated to avoid excessive alcohol intake since it may contribute to the development of liver toxicity. Other drugs to be avoided include phenytoin (alters protein binding), trimethoprim/sulfamethoxazole (has anti-folate activity), aminoglycosides (is nephrotoxic) and probenecid (is nephrotoxic). Concurrent administration of any of these medications significantly increases the risk of developing toxicity.
Gold and penicillamine have been used for many years in the treatment of rheumatoid arthritis. Although neither agent is used frequently anymore, they may be utilized in refractory cases of rheumatoid arthritis. While patients respond successfully to gold therapy, many have to discontinue therapy within 1 year due to development of toxicity (anemia, leukopenia, thrombocytopenia, proteinuria) or decrease in efficacy. Penicillamine is comparable to gold in efficacy; however, side effects (nausea, vomiting, diarrhea, hypogeusia) limit its clinical use. A word of caution when using penicillamine is that 10% of patients who have an allergic reaction to penicillin will have a hypersensitivity to penicillamine; however, this is not an absolute contraindication to therapy

Immunosuppressive Agents: In addition to MTX, cyclophosphamide, cyclosporin A and AZA are immunosuppressive agents used to manage rheumatoid arthritis. These therapies are generally reserved for severe cases unresponsive to other treatments. These agents are effective in controlling the symptoms of rheumatoid arthritis but have the same toxicities associated with any chemotherapeutic agent. Side effects such as myelosuppression, hepatotoxicity, GI disturbances, and hemorrhagic cystitis are commonly seen with cyclophosphamide, cyclosporin A and AZA. Cyclosporin A has proven beneficial in patients who fail to respond to DMARD therapy but is more toxic than DMARDs. Women should be informed of the fetal risk associated with the agent being used, and appropriate measures should be taken to ensure effective contraception.