Patients who present with complications of RA outside the joints- what is termed extra-articular disease- are at particular risk for early death. Extraarticular problems that can be seen in RA include, skin ulcers, anemia, eye inflammation, lung inflammation and damage, heart disease, inflammation of blood vessels, and rheumatoid nodules(these are bumps consisting of inflamed tissue that grow at certain areas such as the fingers, elbows, heels, and back of the skull).

A predictor of the presence of extra-articular disease is the level of rheumatoid factor in the blood. The higher the rheumatoid factor, the more likely a patient will have extra-articular disease.

A newer blood marker, the anti-CCP (anti cyclic citrullinated peptide), also appears to predict higher risk of extra-articular problems as well as more severe disease.

The bottom line is that RA is not a benign condition. In fact, it carries the same mortality as first heart attacks, untreated diabetes, and stage 4 Hodgkins disease in some studies. RA must be diagnosed and treated aggressively.

Probably the primary cause of the increased mortality is cardiovascular death. Estimates range from 33-50% of all deaths in RA patients are due to cardiovascular causes. Patients with RA are at significantly increased risk for atherosclerosis, congestive heart failure, heart attack, and vasculitis (inflammation of blood vessels).

So what are some of the risk factors that particularly are important?

Among them are:

• Severe RA disease

• Severe extra-articular disease

• Elevated blood levels of homocysteine which is aggravated by methotrexate therapy

• Abnormalities of blood vessel walls

• Drugs that are used to treat RA such as corticosteroids and non-steroidal anti-inflammatory drugs

• Overproduction of inflammatory cytokines (chemical messengers of disease)

• Rheumatoid nodules

A note about drugs…

Methotrexate, the most commonly used disease-modifying anti-rheumatic drug is associated with a significant reduction in the incidence of cardiovascular death. Unfiortuantely, nonsteoridal anti-inflammatory drugs which are commonly used to treat symptoms in RA increase the risk of blood clots, cardiovascular disease, and congestive heart failure.

The role of other medical problems such as blood sugar, elevated lipids, and so forth are a subject for another article.

Recommendations for reduction of cardiovascular risk in RA patients include:

• Low dose aspirin (which should be supplemented with some type of stomach protection) particularly in patients who are taking non-steroidal anti-inflammatory drugs.

• Statin drugs for people with elevated lipids

• Folic acid supplementation to minimize the elevated homocysteine levels seen in RA

• Caution with the use of TNF-inhibitors in patients with congestive heart failure

• Control of co-morbid conditions such as smoking, diabetes, and hypertension that might aggravate the tendency towards cardiovascular risk.

Complicating this issue is some data showing that TNF inhibitors can elevate serum lipids in some instances. The implications of this phenomenon on the overall picture is still unknown.

A bright note: there is increasing evidence that aggressive treatment with methotrexate and TNF-inhibitors reduces the incidence of cardiovascular events. Therefore, the above-mentioned lipid problem may not be that important. Further studies are obviously needed to confirm these findings.

However, within the last 10-15 years, biologic therapies aimed at the immune dysfunction that occurs in RA have enabled physicians to treat patients with much more success… in fact, often allowing the achievement of remission.

Gene therapy approaches have been employed recently in the hopes that patients who do not achieve remission may still yet get needed relief.

The first gene therapy approach was developed by Targeted Genetics in Seattle, Washington. Their compound, tgAAC94 was developed as a potential supplement to systemic anti-TNF-alpha (anti-tumor necrosis factors drugs such as Enbrel, Humira, and Remicade have become the standard of care for rheumatoid arthritis) therapy for use in patients with inflammatory arthritis who had one or more joints that did not respond to systemic therapy.

The product used a recombinant adeno-associated virus to deliver a DNA sequence that coded for a form of the TNF-alpha receptor (TNFR). TNFR blocks the immune stimulating activity of TNF-alpha. Direct injection of tgAAC94 into affected joints leads to the localized production of soluble TNFR within joint cells, reducing the activity of TNF-alpha within the joint and, potentially, leading to a decrease in the signs and symptoms of disease and stopping joint destruction.

The adeno-associated virus is a naturally occurring virus that has not been associated with any disease in humans.

Data from an initial Phase I trial demonstrated that injecting tgAAC94 into joints was safe and well-tolerated in patients taking conventional disease modifying anti-rheumatic drugs (DMARDS).

No drug-related serious adverse events were reported. Beneficial results as far as signs and symptoms were also demonstrated.

While this first study demonstrated both the safety and efficacy of gene therapy, a more recent study confirmed it.

Dr. Christopher H. Evans and co-investigators reported their findings using a viral vector that carried the gene that blocks interleukin-1, another protein that promotes inflammation and causes cartilage breakdown, in the February issue of Human Gene Therapy.

“Arthritis is a good target for (gene therapy) because the joint is a closed space into which we can inject genes,” was a statement issued by Evans.

Unlike the tgAAC94 study, tissue was removed from the knuckle joints of two patients with severe RA and a harmless virus was inserted into the tissue cells, in order to serve as a vector to carry a gene that blocks action of the interleukin-1 protein to the joint. After being placed in culture to grow and multiply, the cells were injected back into the afflicted joints.

One patient who received gene therapy in two joints experienced an 85 percent reduction in pain in one joint within 1 day, and both joints were pain-free from 1 week onward. Remarkably, the researchers report, joints receiving the therapy were protected from flares that occurred during the study period.

The second patient also responded to gene therapy, with a 70 percent reduction in pain between weeks 2 and 3.

This paper, therefore, also showed that painful symptoms can be lessened through gene therapy.

Both of these studies have demonstrated that gene therapy is feasible in humans. More importantly, it has been shown that this approach may be helpful for delivering biologic agents into stubborn joints that do not respond to systemic therapies.

Patients will sometimes ask about them and physicians who see these patients sometimes wonder if these drugs should be considered.

Skeletal muscle relaxants are the most widely prescribed drug class in the United States for non-specific low back pain.

In addition, this class of drugs is used for neck pain, muscle spasms, fibromyalgia, and myofascial pain.

Goals for the treatment of musculoskeletal conditions include relief of muscle pain and improvement in function and therefore, a return to normal activities of daily living.

The two primary categories of skeletal muscle relaxants are anti-spastic agents (eg, baclofen [Kemstro and Lioresal] or dantrolene [Dantrium]) for diseases like cerebral palsy, spastic torticollis, and multiple sclerosis and anti-spasmodic agents for muscle-related conditions.

Anti-spastic agents are rarely used for musculoskeletal conditions; however, some rheumatologists report success in treating fibromyalgia using baclofen. Since this is an “off-label” use, caution should be exerted and the lowest possible doses should be prescribed… and then only by specialists who have much experience. Patients should be informed as to the potential side effects.

Antispasmodic agents are much more widely used for musculoskeletal conditions.

The most often prescribed antispasmodic agents are carisoprodol [Soma}, cyclobenzaprine (Flexeril), metaxalone (Skelaxin), and methocarbamol (Robaxin). In terms of effectiveness, there appears to be no one muscle relaxant that is superior to another. Often, physicians will prescribe the muscle relaxant they are most familiar with. Another reason one is selected over another is that a physician may have samples in his closet that he can give to a patient to try before giving the patient a prescription.

The most widely studied and used agent is cyclobenzaprine. This has been shown to be effective for various musculoskeletal conditions but causes drowsiness, as does tizanidine [Zanaflex]. As a result, patients with insomnia caused by muscle spasms, may find tizanidine or cyclobenzaprine to be useful. Cyclobenzaprine is particularly helpful for many patients with fibromyalgia.

All skeletal muscle relaxants have adverse effects which include most commonly dizziness, drowsiness, and dryness of the mouth.

Methocarbamol and metaxalone may be are less sedating than tizanidine and cyclobenzaprine. However, they may also be more habituating in some cases.

Skeletal muscle relaxants are generally not considered first-line therapy for musculoskeletal conditions. Most physicians will start with acetaminophen (Tylenol) or non-steroidal-anti-inflammatory drugs (NSAIDS) first. Many clinical trials have supported the notion that NSAIDS are superior to muscle relaxants in patients suffering from acute low back pain. However, it is also known from the data that muscle relaxants are superior to placebo.

For acute low back pain syndromes, skeletal muscle relaxants may be used as additional therapy to NSAIDS.

For acute low back pain, muscle relaxants should be used short term (2 weeks). Some patients with chronic back conditions as well as patients with fibromyalgia may require chronic long-term use of muscle relaxants.

Muscle relaxants should be avoided in frail elderly patients because of the danger related to sedation and falling.