Yes. Charles Moxin, PA-C says anti-TNF medications provide valuable treatment options for ankylosing spondylitis. No. Robert Thoemke, PA-C says many considerations may thwart the use of these drugs in certain patients.

Yes. Citing literature on this subject, Charles Moxin, PA-C advocates including anti-tumor necrosis factor (anti-TNF) medications within the armamentarium of care for ankylosing spondylitis (AS) as they facilitate symptom relief and improvements in quality of life.

Anti-tumor necrosis factor (anti-TNF) therapies do provide a valuable option of therapy for the treatment of ankylosing spondylitis (AS). While these treatments are not without controversy, recent studies have shown that anti-TNF medications reduce clinical symptoms in patients with AS. These medications have also demonstrated clinical improvement on radiological studies.

Questions do arise in regard to the use of these medications. Who should initiate this therapy? How severe should the condition be prior to using anti-TNF drugs? What should the preliminary workup entail? Who should be able to conduct follow-up evaluations? Additional factors may include: availability of the medication to patients due to cost or insurance coverage; the ability to administer medications appropriately (patient administration, home health provider or office visit); and the patient’s ability to identify possible adverse reactions and report them to his or her provider.

It is important to keep in mind that clinicians and physicians typically prescribe these medications for more advanced moderate to severe disease. However, in a previous article, I noted that one may not diagnose AS until the disease has advanced to some degree. With this in mind, clinicians should employ a multifaceted treatment approach that incorporates medications, physical therapy and exercise.

In the family medicine setting in which I practice, we believe treatment and therapies should be as uncomplicated as possible while still achieving the goal of a positive clinical response.

We initially emphasize using non-steroidal antiinflammatory drugs (NSAIDs) such as indomethacin as well as exercise and physical therapy. However, NSAIDs are more for symptomatic relief and do not reverse the disease process. As NSAIDs become less effective, it will be necessary for primary care providers to refer to a rheumatologist for further evaluation and treatment. It is at this point within the treatment armamentarium where one may consider the initiation of anti-TNF therapy. However, there may be additional benefits for early intervention with these medications.

What The Current Literature Reveals About Anti-TNF Drugs For AS
There have been a number of studies demonstrating the efficacy of anti-TNF medications in treating AS.

In one three-month trial, researchers used infliximab (Remicade, Centocor) to treat patients with AS and assessed function, pain, stiffness and other criteria via the Assessments In Ankylosing Spondylitis (ASAS) scores. The study authors noted that 53 percent of the infliximab group achieved statistically significant improvement in all measured outcomes. Another randomized study using etanercept (Enbrel, Wyeth) found that 59 percent of patients achieved ASAS response goals after 24 weeks, even though the average patient in the study had suffered from AS for over ten years.

At the 2006 European League Against Rheumatism (EULAR) conference, researchers presented a five-year study of infliximab. The study consisted of a placebo-controlled and open treatment phase. Researchers administered infliximab 5 mg/kg intravenously in patients every six weeks for three years. The researchers retreated patients on a case-by-case basis if relapses occurred. Out of those patients who completed the study, 68.3 percent demonstrated a 50 percent reduction in disease progression and remission as determined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

At the same EULAR conference, researchers presented the results of the Adalimimab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS) study. The majority of the 315 enrolled patients achieved a 20 percent reduction in symptoms after 12 weeks. At the end of the open-label phase of the study, 75 percent of patients achieved a 20 percent reduction of symptoms at one year. Researchers also noted that patients experienced major reductions in AS-related pain and fatigue as early as two weeks into treatment, and maintained these improvements for at least six months.

These are just a few of the studies regarding the use of anti-TNF medications in the treatment of AS. In 2002, researchers did a composite review of eight studies involving infliximab and two studies on etanercept. The study authors reported a median reduction in the BASDAI score that ranged between 55 and 93 percent for the infliximab trials and between 51 and 79 percent for the etanercept trials.

Based on these figures, it is clear that anti-TNF medications are an effective tool in treating AS. If anything, using these modalities earlier in the progression of the disease may significantly reduce symptoms and increase the quality of life for our patients.

Addressing Potential Complications
As with any medication, there is always a risk of complications or adverse reactions. Clinicians should monitor for potential injection site reactions with drugs such as etanercept and adalimumab, and infusion reactions with infliximab.

Additionally, one should bear in mind that some patients may not be comfortable with injecting the medications themselves. Simple patient education can address this issue. For those who do not desire to administer the medications themselves, clinicians can do this during an office visit.

In terms of side effects, reactivation of latent tuberculosis has been well documented. Prior to initiating anti-TNF therapy, clinicians should screen patients with Mantoux skin testing and a chest X-ray. These medications are contraindicated in patients with congestive heart failure.

Recently, concerns have been raised that anti-TNF agents suppress the immune system and can make patients more susceptible to infections such as pneumonia and meningitis. Other potential problems that may arise include osteomyelitis and sensitivity reactions at injection sites.

In addition, there may be increased risk of developing several forms of cancer with anti-TNF use. However, studies suggesting this are inconclusive.

Needless to say, providers should give due consideration to the benefit-to-risk ratio when considering the use of these medications. Regular follow-up evaluations are essential and one must discontinue anti-TNF medications if the aforementioned adverse reactions occur.

In Conclusion
It has been well documented in the literature that anti-TNF medications are beneficial in reducing symptoms and improving the quality of life for patients with AS. There is no doubt that anti-TNF medications should be part of an arsenal for combating the effects of AS. While I believe rheumatologists should initiate these medications, primary care providers can play an important role with follow-up evaluations and maintenance therapy.

References
1. Moxin CA, Markowitz LJ. How To Manage Ankylosing Spondylitis. Arthritis Practitioner 2(1): 16-19, 2006.
2. Leone, A. Studies show impact of Anti-TMF meds for Ankylosing Spondylitis, Arthritis Practitioner 2(5): 5-7, 2006.
3. van der Heijde, D, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 54(7): 2136-2146, 2006.
4. Brandt, J,et al. Successful treatment of active Ankylosing Spondylitis with anti-tumor necrosis factor alpha monoclonal antibody. Arthritis Rheum. 43(6):1346, 2000.
5. Gorman, JD et al. Treatment of active Ankylosing Spondylitis by inhibition of tumor necrosis factor alpha. NEJM 346(18): 1349-1356, 2002.
6. Braun J, et al. Anti-tumour necrosis factor alpha therapy for ankylosing spondylitis: international experience. Annals of Rheumatic Disease (61): iii51-iii60, 2002.
7. Antoni C, Braun J. Side effects of Anti-TNF therapy: Current knowledge. Clin Exp Rheumatol. (20) suppl 28: S152-S157, 2002
8. Leone, A. Study Raises Questions on Anti-TNF Therapy. Arthritis Practitioner 2(4): 5-6, 2006.

No. Robert J. Thoemke, PA-C elaborates that while studies have shown benefits with these therapies in symptom relief and curbing the progression of the disease, potential side effects and cost considerations may thwart the use of these drugs in certain patients.

Researchers have been studying the use of anti-tumor necrosis factor (anti-TNF) drugs for the treatment of ankylosing spondylitis (AS) for almost a decade. Clinicians have employed drugs such as etanercept (Enbrel, Wyeth), adalimumab (Humira, Abbott) and infliximab (Remicade, Centocor) for radigraphically evident moderate to severe AS.

However, one should consider factors such as the patient’s age, comorbidities, cost and potential side effects when determining whether anti-TNF medications are the best treatment course for patients with AS.

First of all, it is important to understand the impact of TNF in the inflammation of autoimmune diseases and immunosurveillance. Tumor necrosis factor is one of several cytokines that help the body defend against viruses and bacteria by causing inflammation. Tumor necrosis factor is of major importance when it comes to the function of B-cells, T-cells, monocytes and neutrophiles. At times, the body fails to recognize when the danger period has ended and chronic inflammation occurs. In these cases, the body continues to produce cytokines when they are no longer needed.

Understanding The Possible Risks Of Anti-TNF Drugs
Anti-TNF medications modify the normal immune response and accordingly attempt to stop the inflammatory response. However, use of these medications does put the patient at risk for certain adverse effects. Currently, the risks of anti-TNF drugs include:
• malignancy (especially lymphoma);
• solid organ cancers;
• increased susceptibility to infectious diseases (such as respiratory infections, tuberculosis, urinary tract infections, skin infections and osteomyelitis);
• further deterioration of congestive heart failure;
• demyelinating diseases;
• the development of autoantibodies; and
• local or systemic sensitivity reactions.

While the risk of cancer is theoretically present when the immune system is compromised, researchers have not seen an overall statistically significant increase in cancer cases associated with the use of anti-TNF medications. Whether the occurrence or severity of adverse events is due to AS itself or anti-TNF treatment has always been in question.

That said, anti-TNF therapies do seem to modify the progression of AS in 50 percent or more of patients, and seem to have an added benefit of increasing bone density.

Comparing The Modalities On Their Impact For Curbing Disease Progression
The mainstays of treatment for AS have been exercise, increasing range of motion and reducing pain, and non-steroidal antiinflammatory drugs (NSAIDs) to modify the symptoms of AS. Unfortunately, not one of these modalities change the progression of the disease.

While corticosteroids may help alleviate the symptoms of AS, they also do not alter disease progression. Corticosteroids also have the additional risk of decreasing bone density, which puts patients at risk for fractures and spinal cord or nerve decompression.

Clinicians have used disease-modifying anti-rheumatic drugs (DMARDs)for decades to treat AS. However, there is a dearth of studies that indicate actual disease modification with methotrexate. Sulfasalazine is not useful for axial AS. Bear in mind that DMARDs can also have serious side effects.

In several European countries, the United States and Canada, trials involving anti-TNF drugs for AS have shown improvement in function, reductions in pain and fatigue, and positive changes reflected in imaging. Research shows decreases in disease activity ranging from 45 to over 90 percent. Whether these changes will continue over decades remains to be determined. Of course, there are some non-responders who have no change in disease activity.

Raising Questions About Patient Compliance And The Need For Close Monitoring
Additionally, there are a variety of factors that may influence whether anti-TNF medications offer the best course of treatment for patients with AS.

In addition to a patient’s age, comorbidities and overall health, clinicians must consider potential interaction with concomitant medications. Cost-effectiveness is a major issue for patients as the annual cost of an anti-TNF medication can exceed $30,000.
Furthermore, very close follow-up is necessary to assess for infectious disease or malignancies. Frequent laboratory analysis and physical exams are essential. Clinicians must educate the patient on signs and symptoms that would signal the need for immediate assessment. Bear in mind that side effects seem to increase with the duration of anti-TNF treatment.

Patient compliance may be an issue with anti-TNF medications. In regard to the use of etanercept and adalimumab, patients must be able and willing to give themselves injections at home or have clinicians administer medication at a clinic. When it comes to infliximab, a patient with AS would receive this intravenously in a hospital or clinic. These factors, coupled with the possibility of a limited result, can be stressful psychologically as well in terms of the amount of time in addition to the money spent.

Similar circumstances occur with chemotherapy for cancer. However, there are many drugs and combinations clinicians can choose from when it comes to chemotherapy. Accordingly, they can switch to another drug if one is not successful. Yet when it comes to treating AS, switching from one anti-TNF therapy to another is not an option. If one anti-TNF modality does not help, it obviates the entire class of drugs.

Final Notes
Assessing the benefit-to-risk ratio of anti-TNF medications can be daunting in many cases. We do need to keep in mind that health care providers are using anti-TNF medications to help treat early rheumatoid arthritis (RA) and adverse effects are occurring less often. This indicates that comorbidities, age and disease severity contribute to adverse effects.

Studies have also indicated that using anti-TNF drugs in combination with methotrexate has greater efficacy in treating AS. Note that many patients take concomitant steroids while they are on anti-TNF therapies.

Granted, it is unreasonable to be completely negative regarding anti-TNF use in treating AS as these modalities can be helpful in improving the quality and length of life for those suffering from a potentially severe, crippling and life-threatening disease.

However, one should emphasize caution and proper patient selection in regard to the use of anti-TNF therapies until more long-term results are available. These drugs should be reserved for use by rheumatologists, pain management specialist and oncologists in order to ensure accurate reporting of benefits and adverse events, as well as adherence to specific criteria for treatment and standardized follow-up.

References
1. Antoni C, Braun J. Side effects of anti-TNF therapy: Current knowledge. Clin Exp Rheumatol (20)Suppl. 28: S152-S157, 2002.
2. Braun J et al. Therapy of ankylosing spondylitis and other spondyloarthritities: established medical treatment, anti-TNF alpha therapy and other novel approaches. Arthritis Res (4)5: 307-21, 2002.
3. Baecklund E, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. (54)3: 692-701, 2006.
4. Costenbader KH, Glass R, Cui J, Shadick N. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis. JAMA (296)18: 2201, 2006.
5. Keystone EC. Safety of biologic therapies — an update. J Rheumatol (32)Suppl 74: 8-12, 2005.
6. Listing J, et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum. (52)11: 3403-3412, 2005.
7. Ellerin T, Rubin RH, Weinblatt ME. Infections and anti tumor necrosis factor alpha therapy. Arthritis Rheum (48)11: 3013-3022, 2003.
8. Braun J, et al. Anti-tumour necrosis factor-alpha therapy for ankylosing spondylitis: international experience. Ann Rheum Dis. (61)Suppl 3: 11151-11160, 2002.
9. Gorman J et al. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. NEJM (346)18: 1349-56, 2002.
10. Oran MF, et al. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population based study. Arthritis Rheum. (46)9: 2287-2293, 2002.