In this month’s Q&A, the panelists explore biologic therapy in the treatment of rheumatoid arthritis (RA). Sharing their clinical experiences, they discuss key considerations for the use of these agents, the potential for patient resistance, how to gauge efficacy and monitor for potential side effects.

Q: What factors influence your decision to initiate biologic therapy in a patient with RA?
A: There are really two different answers to that question, according to Alan J. Kivitz, MD, FACR, FACP. Traditionally, if a patient has ongoing disease despite an adequate trial of methotrexate — both in terms of dose and duration — then Dr. Kivitz would initiate a biologic therapy. However, Dr. Kivitz says the answer depends upon how one defines ongoing disease. According to Dr. Kivitz, there are several factors to consider. These factors include:

• the number of swollen and tender joints;
• the duration of morning stiffness;
• the degree of ESR and/or CRP elevation;
• radiographic progression;
• persistent disease as assessed by radiographic parameters such as ultrasound and MRI; and
• the patient’s self health assessment as per a HAQ (Health Assessment Questionnaire).

In addition to these parameters, Nathan Wei, MD, FACP, FACR, notes that he will evaluate parameters such as the Ritchie-Camp Articular Index and Disease Activity Score (DAS) in clinical trials. In his practice, Dr. Kivitz notes that all patients complete a visual analog scale (VAS) and mHAQ that assist in the evaluation.

“There is more than adequate data to support the positive effects of combining a biologic with methotrexate,” claims Dr. Kivitz. “We all have seen wonderful examples of dramatic patient responses to these therapies.”

However, Dr. Kivitz says it is important to assess potential benefits and risks with the patient. One should consider potential toxicities as they have been well documented, according to Dr. Kivitz. He says clinicians can minimize these risks by ensuring proper patient selection. Dr. Kivitz notes one can do this via appropriate screening for tuberculosis as well as other underlying disease states that could put the patient at greater risk from a biologic agent.

Dr. Kivitz says other factors that patients weigh include insurance coverage and whether they are willing to receive an injection therapy, whether it occurs via infusion or self-administration. Indeed, Dr. Kivitz notes that some patients decline more aggressive therapy even though it will help them.

“The majority of such patients tend to be people who have had RA for a number of years, are very content with how they are doing and remind me of this frequently,” explains Dr. Kivitz. “I consider this subgroup of patients a mismatch between what we are theoretically capable of doing to control active RA and what patients are content with.”

Dr. Wei has also encountered these patients in his practice.

“Often, patients are content with where they are,” concedes Dr. Wei. “They often will remind me of how bad they were before they saw me. They often express concern about potential side effects and also express that that their family is concerned about side effects as well.”

(Photo courtesy of Nathan Wei, MD, FACP, FACR)

When it comes to treating rheumatoid arthritis (as shown above), Dr. Kivitz says there is “more than adequate data to support the positive effects of combining a biologic with methotrexate.”

In regard to patients who are hesitant to opt for aggressive therapy, Dr. Kivitz notes they usually do not have as many complaints of pain but do have persistent synovitis. Dr. Kivitz believes it is important to educate these patients and let them know that the treatment of RA has greatly evolved.

“It is ultimately up to all of us to educate our patients about their disease and the extraordinary improvement that may result from the addition of a biologic agent,” emphasizes Dr. Kivitz.

Dr. Wei concurs, noting that it is important to educate patients about the potential effect of RA on other organ systems. For example, he says a “sobering” study in a recent issue of Annals Of Internal Medicine showed active RA is also associated with a significant increase in cardiovascular mortality.1

That said, no matter how persuasive the clinician is, it is ultimately the patient’s decision on whether he or she will opt for the biologic therapy, according to Dr. Wei.

“In an ideal world, patients with active disease would gladly elect to start biologic therapy,” says Dr. Wei. “However, the ultimate decision to initiate such therapy resides with the patient. After all, it is (his or her) health that is the subject of interest.”

Q: When treating patients with biologic therapy, what are the parameters you measure to gauge efficacy?
A: Given the increasing use of biologic agents, monitoring patients for efficacy has now become a routine part of the rheumatologist’s workday, according to Jeffrey Kaine, MD. While the majority of the published rheumatic disease literature on biologic agents relates to RA, Dr. Kaine points out that the Food and Drug Administration (FDA) has approved many new indications (ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease) for biologic agents in the past several years. The majority of the published literature with biologic therapy refers to the use of anti-TNF agents but Dr. Kaine believes the emergence of T-cell co-stimulation inhibitors (Orencia) and peripheral B-cell depleting agents (Rituxan) in the next year will change usage profiles significantly.

Numerous guidelines for monitoring clinical improvement in RA disease trials are now widely accepted, according to Dr. Kaine. These guidelines include subjective measurements such as VAS, tender joint counts, general quality of life measurements (SF-36) and specific disease activity measurements (MHAQ). He notes that objective measurements of disease activity include acute phase reactants (ESR/CRP), swollen joint counts (SJC) and measurements of X-ray progression (Sharp score, van der Heijde score).

Dr. Kaine says Disease Activity Scores, such as the DAS28, combine subjective and objective data to provide a numeric value. This value correlates with the rate of radiographic disease progression and the prevailing thinking is this value is independent of initial disease activity, according to Dr. Kaine.

Clinicians would use ACR improvement criteria (e.g. ACR50, ACR70) to define improvement over time in response to drug therapy. However, Dr. Kaine cautions that these measurements are not useful for an individual assessment at a single point in time.

Dr. Kaine notes that all of these research guidelines have limited utility in routine clinical practice largely due to the time required for data collection and analysis.

Due to this conflict, rheumatologists frequently devise their own individual methods for monitoring and disease assessment. Unfortunately, there is no uniform acceptance of a clinical definition of “RA activity” for the individual patient, concedes Dr. Kaine. Some physicians and some experimental protocols have advocated decision making based primarily on changing tender and swollen joint counts.

“In my opinion, using this modality solely to make clinical decisions neglects other important variables,” points out Dr. Kaine.

He notes that experienced clinicians perform their own assessment of disease activity by eliciting answers to several questions they routinely pose to the patient during a typical office visit. Dr. Kaine says the clinician should subsequently perform a joint examination in order to corroborate one’s clinical impression. Typically, one needs to answer the following questions.

• Which joints are inflamed?
• Which joints are painful?
• Are the painful joints clinically inflamed (or might there be another explanation for the patient’s discomfort)?
• Has the examination changed from the last visit?
• Has the degree of morning stiffness or gelling changed from prior visits?
• Are there important life changes to consider when evaluating changes in objective findings?
• Are the changes one sees likely related to any type of intervention made at recent visits?
• Has there been a change in laboratory findings consistent with the clinical impression?

By combining the answers to these questions with the joint examination, Dr. Kaine says one can arrive at a medical opinion that may necessitate maintaining or changing therapy.

Q: When using biologic therapy, how do you measure for potential toxicity and side effects?
A: Widely accepted guidelines for monitoring laboratory toxicity of biologic agents have never been published, according to Dr. Kaine. He points out that a substantial percentage of patients using anti-TNF inhibitors are also taking concomitant DMARD therapy (primarily methotrexate). Dr. Kaine notes that ACR guidelines for laboratory monitoring of MTX therapy will be more than adequate for the patient who is also taking a TNF-antagonist.

(Photo courtesy of Babak Baravarian, DPM)

A 27-year-old woman presented with a 12-year history of rheumatoid arthritis, extreme pain and forefoot deformity (see above photo). Unfortunately, Dr. Kaine says there is no uniform acceptance of a clinical definition of “RA activity” for the individual patient.

Assuming the patient is not taking a concomitant DMARD, most clinicians choose to check routine blood counts, liver function tests and renal function every three to six months although no definite data exists to support this policy, adds Dr. Kaine.

More important than laboratory testing is an awareness of the rare and idiosyncratic toxicity of the anti-TNF agents, emphasizes Dr. Kaine. He says symptoms suggestive of any of these toxicities require a complete evaluation and extensive laboratory testing. Dr. Kaine points out that almost all studies of the anti-TNF agents reveal a greater incidence of complications in patients with preexisting pulmonary disease.

“This subgroup of patients deserves careful monitoring with attention to any new infectious-type symptoms,” notes Dr. Kaine. “The consequences of immunosuppression are well known and the incidence of reactivation of latent TB has been reported in many series of patients.”

Dr. Kaine says it is mandatory to have a low threshold for evaluating symptoms of infection in the anti-TNF treated individual. Transient cessation of therapy during an infectious event is the routine standard of care although there are no absolute guidelines, cautions Dr. Kaine.

He adds that routine PPD testing is necessary prior to initiating biologic therapy. Individuals with a positive PPD (and normal CXR) without prior INH therapy require a total of nine consecutive months of isoniazid/pyridoxine therapy, according to Dr. Kaine. After three to four weeks of INH therapy, one may initiate anti-TNF therapy assuming there is no evidence of INH toxicity. If a CXR is suggestive of tuberculosis, Dr. Kaine says standard anti-tuberculous therapy for several months under infectious disease supervision is mandatory before adding any anti-TNF therapy.

Dr. Kaine notes there are rare care reports of neurologic toxicity including demyelinating disorders, transverse myelitis, optic neuritis and multiple sclerosis in the literature. Cytopenias, including aplastic anemia, have been reported as well, points out Dr. Kaine. He adds that exacerbations of CHF as well as autoantibody production are rare reported events. There are also case reports of drug-induced lupus, according to Dr. Kaine.

He emphasizes that all of the patient’s immunizations should be up to date prior to starting therapy with an anti-TNF agent. Dr. Kaine notes that individuals are able to mount an adequate immune response to both influenza and pneumococcal vaccines. Accordingly, he says one should consider these part of standard therapy.

Dr. Kaine notes that assessing an increased risk of malignancies in anti-TNF treated patients is currently a controversial topic with conflicting data. He points out that true incidence figures are difficult to interpret and discussion of this issue is beyond the scope of this commentary. Nevertheless, clinicians should ensure routine health maintenance monitoring of the patient receiving anti-TNF therapy, emphasizes Dr. Kaine.
Infusion related events are usually mild but can occasionally be severe with reports of focal swelling, angioedema and rarely anaphylactoid-like reactions, adds Dr. Kaine.

“Constant vigilance is important,” sums up Dr. Wei. “It is not always possible to spot the side effect that is coming from around the corner. Arming yourself with the knowledge of what is potentially possible will help both you and your patient make reasonable decisions.”

Dr. Kaine is a board-certified rheumatologist and is the Director of the Sarasota Arthritis Research Center in Sarasota, Fla.

Dr. Kivitz is a board-certified rheumatologist. He is the Director of the Altoona Arthritis Center in Altoona, Pa.