Topic: Management of Suboptimal Responders
By Kristin Jenkins

What should a clinician do when faced with an MS patient who’s a suboptimal responder? “Well, you can throw up your hands,” Patricia K. Coyle MD told delegates, “or you can look at the pilot data because there’s enough to offer us options.”

Dr. Coyle is Professor and Acting Chair of the Department of Neurology and Director of the Multiple Sclerosis Comprehensive Care Center at the School of Medicine, State University of New York (SUNY) at Stony Brook, NY. “We haven’t determined the optimum dose of beta interferon or GA (glatiramer acetate), the current immunomodulator, but we do suspect that they aren’t being used at optimum efficacy,” she added.

The available evidence, including results out of the CLIMB study (Gauthier S. et al, Poster PO1.080, American Academy of Neurology 2006, San Diego, CA.), suggests that there’s a 30% probability of treatment failure within three years. CLIMB, a comprehensive, longitudinal investigation in 135 clinically isolated syndrome/MS patients at the Brigham and Women’s Hospital, Boston, showed that treatment failure was predicted by younger age and T2 lesion volume.

Despite the availability of pivotal clinical trial data evaluating the mean efficacy of disease-modifying drugs for MS, however, clinicians’ main concern is the response of the individual patient, noted Dr. Coyle. “Identification of a suboptimal response or treatment failure at an early stage is an important clinical issue allowing the clinician to modify therapy and potentially improve treatment outcome,” she said.

Therapeutic response is fluid, not fixed, added Dr. Coyle, and in any given patient it falls along a spectrum that ranges from super responder to partial responder or biologic non-responder. The  response also may vary over time depending on different factors, such as clinical subtype and stage of disease.

In assessing the therapeutic response, “you need to think about co-morbidity but you must also think about other reasons a patient may not be doing well on the drug,” said Dr. Coyle.

At the present time, there are no uniform endorsed criteria for determining suboptimal response. Nevertheless, warned Dr. Coyle, you can’t wait for a phone call from the patient on a new treatment. In general, she said, clinicians should be assessing patients with MS for treatment response every 3-6 months for the first two years or after treatment change, with a quantitative neurologic examination. Focus on relapses, disability/progression and MRI findings.

Clinical criteria for a suboptimal response include an unacceptable, untreatable side effect. “If the patient can’t tolerate the drug,” said Dr. Coyle, “then the drug doesn’t work in that patient.” Similarly, relapses in rate, severity and/or recovery would suggest a suboptimal response as would sustained disability. The Expanded Disability Status Scale (EDSS) is a “tarnished gold standard” upon which to evaluate disability, said Dr. Coyle. Instead, she recommended, “count the relapses and judge the degree of recovery.”

Finally, progression—a slow, worsening of disease—meets the clinical criteria for a suboptimal response, noted Dr. Coyle. Conventional MRI criteria for a suboptimal response include the number and volume of gadolinium-enhancing (Gd+) lesions, T2 hyperintense lesions and T1 hypointense lesions. “Count ‘em and look at their size,” suggested Dr. Coyle. “We don’t want to see a lot of lesions.”

Nonconventional MRI criteria for suboptimal response include atrophy of the brain and/or spinal cord, magnetic resonance spectra (N-acetyl aspartate); magnetization transfer imaging, magnetic resonance ratio, diffusion tensor imaging and diffusion weighted imaging. “We’re not ready to use these yet,” noted Dr. Coyle.

Proposed criteria for a suboptimal response (Cohen BA. et al. Neurology. 2004; 63 (12 supple 6): S33-S40) include:

* more than one attack per year (or no decrease in attack rate);

* incomplete attack recovery, especially when there is accumulating disability;

* new or recurrent brainstem or spinal cord lesions;

* polyregional disease; and/or

* a worsening of motor and cognitive impairment that disrupts the activities of daily living.

 “I would tolerate one attack per year but no more attacks than before treatment,” said Dr. Coyle. “Otherwise, I would see this as a treatment failure.”

When faced with a suboptimal responder, options include discontinuing therapy, changing agents, or modifying treatment by increasing beta interferon dose and/or frequency, or using combination therapy. Combination strategies include interferon beta plus glatiramer acetate or interferon beta/glatiramer acetate combined with one of the following: natalizumab; mitoxantrone; methotrexate (20 mg PO weekly); azathioprine (150 mg PO QD); pulse IV methylprednisolone: or doxycycline/minocycline (100-200 mg PO QD).

Future research goals include developing reliable clinical criteria for identifying suboptimal responders as well as the identification of biomarkers for disease activity and treatment response, said Dr. Coyle.