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Too Difficult to Diagnose

Tolerization isn’t always obvious. The decline in drug
efficacy can be subtle, gradual, and clinically ambiguous. A
patient flares—was it stress? A missed dose? A dietary
change? Is it disease progression or a random setback? Or
is the immune system quietly, methodically, rejecting the
biologic therapy designed to keep the disease in check?

Most of the time, no one can say with certainty. Measuring
anti-drug antibodies (ADAs) isn’t part of standard
protocol in most clinics. The tests are expensive, often not
reimbursed by insurance, and available only through select
reference labs. Even when they are available, the results
can be difficult to interpret:

• Are the antibodies transient or persistent?
• Are they binding or neutralizing?
• Do they actually correlate with the patient’s
symptoms or lab values?

There are no universally accepted thresholds for what
constitutes clinically significant ADA levels. There’s no
clear decision tree that tells a clinician what to do next.
Should the dose be increased? Should the drug be stopped?
Should an immunosuppressant be added? The answers are
murky, so many physicians default to clinical intuition—
and in the absence of clear data, they often attribute the
loss of efficacy to anything but immunologic rejection.

This diagnostic fog allows tolerization to hide in plain
sight. Even when it’s suspected, it rarely gets named. It’s
masked under euphemisms like “loss of response,”
“secondary non-response,” or “disease breakthrough.”

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