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shortens. Therapeutic efficacy begins to fade—but not
enough to trigger alarm.

Patients may report that the drug “doesn’t feel quite as
strong,” or that they have “a few more bad days than
usual.” These complaints are often dismissed as noise—
variability, placebo effect, or progression of the disease.

Clinicians may not test for ADA levels right away—those
tests are expensive, not always available in real time, and
their interpretation is complicated. As a result, valuable
time is lost, and the immune system continues to mount a
more robust and targeted defense.

This is when the opportunity for early intervention—such
as dose adjustment, immunomodulator co-therapy, or
switching to a more tolerogenic format—is greatest. And
yet, it’s also when the alarm is least likely to be sounded.

3. Clinical Failure (The Crash)

Eventually, the antibodies win. The biologic is either
neutralized by direct binding or cleared from the body too
quickly to maintain therapeutic levels. The patient’s
symptoms flare. Inflammatory markers spike. Disease
activity rebounds.

This stage is often misinterpreted as treatment failure or
disease progression, rather than what it truly is:
immunologic rejection of a previously effective therapy.

Now the process of therapeutic switching begins. The
patient may move to another biologic in the same class
(e.g., from Humira to Cimzia), or escalate to a different

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