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Rethinking the utility of acetylcholine receptor antibody titer as a pharmacodynamic biomarker for myasthenia gravis

In 1973, Patrick and Lindstrom serendipitously demonstrated the pathogenic effect of acetylcholine receptor (AChR) antibodies when they immunized rabbits with AChR purified from the electric organ of eels. The rabbits developed paralysis that was reversed by injection of edrophonium and all had precipitating antibodies to eel AChR. Subsequently, AChR binding antibodies (AChR-Abs) measured with a radioimmunoprecipitation assay (RIA) were found in 87% of sera from myasthenia gravis (MG) patients. RIA using radiolabeled α-bungarotoxin remains the predominant method for measuring the presence and quantity of antibodies binding to AChR. AChR antibodies can accelerate endocytosis of the receptors by cross-linking them (modulating) and/or blocking the acetylcholine binding sites. These functional activities can be measured by an assay using cultured human muscle cells to detect reduction in the number of cell-surface binding sites for radiolabeled α-bungarotoxin. Enzyme-linked immunosorbent assays (ELISAs) have been developed as an alternative method to measure binding antibodies, although these assays may not detect very low concentrations of antibodies nor measure their functions. AChR-Abs are highly specific for MG, being positive in up to 90% of patients with generalized MG and in over 50% of those with ocular MG. Some MG patients without AChR-Abs on RIA have been found to have either AChR antibodies detected on cell-based assay, antibodies to muscle-specific kinase (MuSK), or low-density lipoprotein receptor–related protein 4 (LRP4). With the incremental discovery of pathogenic antibodies, serologic testing has become the predominant method for establishing the diagnosis of MG. The presence of AChR-Abs in the right clinical context not only establishes the diagnosis of MG but also informs treating physicians or researchers of the patient's serologic subgroup. This information can be used to guide development of novel therapeutics or implementing treatments. It would be very helpful if the antibody titer correlated with clinical severity or treatment response, and this has been the subject of many studies since the antibodies were discovered. However, these studies have consistently shown that the AChR-Ab titer varies markedly among patients, and does not correlate or correlates only loosely with disease severity. Change in the antibody titer also correlates weakly and inconsistently with change in disease severity. Among other things, this may be due to individual differences in affinity, binding sites, or pathogenicity of the antibodies. Notably, an early study showed that the correlation with severity improved when the functional antibody properties of “degradation” and blocking were combined. Currently, the utility of the AChRAb titer as a biomarker to follow the clinical course is limited, and repeated measurements are not routinely recommended for this purpose. In this issue of the Journal, Ching et al report five MG patients treated with plasma exchange (PLEx) who had AChR-Ab titers up to tenfold higher after PLEx compared with their baseline titers. In four of these patients, antibody overshoot was associated with clinical deterioration requiring additional treatments with subsequent PLEx, eculizumab, rituximab, or immunosuppressants. In one patient, the antibody overshoot was not associated with clinical deterioration. The antibody titers subsequently returned to baseline levels in all these patients. Although there seems to be a correlation between the clinical course and the antibody titers in most of these patients, one can only speculate on the true relationship because of the retrospective nature of this study-there may be other patients in whom antibody overshoot occurred without clinical deterioration and in whom further AChR-Ab measurements were not made or reported. Furthermore, it is not clear whether the antibody titer was on the rise before PLEx or the PLEx itself triggered higher production of antibodies. Another important consideration when comparing antibody titers is whether this is simply due to measurement variability, although this is unlikely because the measurements were made in the same commercial laboratory. Considering all these limitations, we agree with the authors that monitoring antibody titers after PLEx cannot be used to make treatment decisions. Antibody overshoot after PLEx was initially described in the 1980s, when the AChR-Ab had been recently discovered and PLEx was a prominent treatment for MG exacerbations. In one report, 5 of 17 patients treated with PLEx had antibody overshoot, which was accompanied by recurrence of MG symptoms in 3. Four additional patients had relapses after PLEx, and three of these were associated with rising antibody titers that did not exceed the baseline value. The report suggested that antibody overshoot may not be rare. However, there have not been any further reports of antibody overshoot in the past four decades, which may reflect the clinical practice of using immunosuppression after PLEx to prevent overshoot, and the fact that AChR-Ab is not widely used to monitor disease progression. The report by Ching et al provides an opportunity to ask whether there is value in following the AChR-Ab titer in some cases or circumstances. In a recent study of 53 MG patients, an average daily reduction of 0.64% or more from the baseline AChR-Ab titer within 100 days of beginning immunosuppressive treatment predicted achievement of minimal manifestation status. This result is consistent with findings from Received: 6 July 2021 Revised: 9 July 2021 Accepted: 18 July 2021