Neutralizing Antibody and Botulinum Toxin Therapy: A Systematic Review and Meta-analysis

Fabbri, Margherita; Leodori, Giorgio; Fernandes, Ricardo M; Bhidayasiri, Roongroj; Martı́, Marı́a José; Colosimo, Carlo; Ferreira, Joaquim J.

doi:10.1007/s12640-015-9565-5

Cited by 89 publications

(101 citation statements)

References 31 publications

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“…25 Some discrepancy between the identification of neutralizing antibodies and secondary nonresponse has been described previously. 29 No lasting immunogenicity was recorded with increasing incobotulinumtoxinA dose across the entire study period (up to 48 weeks) and higher than labeled doses were administered in both cycles 2 and 3. Further studies are required to investigate the effect of long-term treatment with high doses of incobotulinumtoxinA on the development of immunogenicity.…”

Section: Discussionmentioning

confidence: 94%

Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity

et al. 2017

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Objective:To evaluate safety (primary objective) and efficacy of increasing doses (400 U up to 800 U) of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) for patients with limb spasticity.Methods:In this prospective, single-arm, dose-titration study (NCT01603459), patients (18–80 years) with spasticity due to cerebral causes, who were clinically deemed to require total doses of 800 U incobotulinumtoxinA, received 3 consecutive injection cycles (ICs) with 400 U, 600 U, and 600–800 U incobotulinumtoxinA, respectively, each followed by 12–16 weeks' observation. Outcomes included adverse events (AEs), antibody testing, Resistance to Passive Movement Scale (REPAS; based on the Ashworth Scale), and Goal Attainment Scale.Results:In total, 155 patients were enrolled. IncobotulinumtoxinA dose escalation did not lead to an increased incidence of treatment-related AEs (IC1: 4.5%; IC2: 5.3%; IC3: 2.9%). No treatment-related serious AEs occurred. The most frequent AEs overall were falls (7.7%), nasopharyngitis, arthralgia, and diarrhea (6.5% each). Five patients (3.2%) discontinued due to AEs. No patient developed secondary nonresponse due to neutralizing antibodies. Mean (SD) REPAS score improvements from each injection to 4 weeks postinjection increased throughout the study (IC1: −4.6 [3.9]; IC2: −5.9 [4.2]; IC3: −7.1 [4.8]; p < 0.0001 for all). The proportion of patients achieving ≥3 (of 4) treatment goals also increased (IC1: 25.2%; IC2: 50.7%; IC3: 68.6%).Conclusion:Escalating incobotulinumtoxinA doses (400 U up to 800 U) did not compromise safety or tolerability, enabled treatment in a greater number of muscles/spasticity patterns, and was associated with increased treatment efficacy, improved muscle tone, and goal attainment.ClinicalTrials.gov identifier:NCT01603459.Classification of evidence:This study provides Class IV evidence that, for patients with limb spasticity, escalating incobotulinumtoxinA doses (400 U up to 800 U) increases treatment efficacy without compromising safety or tolerability.

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Section: Discussionmentioning

confidence: 94%

Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity

et al. 2017

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“…These patients often are thought to have acquired antibody-mediated resistance that blocks the BoNT protein from its normal action [19–22]. This mechanism for non-response was studied extensively with early BoNT preparations, but more recent studies have suggested that antibody formation is uncommon with the currently available highly purified BoNT preparations.…”

Section: Discussionmentioning

confidence: 99%

“…When formal tests of resistance are indicated, there are two options. The first option involves commercially available tests for antibodies to BoNT, although these have fallen out of favor because of poor clinical correlations [15–17, 20, 22, 38]. The preferred option involves performing a functional test for muscle weakness, such as injection of a small dose of BoNT into the frontalis, corrugator, or extensor digitorum brevis [19].…”

Section: Discussionmentioning

confidence: 99%

Botulinum toxin treatment failures in cervical dystonia: causes, management, and outcomes

et al. 2016

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Botulinum toxin (BoNT) is highly effective in the treatment of cervical dystonia (CD), yet a significant proportion of patients report low levels of satisfaction following treatment and fail to follow-up for repeated treatments. The goal of this study was to determine the reasons some patients have unsatisfactory responses. A total of 35 subjects who came to our center requesting alternative treatments due to unsatisfactory responses following BoNT treatment for CD were evaluated. Included were 26 women and 9 men with an average age of 57.1 years (range, 25–82 years), and an average duration of illness of 12.5 years (range, 1–55 years). Details of unsatisfactory BoNT treatments were methodically collected by a movement specialist using a standardized intake form, including provider subspecialty, product used, number of satisfactory or unsatisfactory trials, doses given, specific muscles treated, use of electromyographic guidance, side effects, and tests of resistance. The specialist then provided repeat treatments if indicated, and followed each case until the reasons for unsatisfactory outcomes could be determined. Multiple reasons for unsatisfactory outcomes were found. They included suboptimal BoNT doses, suboptimal muscle targeting, intolerable side effects, complex movement patterns, discordant perceptions, and incorrect diagnoses. Only 1 patient was functionally resistant to BoNT. Of 32 subjects who received repeat BoNT treatments, 25 (78%) achieved satisfactory responses after revision of the original treatment plan. These results indicate that the majority of unsatisfactory responses to BoNT treatment of CD were caused by correctible factors and imply a need for improved education regarding optimal treatment methods.

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“…Secondary non-response is partially explained by the formation of neutralizing antibodies, though it is worth noting that there are cases of secondary non-responders without positive antibody titers (Hanna 1998;Lange 2009) as well as cases with positive titers but with an adequate sensitivity to Bt (Brin 2008;). An estimated 4-20% of patients develop neutralizing antibodies to the toxin (Brashear 2008;Fabbri 2015), and if secondary non-responsiveness occurs, it is partially related to the protein load, with higher protein load per dose generating higher antibody titers (Benecke 2012;Frevert 2010). …”

Section: Why It Is Important To Do This Reviewmentioning

confidence: 99%