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With biologic drugs dominating the therapeutic space for severe immune‐mediated inflammatory disease, it is critical for clinicians to be familiar with the concept of drug immunogenicity, with the potential for our patients to develop antidrug antibodies (ADA) of clinical relevance. Whilst there are clear differences between different therapeutic biologics in terms of reported ADA rates, there is no accepted dermatology guideline or grouping of drugs by risk of clinically relevant ADA, nor a consensus on approach to ADA management. This is partly because making valid comparisons of immunogenicity across drugs is fundamentally flawed: the differing types of ADA assay, trial design and included patient population – as well as the molecular structure of the biologic molecules themselves – are all highly influential on reported ADA prevalence and impact on clinical response. Therefore, the first part of this article aims to give an overview of ADA that also clarifies common misconceptions on the subject, whilst the second part of this article outlines Phase III immunogenicity data on commonly used biologics for psoriasis, the most common dermatological indication. Based on this, and acknowledging current limitations in available evidence, we propose a working categorization of biologics together with a broad approach to management: Group 1 – biologics with higher risk of clinically relevant ADA; Group 2 – biologics with lower risk of clinically relevant ADA; and Group 3 – biologics with no established risk of clinically relevant ADA. However, these groupings represent a working concept only; more research is required, using comparable ADA assays and consistent reporting of related outcomes. Finally, there is an urgent need for better characterization of individuals at particular risk of developing ADA to inform future clinical decision‐making. [ABSTRACT FROM AUTHOR]

The article provides information on a research letter based on vaccination for tetanus toxoid and induction of allergic symptoms. Topics discussed include IgE production to elevate tetanus and analyse plasma donors; DTP vaccination programme for infancy and sensitivity reactions; and antibody responses.

Background and purpose Infection with the John Cunningham virus ( JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of natalizumab treatment in multiple sclerosis patients. The JCV seroconversion rate seems higher in natalizumab treated patients than in the normal population, with an unknown cause. Methods Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients. Results One hundred and thirty-five patients were included. No correlation was found between natalizumab concentration and JCV status, JCV seroconversion or JCV index. Conclusions Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients. [ABSTRACT FROM AUTHOR]

Background and purpose John Cunningham virus ( JCV) seropositivity is a risk factor for the development of natalizumab-associated progressive multifocal leukoencephalopathy ( PML) in multiple sclerosis ( MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab-treated relapsing−remitting MS ( RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab-treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing. Methods and results In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti- JCV antibody indices were measured in 933 available samples. Eighty-six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow-up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow-up duration. No significant increase was seen in the anti- JCV antibody index in the non-converting patients during the follow-up. Conclusion The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy. [ABSTRACT FROM AUTHOR]

The author reflects on a study regarding IgE anti-alpha-gal antibodies. He mentions that IgE antibodies to alpha-gal were detected in several individuals and is associated to hypersensitivity reactions following consumption of red meat. He provides information concerning glycolipids, which contains the alpha-gal epitope.

Background Formation of antibodies to infliximab ( ATI) inversely correlates with functional drug levels and clinical outcome. Comparison of drug levels and anti-drug antibody monitoring is hampered by lack of standardisation. Aim To determine the correlation between three different assays for measuring infliximab and ATI. Methods Serum samples and spiked controls (total 62) were evaluated in a blinded way in infliximab and ATI assays developed by Sanquin Amsterdam, Netherlands (A), Laboratory for Pharmaceutical Biology, KU Leuven, Belgium (B) and a commercially available kit from Biomedical Diagnostics ( BMD), Paris, France (C) performed by the University Medical Center Groningen ( UMCG), Netherlands. Results All infliximab assays showed a linear quantitative correlation (Pearson r = 0.91 for A vs. B, 0.83 for A vs. C and 0.73 for B vs. C). Assay C detected infliximab in 11 samples (18%) not detected by A and B, including samples containing only ATI. All ATI assays showed a good linear correlation (Pearson r = 0.95 for A vs. B, 0.99 for A vs. C and 0.97 for B vs. C). Assay A detected ATI in five samples with low ATI that were not detected by assays B and C. Assay B did not detect ATI in three patient samples with low ATI according to assays A and C. Conclusions There is a good correlation of infliximab and antibodies to infliximab measurements between these assays. Nevertheless, the Biomedical Diagnostics kit detected false positive infliximab levels in 18% of the samples. [ABSTRACT FROM AUTHOR]

Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as ‘Fab-arm exchange’, results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Detection of infliximab levels and anti-infliximab antibodies--comparison of three different assays," in a previous issue is presented.

During the COVID-19 pandemic, the daily life of many patients with dermatological immune-mediated inflammatory diseases (DIMIDs), such as atopic dermatitis (AD), psoriasis, and vitiligo, was impacted by social restrictions caused by (fear of) morbidity, mortality associated with COVID-19, and vaccine hesitancy. This prospective observational, multicenter, multidisciplinary cohort study explored the impact of COVID-19 disease and vaccination on DIMIDs, specifically AD, psoriasis, and vitiligo. Data from patients with DIMIDs were collected as part of the Target2B! study (between February 2021 and October 2022). We analyzed the differences in baseline characteristics, risk of developing COVID-19, proportion of DIMIDs in patients reaching seroconversion upon vaccination per DIMID, and self-reported increase in DIMID activity by multivariable logistic regression and sensitivity analyses. A total of 424 patients with DIMID were included. COVID-19 disease commonly occurred in patients with vitiligo (51.1%), AD (42.0%), and psoriasis (34.3%) (p = 0.038). COVID-19 was not associated with the use of immunosuppressive therapy. Three patients (two with AD and one with vitiligo) were hospitalized due to COVID-19. Nearly all patients with DIMIDs exhibited effective seroconversion after regular vaccination regimens (vitiligo 100%, psoriasis 97.9%, AD 96.5%). Increased DIMID activity after COVID-19 (6.6%) or severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) vaccination (12.26%) was reported in a minority of patients, with baseline progressive disease (disease activity 3 months preceding baseline survey) being the only associated risk factor (COVID-19: odds ratio [OR], 4.27 [p = 0.02]; vaccination OR, 3.45 [p = 0.002]). In conclusion, no alarming signs were shown in this study regarding (severe) COVID-19 in patients with AD, psoriasis, or vitiligo. Vaccination against COVID-19 is advised in patients with DIMIDs. Moreover, patients with DIMIDs can safely continue their immunosuppressant therapy, since this does not increase the risk of COVID-19, while vaccination-induced humoral responses are adequate. In only a minority of patients, increased DIMID activity after COVID-19 or SARS-CoV-2 vaccination occurred., (© 2025 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated., Methods: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination., Results: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based., Conclusions: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Anti-drug antibodies (ADA) are formed in patients treated with adalimumab (ADL). This might increase clearance of ADL, potentially causing a (secondary) non-response. Combination therapy of ADL and methotrexate (MTX) reduces ADA levels and has a clinical benefit in rheumatologic diseases. In psoriasis however, the long-term effectiveness and safety have not been studied., Objectives: To investigate the three-year follow-up data of ADL combined with MTX compared to ADL monotherapy in ADL-naive patients with moderate to severe plaque type psoriasis., Methods: We conducted a multicentre RCT in the Netherlands and Belgium. Randomization was performed by a centralized online randomization service. Patients were seen every 12 weeks until week 145. Outcome assessors were blinded. We collected data on drug survival, effectiveness, safety, pharmacokinetics and immunogenicity of patients that started ADL combined with MTX compared to ADL monotherapy. We present descriptive analysis and patients were analysed according to the group initially randomized to. Patients becoming non-adherent to the biologic were excluded from analyses., Results: Sixty-one patients were included and 37 patients (ADL group n = 17, ADL + MTX group n = 20) continued in the follow-up study after 1 year. After 109 weeks and 145 weeks, there was a trend towards longer drug survival in the ADL + MTX group compared to the ADL group (week 109: 54.8% vs. 41.4%; p = 0.326, week 145: 51.6% vs. 41.4%; p = 0.464). At week 145, 7/13 patients were treated with MTX. In the ADL group, 4/12 patients that completed the study developed ADA, and 3/13 in the ADL + MTX group., Conclusions: In this small study, there was no significant difference in ADL overall drug survival when it was initially combined with MTX, compared to ADL alone. Discontinuation due to adverse events was common in the combination group. To secure accessible healthcare, combination treatment of ADL and MTX can be considered in individual patients., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: At present, no real-world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient-centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers., Methods: Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient-centered dosing regimen. Group A (n = 30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n = 30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n = 30) prolonged dupilumab interval with 66%-75% (300 mg/6-8 weeks). AD severity score, patient-reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time., Results: Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)-pruritus temporarily significantly increased after interval prolongation but remained low (median NRS-pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR = 17.1-45.6); 12.5 mg/L (IQR = 1.7-22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR = 67.1-123.0, p < .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period., Conclusions: This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient-centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Aims: To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle., Methods: In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device., Results: While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100-point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47-120]; F rel = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96-221]). Anti-adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes., Conclusions: Intradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Therapeutic drug monitoring (TDM) can optimize the efficacy of infliximab (IFX) in patients with inflammatory bowel disease (IBD). Because of the delay between blood samples taken at trough and availability of results, dose adjustments can only be carried out at the next infusion, typically 8 weeks later. Dried blood samples (DBS) performed at home to measure IFX concentrations can reduce the time to adapt dose/dosing interval. Here, we aimed to validate the clinical application of DBS for IFX in IBD patients and to evaluate the feasibility of home sampling., Methods: DBS results from 40 IBD patients on IFX treatment were compared to serum sample results at trough, peak, and 3-5 weeks after IFX infusion. Subsequently, patients performed DBS home sampling one week before the next IFX infusion. These were compared to serum concentrations as predicted by Bayesian analysis., Results: IFX concentrations from finger prick and venous puncture correlate well. DBS IFX concentrations showed high correlation with serum IFX concentrations (Spearman correlation: ≥0.965), without bias. Passing-Bablok regression for IFX concentrations in DBS from home sampling also showed no bias (intercept: 1.02 mg L -1 (95% CI -1.77-2.04 mg L -1 ), slope: 0.82 (95% CI 0.63-1.40)), with reasonable correlation (Spearman correlation: 0.671)., Conclusions: Timely adjustment of IFX dose/dosing interval can be facilitated by IFX concentration measurement in home-sampled DBS. DBS is a reliable method to measure IFX and can be used to predict IFX trough concentrations., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Development of a self-sampling method for therapeutic drug monitoring (TDM) of biologicals will enhance TDM implementation in routine care and pharmacokinetic knowledge. The aim of this study was to compare adalimumab and anti-adalimumab antibody (ADA) concentration measurements in dried blood spots (DBS) obtained from finger prick with measurements in serum obtained via venepuncture, from patients with rheumatic inflammatory diseases., Methods: In this cross-sectional study, 161 consecutive patients were included. For clinical validation, DBS from finger prick and serum from venepuncture were collected simultaneously and adalimumab and ADA concentration were assessed by ELISA and antigen binding test (ABT), respectively. To convert DBS eluate results to values which can be compared to serum concentrations, five different methods were investigated, using a marker protein or a volumetric approach., Results: Adalimumab and ADA concentrations obtained from the finger prick/DBS method correlated well with serum results from the same patient (correlation coefficient > 0.87). Interestingly, antibody concentrations (either adalimumab, ADA or total immunoglobulin G) in DBS from finger prick, but not albumin, were systematically lower compared to serum. Spike experiments demonstrated a quantitative recovery for all tested proteins in DBS, suggesting a slightly different protein composition of blood collected via finger prick vs. venepuncture. We established a correction factor to relate finger prick/DBS values with serum values (approximately 1.2)., Conclusions: We show here for the first time that adalimumab and ADA serum concentrations can be satisfactorily estimated by measuring concentrations in DBS eluates, collected by finger prick. This method offers great opportunity to simplify TDM of adalimumab., (© 2017 The British Pharmacological Society.)