Search

BackgroundImmunoglobulin G (IgG) levels are maintained by the IgG-recycling neonatal Fc-receptor (FcRn). Pemphigus vulgaris and pemphigus foliaceus are debilitating autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. Recently, a phase 2 clinical trial (NCT03334058; https://clinicaltrials.gov/NCT03334058) was completed in participants with pemphigus using efgartigimod, an FcRn inhibitor, in combination with prednisone. Efgartigimod demonstrated an early effect on diease activity and was well tolerated. In addition to the safety and efficacy assessment, clinical trials present an opportunity to gain more insights into the mechanism of disease, the mode of action of treatment, and potential for corticosteroid-sparing activity.ObjectiveThe aim of our study was to assess the impact of FcRn antagonism by efgartigimod on immunological parameters known to be directly involved in pemphigus pathology, such as cellular and serological responses.MethodsWe investigated total and antigen-specific IgG subclass level kinetics during and after treatment, assessed antigen-specific B-cell responses, followed T- and B-cell immunophenotypes, and analyzed how different immunophenotypes link to clinical response.ResultsTreatment resulted in reduction of total IgG as well as autoreactive IgG antibody levels. Surprisingly, unlike total IgG and vaccine- or natural-infection-elicited IgG, which returned to baseline levels after stopping efgartigimod treatment, autoreactive antibody levels remained low in several study participants. Efgartigimod showed no effect on total leukocytes, neutrophils, monocytes, or lymphocytes in patients treated with extended efgartigimod therapy. Intriguingly, antigen-specific analyses revealed a loss of desmoglein-specific B cells in several participants responding to efgartigimod, in line with prolonged reduction of pathogenic IgG levels.ConclusionsEfgartigimod treatment of participants with pemphigus improved their conditions and exerted an immunomodulatory effect beyond the blockade of IgG recycling. Further studies in larger populations with an appropriate placebo control are needed to confirm these potentially important observations to establish long-term clinical responses in autoimmune diseases.

Additional file 1: Diagnosis and sensitization to different ��-lactams in 205 patients with allergic hypersensitivity (data from allergist directed testing) (modified from [19]).

Additional file 2: Two X Two table depicting results of allergy testing and outcome of the de-labelling algorithm in total 800 patients.

Additional file 1. Grading the severity of anaphylaxis [modified from (7)].

Background Penicillins and other beta-lactam antibiotics are the most common elicitors of allergic drug reaction. However, data on the pattern of clinical reaction types elicited by specific beta-lactams are scarce and inconsistent. We aimed to determine patterns of beta-latam allergy, i.e. the association of a clinical reaction type with a specific beta-lactam antibiotic. Methods We retrospectively evaluated data from 800 consecutive patients with suspected beta-lactam hypersensitivity over a period of 11 years in a single German Allergy Center. Results beta-lactam hypersensitivity was definitely excluded in 595 patients, immediate-type (presumably IgE-mediated) hypersensitivity was diagnosed in 70 and delayed-type hypersensitivity in 135 cases. Most (59 out of 70, 84.3%) immediate-type anaphylactic reactions were induced by a limited number of cephalosporins. Delayed reactions were regularly caused by an aminopenicillin (127 out of 135, 94.1%) and usually manifested as a measles-like exanthem (117 out of 135, 86.7%). Intradermal testing proved to be the most useful method for diagnosing beta-lactam allergy, but prick testing was already positive in 24 out of 70 patients with immediate-type hypersensitivity (34.3%). Patch testing in addition to intradermal testing did not provide additional information for the diagnosis of delayed-type hypersensitivity. Almost all beta-lactam allergic patients tolerated at least one, usually several alternative substances out of the beta-lactam group. Conclusions We identified two patterns of beta-lactam hypersensitivity: aminopenicillin-induced exanthem and anaphylaxis triggered by certain cephalosporins. Intradermal skin testing was the most useful method to detect both IgE-mediated and delayed-type beta-lactam hypersensitivity.

Additional file 2. Concentration of β-lactam antibiotics for skin testing and sequence of increasing doses used in single-blinded challenge. * For prick and patch testing, tablets were ground in a mortar and suspended with 1 mL physiological saline solution. iv, intravenous; n.d., not done.