Influencing factors on the safety and effectiveness of venom immunotherapy.

BACKGROUND AND OBJECTIVE: The safety profile of venom immunotherapy (VIT) is a relevant issue and considerable differences in safety and efficacy of VIT have been reported. The primary aim of this study was to evaluate the safety of ACE inhibitors and beta-blockers during VIT, which has already been published. For a second analysis, data concerning premedication and venom preparations in relation to systemic adverse events (AE) during the up-dosing phase and the first year of the maintenance phase were evaluated as well as the outcome of field stings and sting challenges. METHODS: The study was conducted as an open, prospective, observational, multicenter study. In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during the up-dosing and 19.7% of patients during the maintenance phase. Taking antihistamines had no effect on the frequency of systemic AE (p=0.11) but large local reactions (LLR) were less frequently seen (OR: 0.74; 95% CI: 0.58-0.96; p=0.02). Aqueous preparations were preferentially used for up-dosing (73.0%) and depot preparations for the maintenance phase (64.5%). The type of venom preparation neither had an influence on the frequency of systemic AE nor on the effectiveness of VIT (p=0.26 and p=0.80, respectively), while LLR were less frequently seen when depot preparations were used (p<0.001). CONCLUSION: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLR but not systemic AE. All venom preparations used were equally effective and did not differ in the frequency of systemic AE.

Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

Interferon alfa-2a maintenance after salvage autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement.

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma with unfavourable prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We report on a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization-European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Interestingly, readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a durable complete remission during the follow-up period of currently 17 months after autologous SCT. What's already known about this topic? Mycosis fungoides is a primary cutaneous T-cell lymphoma with unfavourable prognosis for the advanced stages of the disease. A refractory course of disease requires systemic therapy. What does this study add? We report on an unusual case of a patient with mycosis fungoides with cerebral involvement, in which a durable complete remission was achieved upon autologous stem cell therapy and interferon alfa-2a maintenance therapy.

Systemic corticosteroids for subcutaneous panniculitis-like T-cell lymphoma.

BACKGROUND: Primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL) is aggressive and has a poor prognosis. In contrast, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) of the α/ß T-cell receptor phenotype is known to follow an indolent course and have a more favourable prognosis. In the past, PCGD-TCL and SPTCL were often considered to be a manifestation of the same disease, and aggressive systemic polychemotherapy has commonly been the first-line therapy for both. Given the understanding that SPTCL is a separate and less aggressive entity, clinical data exclusively evaluating the efficacy of conservative treatment in SPTCL are needed. OBJECTIVES: To assess the overall clinical response to systemic corticosteroids in the treatment of SPTCL. METHODS: This was a retrospective cross-sectional study based on a patient data repository from two tertiary care university hospitals in Zürich (Switzerland) and Tübingen (Germany). The repository spanned 13 years. RESULTS: In four of the five patients (80%) with SPTCL, treatment with systemic corticosteroids induced a complete remission. CONCLUSIONS: Systemic corticosteroids may be an excellent first-line single-agent therapy for SPTCL.

Efficacy of bath psoralen plus ultraviolet A (PUVA) vs. system PUVA in psoriasis: a prospective, open, randomized, multicentre study.

BACKGROUND: Plaque psoriasis is an inflammatory disease affecting approximately 2% of the population. The clinical hallmarks of psoriasis are sharply demarcated, erythematous plaques with thick scales. Photochemotherapy (psoralen plus ultraviolet A, PUVA) is one of the most effective therapies of psoriasis. The photosensitizer 8-methoxypsoralen (8-MOP) can be applied either orally (system PUVA) or topically in a warm water bath (bath PUVA). OBJECTIVES: To compare bath PUVA and system PUVA in the treatment of plaque psoriasis. METHODS: This was a randomized, open, prospective, multicentre trial. We included 74 patients with moderate-to-severe plaque psoriasis during a 6-week treatment and a 4-week follow-up period. Of the patients enrolled in the study, 38 received bath PUVA and 36 system PUVA. RESULTS: Both treatment modalities significantly reduced the median Psoriasis Area and Severity Index (PASI) score in the intention-to-treat population. Within 6 weeks bath PUVA reduced the median PASI by 74% (16·4 to 4·2) while system PUVA did so by 62% (15·3 to 5·8). The difference between the two modalities was not significant with regard to treatment efficacy (P = 0·389). CONCLUSION: There is no difference between bath PUVA and system PUVA in the treatment of psoriasis.

Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly.

BACKGROUND: Epidemiologic studies suggest that elderly people are more prone to develop severe anaphylactic reactions. However, the exact cause for this phenomenon remains unclear. AIMS OF THE STUDY: To study the role of the serum tryptase as a diagnostic parameter for individual risk evaluation and its impact on the severity of allergic reactions in elderly people. METHODS: Two hundred and seventy-four consecutive patients visiting the Department of Dermatology, Tübingen, Germany, who were diagnosed with honeybee or wasp venom allergy, were included in the study. RESULTS: Sting reaction severity increased with increased age and tryptase levels (P = 0.001 and P = 0.0003, respectively). Furthermore, we find not only a general increment in tryptase levels in elderly people (P = 0.0001) but also a continuous increase in tryptase concentrations even below the cut-off (11.4 microg/l) with increasing age (P = 0.0026). CONCLUSIONS: Our data confirm serum tryptase as a risk factor for severe anaphylactic reaction to hymenoptera stings. Furthermore, we give first evidence that basal serum tryptase levels increase continuously with age and being an indicator for either increased mast cell load or reactivity this can at least partly be responsible for the observed aggravated allergic reactions in elderly people. As those patients are at increased risk for life-threatening anaphylactic reactions, it should be considered to adjust VIT especially in elderly patients with elevated tryptase levels as recommended for patients with mastocytosis by increasing venom doses during VIT and by considering its life-long continuation.

Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab.

Treatment of advanced PCLs is limited and rarely reaches complete remission despite aggressive treatment modalities, such as polychemotherapy with various adverse effects. However, several monoclonal antibodies drug agents in patients with advanced primary cutaneous lymphomas demonstrate promising efficacy and manageable safety profiles. The monoclonal antibodies drug agents have favourable tolerability compared with multi-agent cytotoxic chemotherapy. However, adverse effects manifest with a broad clinical spectrum, hence the markers of targeted therapies are not limited to tumour cells but found on tumour cells and also on benign T and/or B cells. Moreover, the safety profile and direct causal association of drug and adverse effects should be interpreted with caution because many of the patients in clinical studies have received multiple treatments. Here, we focus on the safety profile of mAbs therapies that have recently been approved or are currently under preclinical or clinical investigation for CBCLs (rituximab) and CTCLs (brentuximab, mogamulizumab, and alemtuzumab). Further studies to define clinical safety profile in the patient cohort with cutaneous lymphomas are needed.

Fetal and neonatal murine skin harbors Langerhans cell precursors.

Resident epidermal Langerhans cells (LC) in adult mice express ADPase, major histocompatibility complex (MHC) class II, and CD205 and CD207 molecules, while the first dendritic leukocytes that colonize the fetal and newborn epidermis are only ADPase(+). In this study, we tested whether dendritic epidermal leukocytes (DEL) are end-stage cells or represent LC precursors. In epidermal sheets of fetal and neonatal mice, we found no apoptotic leukocytes, suggesting that these cells do not die in situ. To address whether DEL can give rise to LC, sorted DEL from murine newborn skin were cultured with cytokines used to generate LC from human CD34(+) precursors. After 7-14 days, DEL proliferated and acquired the morphology and phenotype of cells reminiscent of LC. In concordance with this finding, we show that neonatal epidermis harbors 10-20 times the number of cycling MHC class II(+) leukocytes as adult tissue. To test whether LC can differentiate from skin precursors in vivo, we developed a transplantation model. As it was impossible to transplant fetal epidermis, whole fetal skin was grafted onto adult severe combined immunodeficient mice. As opposed to the uniform absence of donor LC at the time of transplantation, examination of the epidermis from the grafts after 2-4 weeks revealed MHC class II(+) donor cells, which had acquired CD205 and CD207, thus qualifying them as LC. Finally, we present evidence that endogenous LC persist in skin grafts for the observation period of 45 days. These studies show that hematopoietic precursors seed the skin during embryonic life and can give rise to LC.

Adverse cutaneous drug eruptions: current understanding.

Adverse cutaneous drug reactions are recognized as being major health problems worldwide causing considerable costs for health care systems. Most adverse cutaneous drug reactions follow a benign course; however, up to 2% of all adverse cutaneous drug eruptions are severe and life-threatening. These include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Physicians should be aware of specific red flags to rapidly identify these severe cutaneous drug eruptions and initiate appropriate treatment. Besides significant progress in clinical classification and treatment, recent studies have greatly enhanced our understanding in the pathophysiology of adverse cutaneous drug reactions. Genetic susceptibilities to certain drugs have been identified in SJS/TEN patients, viral reactivation in DRESS has been elucidated, and the discovery of tissue resident memory T cells helps to better understand the recurrent site-specific inflammation in patients with fixed drug eruption.

Number, distribution, and morphologic particularities of encapsulated proprioceptors in pig extraocular muscles.

PURPOSE: To analyze qualitatively and quantitatively the total complement of encapsulated proprioceptors (Golgi tendon organs [GTOs] and neuromuscular spindles) in pig extraocular muscles (EOMs). METHODS: EOMs of four pigs of different ages were prepared for light microscopic histochemical and immunohistochemical analysis and for transmission electron microscopy. RESULTS: GTOs and muscle spindles were numerous in pig EOMs. GTOs were found to be distributed in aponeurotic expansions of the distal and proximal EOM tendons, being more numerous in the distal aponeurosis than in the proximal aponeurosis. The total number of GTOs was higher in the recti EOMs (100-128) than in the oblique EOMs (45-61). Spindles were distributed over the entire muscle length. In each EOM the number of muscle spindles (142-333) exceeded those of GTOs. The morphology of the GTOs was variable. In addition to collagen bundles, approximately one third of the GTOs contained intracapsular muscle fibers that resembled the multiply innervated fiber type. Intracapsular muscle fibers entered the poles of the GTOs and either terminated inside the receptors in collagen bundles or exited the GTOs at the opposite poles. Nerve terminals were numerous in each GTO and established intimate contacts with collagen fibrils. CONCLUSIONS: Most structural particularities formerly observed in GTOs of rhesus monkey and sheep EOMs are also present in GTOs of pig EOMs. The high number of GTOs with their typical nerve terminals indicates functional importance. During muscle activity, afferent signals from GTOs and muscle spindles may provide sufficient information about eye position.

Incidental finding of lamellar calcification of the falx cerebri leading to the diagnosis of gorlin-goltz syndrome.

Here, we report the case of an incidental finding of lamellar calcification of the falx cerebri in a routine computed tomography scan of the head after an accidental trauma. This lamellar calcification led to the diagnosis of Gorlin-Goltz syndrome (GGS) in the patient and her daughter. Lamellar calcification of the falx cerebri is a pathognomonic feature of GGS. Our case report highlights the importance of a multidisciplinary diagnostic approach to GGS.

Cytomegalovirus hyperimmunoglobulin: mechanisms in allo-immune response in vitro.

BACKGROUND: Cytomegalovirus hyperimmunoglobulin (CMVIg) containing drugs are routinely administered in cardiac transplantation for prophylaxis against CMV disease. Yet little is known about their influence on transplant relevant immune functions. The aim of this study was to evaluate the effect of CMVIg on cellular immunity in in vitro experiments and to define their role in tolerance inducing mechanisms. MATERIALS AND METHODS/RESULTS: CMVIg reduces proliferation in mixed lymphocyte reactions and anti-CD3 blastogenesis assays and is related to decreased production of immune modulating cytokines interleukin (IL)-2, interferonr (IFNgamma), IL-10. This antiproliferative effect is associated with a cell-cycle arrest in the G0/G1 phase and induction of apoptosis in CD8+ and natural killer cells. Co-incubation with CMVIg causes down-regulation of cell bound immunoglobulin and FcgammaRIII surface expression on natural killer cells and leads to attenuation of antibody dependent cellular cytotoxicity effector functions. CONCLUSIONS: We conclude that CMVIg induces immunological features on leukocytes in vitro that are known to be related to tolerance induction. Our observations extend the current concept of CMVIg as passive CMV prophylaxis to a therapeutic drug compound capable of reducing allogeneic immune response.

Vitamin D receptor ablation alters skin architecture and homeostasis of dendritic epidermal T cells.

BACKGROUND: 1alpha,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], the active metabolite of vitamin D, exerts its activities by binding to the vitamin D receptor (VDR) with subsequent function as a transcription factor. Targeted ablation of the VDR in mice results in rickets and alopecia. OBJECTIVES: To study the consequences of VDR deficiency for skin physiology, and to investigate the mechanisms of the immunosuppressive effect of 1,25(OH)(2)D(3) on LC. METHODS: We studied the structural, phenotypic and functional properties of skin and individual skin leucocyte populations in VDR(-/-) mice. RESULTS: The lack of VDR induced a wide spectrum of pathologies including dermal deposition of collagen, enlargement of sebaceous glands, dilation of the hair follicles, development of epidermal cysts, increased numbers of dendritic epidermal T cells (DETC) and hyperkeratosis. Ageing aggravated these changes. Intriguingly, Langerhans cells (LC) were indistinguishable in distribution, morphology and number compared with controls. In vitro, LC underwent a maturation/migration process similar to LC from control mice. Pretreatment of epidermal cells or LC-enriched epidermal cell suspensions with 1,25(OH)(2)D(3) impaired LC maturation and T-cell stimulatory capacity from VDR(+/+) but not VDR(-/-) mice, demonstrating that LC are targets of vitamin D(3) and that interaction between vitamin D(3) and LC results in a suppression of LC activity. CONCLUSIONS: Our data imply that VDR expression controls dermal collagen production, hair development and growth, proliferation of sebaceous glands and the homeostasis of DETC. Surprisingly, VDR deficiency does not influence LC phenotype and function.

Alpha-Gal on bioprostheses: xenograft immune response in cardiac surgery.

BACKGROUND: The alpha-Gal (Galalpha1,3-Galbeta1-4GlcNAc-R) epitope is the major xenoantigen causing hyperacute rejection of pig organs transplanted into primates. Porcine bioprostheses are utilized in cardiac surgery. However, premature degeneration of bioprostheses has limited utilization in younger patients and the immune response remains elusive. We sought to investigate whether a specific alpha-Gal immune response may play a role in this clinical scenario. MATERIALS AND METHODS: We investigated the presence of alpha-Gal-epitope on native and fixed porcine valves by means of confocal laser scanning microscope (CLSM). ELISA was utilized to evidence whether implantation of bioprostheses elicits augmentation of pre-existing cytotoxic anti alpha-Gal IgM antibodies within 10 days of surgery. Patients who underwent coronary artery bypass grafting (CABG) or mechanical valve replacement served as controls (each group, n = 12). To corroborate the clinical relevance of the alpha-Gal immune response in vivo, we studied serum obtained before and after implantation of bioprostheses and its potency to lyse porcine alpha-Gal-bearing PK15 cells. RESULTS: We found the immunogenic alpha-Gal-epitope on fibrocytes interspersed in the connective tissue of porcine valves as determined by vimentin/IB4 lectin binding. Moreover, patients who were provided with a bioprostheses had developed a significant increase of naturally occurring cytotoxic IgM antibodies directed towards alpha-Gal after surgical intervention as compared with control patients (P < 0.0001, respectively). Sera obtained from the patients after the implantation of bioprostheses demonstrated an increased cytotoxicity against alpha-Gal-bearing PK-15 cells as compared with preoperative sera (P < 0.001). The specificity of the cytotoxic effects was proven as soluble Galalpha1-3Galbeta1-4GlcNAc markedly inhibited cell death of alpha-Gal-bearing PK15 cells (P < 0.001). CONCLUSION: Our data suggest that implantation of bioprostheses in cardiac surgery induces a xenograft-specific immune response. Procedures diminishing the presence of alpha-Gal on bioprostheses, such as utilization of genetically manipulated alpha-Gal-deficient xenograft or pretreatment with alpha-Galactosidase, might diminuate the immune response against bioprostheses and extend durability.