Where are we now in biological drugs for myositis?

Idiopathic inflammatory myopathies (IIM) are a rare and heterogeneous group of chronic autoimmune disorders. Up to 40% of IIM patients have long-term sequelae and significant functional disability. Its management can be challenging. New therapies are badly needed. The small number of cases with diverse presentations, and different diagnostic criteria interfere significantly with clinical trial results. Only intravenous immunoglobulin has been internationally approved for IIM patients. Most clinical trials of new biological therapies have failed to meet their primary endpoints in IIM, with only one biological drug recommended for refractory IIM treatment (rituximab), although not approved. We review several new emerging biological drugs including B cell depletion therapies, abatacept, janus-kinase inhibitors, and aldesleukin. Encouragingly, some phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in IIM, demonstrating an improvement in clinical and laboratory measures.

Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis on anti-interleukin-1 or -6 therapy.

OBJECTIVES: The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS). METHODS: Demographic, clinical, and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen pediatric rheumatology centers across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment. RESULTS: One hundred and sixty-two patients were included in the study. 45 of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72-232) vs 199 (130-371) 109/l], ferritin level on admission [1107 (676-2050) vs 2863 (1193-9562) ng/ml], C-reactive protein level [15.4 (2.9-56) vs 90 (32-160) mg/l], erythrocyte sedimentation rate [13 (3-36) vs 43.5 (13-77) mm/h] and fever duration [5 (4-7.5) vs 10 (7-14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals. CONCLUSION: Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met.

Association between several immune response-related genes and the effectiveness of biological treatments in patients with moderate-to-severe psoriasis.

Biological therapies are safer and more effective against psoriasis than conventional treatments. Even so, 30-50% of psoriatic patients show an inadequate response, which is associated with individual genetic heterogeneity. Pharmacogenetic studies have identified several single nucleotide polymorphisms (SNPs) as possible predictive and prognostic biomarkers for psoriasis treatment response. The objective of this study was to determine the link between several SNPs and the clinical response to biological therapies in patients with moderate-severe psoriasis. A set of 21 SNPs related to psoriasis and/or other immunological diseases were selected and analysed from salivary samples of patients (n = 88). Treatment effectiveness and patient improvement was assessed clinically through Relative Psoriasis Area and Severity Index (PASI), also called 'PASI response', as well as absolute PASI. Associations between SNPs and PASI factors were assessed at 3 and 12 months for every treatment category of IL-17, IL-23, IL-12&23 and TNF-α inhibitors. Multivariate correlation analysis and Fisher's exact test were used to analyse the relationship between SNPs and therapy outcomes. Several SNPs located in the TLR2, TLR5, TIRAP, HLA-C, IL12B, SLC12A8, TNFAIP3 and PGLYRP4 genes demonstrated association with increased short and long-term therapy-effectiveness rates. Most patients achieved values of PASI response ≥75 or absolute PASI<1, regardless of the biological treatment administered. In conclusion, we demonstrate a relationship between different SNPs and both short- and especially long-term effectiveness of biological treatment in terms of PASI. These polymorphisms may be used as predictive markers of treatment response in patients with moderate-to-severe psoriasis, providing personalized treatment.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Overcoming therapeutic challenges: Successful management of a supposedly triple seronegative, refractory generalized myasthenia gravis patient with efgartigimod.

BACKGROUND AND PURPOSE: This study was undertaken to highlight neonatal Fc receptor inhibition (efgartigimod) as a valuable therapeutic option for patients with refractory seronegative myasthenia gravis (MG) and to emphasize the concept that seronegative MG is greatly constrained by the limitations of currently available diagnostic methods and therapeutic measures. METHODS: We describe the first refractory, generalized MG (gMG) patient successfully treated with efgartigimod after testing negative on standard autoantibody detection tests. RESULTS: Our patient presented with severe fluctuating bulbar and generalized weakness, resulting in multiple myasthenic crises requiring intubation. After a 28-year medical history of multiple failed lines of treatment, our patient was started on efgartigimod. Over five treatment cycles, a definite improvement in her clinical condition was observed (Myasthenia Gravis Foundation of America class: IIIb to IIb; MG-Activities of Daily Living score: 11 to 0; MG-Quality of Life 15 score: 30 to 0; Quantitative MG score: 28 to 6). Standard autoantibody detection tests failed to detect known pathogenic autoantibodies, but cell-based assay (CBA) identified autoantibodies against clustered adult acetylcholine receptor (AChR). CONCLUSIONS: In light of recent approvals of efgartigimod by the European Medicines Agency and US Food and Drug Administration exclusively for AChR-positive gMG forms, our case highlights evidence suggesting that such an approach might be shortsighted and could limit therapeutic options for patients with refractory seronegative gMG. Additionally, introducing more sensitive analytical techniques, exemplified by CBA, may help bridge the gap between seronegative and seropositive patients. This represents an urgent unmet need for gMG patients, as the antibody profile dramatically influences the therapeutic approach.

The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs.

Eosinophilic esophagitis (EoE) is a multifaceted disease characterized by a wide heterogeneity of clinical manifestations, endoscopic and histopathologic patterns, and responsiveness to therapy. From the perspective of an effective approach to the patient, the different inflammatory mechanisms involved in the pathogenesis of EoE and biologics, in particular monoclonal antibodies (mAbs), targeting these pathways are needed. Currently, the most relevant is dupilumab, which interferes with both interleukin (IL)-4 and IL-13 pathways by binding IL-4 receptor α, and is the only mAb approved by the European Medicine Agency and US Food and Drug Administration for the treatment of EoE. Other mAbs investigated include mepolizumab, reslizumab, and benralizumab (interfering with IL-5 axis), cendakimab and dectrekumab (anti-IL-13s), tezepelumab (anti-TSLP), lirentelimab (anti-SIGLEG-8), and many others. Despite the undeniable economic impact of biologic therapies, in the near future, there will be room for further reflection about the opportunity to prescribe biologic agents, not only as a last-line therapy in selected cases such as patients with comorbidities involving common pathways. Although recent findings are very encouraging, the road to permanent success in the treatment of EoE is still long, and further studies are needed to determine the long-term effects of mAbs and to discover new potential targets.

Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.

Study of the Impact of Restrictions on Access to Biological Drugs for the Management of Psoriasis on the Minimum Disease Activity Criteria: Subanalysis of AEDV EQUIDAD and AME Projects. / Estudio del impacto de las restricciones en el acceso a fármacos biológicos en psoriasis sobre la actividad mínima de la enfermedad: subanálisis de los proyectos EQUIDAD y AME de la AEDV.

Spanish Autonomous Communities (ACs) are entitled to decide on the prescription requirements of their own territories, which can create inequalities in access to new drugs in the management of psoriasis. The objective of this study was to assess whether the level of restrictions in the access to new drugs for the management psoriasis was associated with the probability of achieving disease control measured using the Minimum Disease Activity (MDA) criteria. Therefore, we combined the results of 2 previous independent, cross-sectional studies: one that described the MDA in psoriasis by AC, and another that evaluated the level of restrictions to drug access by AC. We found that the higher the number of restrictions the lower the chances of achieving the MDA criteria (P=.013). Our results suggest that, in Spain, geographical differences in the access to new drugs may be creating health inequalities across the country.

Down syndrome and biological treatments in dermatology: Efficacy and safety in our real-life experience and review of literature.

Down syndrome (DS) is the most common chromosomal disorder; several dermatological conditions are common in these patients; among them, psoriasis and atopic dermatitis can be frequently encountered. From 2017 to today, we retrospectively identified 4 adults and 3 under 18-year-old patients treated with biological drugs, from our research database. The first endpoint of this study was to evaluate whether the biological drugs work in these special population, and a secondary endpoint was to evaluate any loss of efficacy or any side effects during follow-up. All patients were treated with biological drugs experience resolution of their psoriasis. Mean PASI (Psoriasis Area Severity Index), BSA (Body Surface Area) and DLQI (Dermatology Life Quality Index) at baseline were 20, 16.5 and 25. At week 4, mean PASI, BSA and DLQI decreased, respectively, to 8, 6 and 12, while at week 24, mean values were, respectively, 3, 1.3 and 1. The patients that started therapy earlier, at week 52, do not have signs of recurrence and side effects. We highlighted that no official guidelines exist to approach these patients, from a literature evaluation the most employed drugs are anti-TNFα and in particular adalimumab. In our experience, the new anti-interleukin drugs seem to be well-tolerated, with no sides effect, good compliance and no loss of efficacy.

Chronic rhinosinusitis with nasal polyps management in the biologic therapy era: an international YO-IFOS survey.

PURPOSE: To investigate the consistency between the international guidelines recommendations and worldwide standard practices regarding diagnostic work-up and follow-up strategies for managing patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) in the era of monoclonal antibodies. METHODS: A questionnaire developed by the Rhinology section of the Young Otolaryngologists of the International Federation of Oto-rhino-laryngological Societies (Yo-IFOS) included items regarding the management of CRSwNP patients, monoclonal prescription, surgical and follow-up procedures, awareness of biologicals availability, and other relevant clinical practices. The online survey was directed to otolaryngologists and distributed in Europe, North America, South America, and the Middle East through otolaryngological and/or rhinological societies. RESULTS: A total of 202 responses were analyzed; the mean participants' age was 45 ± 11 (73% men and 27% women), and 31% were from the United States, Canada 19%, Europe 45%, Middle East and South America 5%. Only 60% of the respondents declared using validated symptoms and endoscopic score systems in their clinical practice. Several practice discrepancies emerged in our cohort, including preferred surgical approach, prescription of preoperative oral steroids, and perioperative antibiotics (59% and 58%, respectively), as well as divergent awareness levels of available biologics for CRSwNP worldwide. CONCLUSIONS: CRSwNP needs a complex and time-consuming assessment, according to the latest guidelines. There seems to be a gap between these recommendations and the real-world data, which should draw more attention to bringing them into uniform clinical practice in the near future.

Vitamin D Status and Psoriatic Arthritis: Association with the Risk for Sacroiliitis and Influence on the Retention Rate of Methotrexate Monotherapy and First Biological Drug Survival-A Retrospective Study.

A growing body of evidence on the importance of vitamin D in immune modulation has increased the interest in its possible impact on the course of rheumatological diseases. The scope of our study is to assess if the presence of different statuses of vitamin D could interfere in the clinical subsets, in methotrexate monotherapy discontinuation, and biological drug (b-DMARDs) survival in psoriatic arthritis patients (PsA). We conducted a retrospective study on PsA patients and split them into three groups based on their vitamin D status: the group with 25(OH)D ≤ 20 ng/mL, the group with levels of 25(OH)D between 20 and 30 ng/mL, and the group with serum levels of 25(OH)D ≥ 30 ng/mL. All patients were required to fulfill the CASPAR criteria for psoriatic arthritis and to have the evaluation of vitamin D serum levels at baseline visit and at clinical follow-up visits. The exclusion criteria were ages less than 18 years old, the presence of HLA B27, and satisfaction of rheumatoid arthritis classification criteria (during the study time). Statistical significance was set at p ≤ 0.05. Furthermore, 570 patients with PsA were screened and 233 were recruited. A level of 25(OH)D ≤ 20 ng/mL was present in 39% of patients; levels of 25(OH)D between 20 and 30 ng/mL presented in 25% of patients; 65% of patients with sacroiliitis presented 25 (OH)D ≤ 20 ng/mL. Methotrexate monotherapy discontinuation for failure was higher in the group with 25 (OH)D ≤ 20 ng/mL (survival time: 92 ± 10.3 weeks vs. 141.9 ± 24.1 weeks vs. 160.1 ± 23.6 weeks; p = 0.02) with higher discontinuation risk (HR = 2.168, 95% CI 1.334, 3.522; p = 0.002) than those with 25(OH)D between 20 and 30 ng/mL and those with 25(OH)D ≥ 30 ng/mL. Significantly shorter survival of first b-DMARDs was assessed in the group with 25 (OH)D ≤ 20 ng/mL versus the other groups (133.6 ± 11 weeks vs. 204.8 ± 35.8 weeks vs. 298.9 ± 35.4; p = 0.028) (discontinuation risk 2.129, 95% CI 1.186, 3.821; p = 0.011). This study highlights significant differences in clinical presentation, in particular sacroiliac involvement and on drug survival (methotrexate and b-DMARDs) in PsA patients with vitamin D deficiency. Further prospective studies, including a larger sample of patients, are needed to validate these data and to assess if the supplementation of vitamin D could improve the b-DMARDs response in PsA patients.

Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn's Disease Patients and Effect of Anti-TNF-α Treatment on Their Modulation.

Biological therapies only benefit one-third of patients with Crohn's disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.

Biological treatment interruption in inflammatory bowel disease: Motivation and predictive factors.

BACKGROUND: Loss-of-response and adverse events (AE) to biologics have been linked to HLA-DQA1*05 allele. However, the clinical factors or biologic used may influence treatment duration. Our objective was to evaluate the influence of clinical and therapeutic factors, along with HLA, in biological treatment discontinuation. METHODS: A retrospective study of consecutive IBD patients treated with biologics between 2007 and 2011 was performed. Main outcome was treatment discontinuation due to primary non-response (PNR), secondary loss of response (SLR) or AE. HLA-DQA1 genotyping was done in all patients. Regression analyses were used to assess risk factors of treatment discontinuation. RESULTS: One hundred fifty patients (61% male) with 312 biologic treatments were included. 147 (47%) were discontinued with a cumulative probability of 30%, 41% and 56% at 1, 2 and 5 years. The use of infliximab (p=0.006) and articular manifestations (p<0.05) were associated with treatment discontinuation. Considering cause of withdrawal, Ulcerative Colitis (UC) had a higher proportion of PNR (HR=4.99; 95% CI=1.71-14.63; p=0.003), SLR was higher if biologics had been indicated due to disease flare (HR=2.32; 95% CI=1.05-5.09; p=0.037) while AE were greater with infliximab (HR=2.46; 95% CI=1.48-4.08; p<0.001) or spondylitis (HR=2.46; 95% CI=1.78-6.89; p<0.001). According to the biological drug, HLA-DQA1*05 with adalimumab showed more SLR in cases with Crohn's disease (HR=3.49; 95% CI=1.39-8,78; p=0.008) or without concomitant immunomodulator (HR=2.8; 95% CI=1.1-6.93; p=0.026). CONCLUSIONS: HLA-DQ A1*05 was relevant in SLR of IBD patients treated with adalimumab without immunosupression. In patients treated with other biologics, clinical factors were more important for treatment interruption, mainly extensive UC or extraintestinal manifestations and having indicated the biologic for flare.

Biologics for severe asthma: The real-world evidence, effectiveness of switching, and prediction factors for the efficacy.

Biologics have been a key component of severe asthma treatment, and there are currently biologics available that target IgE, IL-5, IL-4/IL-13, and TSLP. Randomized controlled trials have established clinical evidence, but a significant portion of patients with severe asthma in real-life settings would have been excluded from those trials. Therefore, real-world research is necessary, and there is a growing body of information about the long-term efficacy and safety of biologics. Multiple clinical phenotypes of severe asthma exist, and it is crucial to choose patients based on their phenotypes. Blood eosinophil count is an important biomarker for anti-IL-5 therapies, and FeNO and eosinophil counts serve as prediction markers for dupilumab. Reliable markers for predicting response, however, have not yet been fully established for omalizumab. Identification of clinical or biological prediction factors is crucial for the path toward clinical remission because the current treatment goal includes clinical remission, which is defined as a realistic goal for remission off treatment. Additionally, since there are now multiple biologic options and overlaps in eligibility for biologics in clinical practice, the evidence regarding the effectiveness of switching the biologics is crucial. Investigations into the clinical trajectory following the cessation of biologics are another important issue. Recent research on omalizumab, mepolizumab, benralizumab and dupilumab's real-world effectiveness, the prediction factor for the efficacy, and the impact of switching or discontinuation will be reviewed and discussed in this review.

Cost-effectiveness analyses of biologic and targeted synthetic disease-modifying anti-rheumatic diseases in patients with rheumatoid arthritis: Three approaches with a cohort simulation and real-world data.

OBJECTIVE: To assess the cost-effectiveness of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in rheumatoid arthritis. METHODS: We conducted three analyses: a lifetime analysis with a cohort model (Study A) and two short-term analyses (Studies B and C). Study A evaluated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained from costs of standard treatments. Study B evaluated yearly costs per person achieving American College of Rheumatology (ACR) response (ACR20, ACR50, and ACR70), and Study C evaluated costs per person achieving previously defined claims-based effectiveness (equivalent to 28-joint Disease Activity Score ≤ 3.2). The proportion of ACR responders to the drugs of interest were determined by mixed treatment comparisons. Studies B and C estimated costs using a claims database. RESULTS: In Study A, ICERs of all b/tsDMARDs were lower than 5.0 million Japanese yen (JPY) per QALY. In Study B, yearly costs per person with ACR50 response were lower for subcutaneous tocilizumab (TCZ-SC; 1.9 million JPY) and SC abatacept (2.3 million JPY). In Study C, costs per person were lower for TCZ-SC (1.3 million JPY) and intravenous TCZ (1.6 million JPY) and effectiveness rates were higher for intravenous TCZ (45.3%) and infliximab (43.0%). CONCLUSION: The b/tsDMARDs with lower prices showed higher cost-effectiveness.

Latest combination therapies in psoriasis: Narrative review of the literature.

Biological therapies revolutionized the treatment of many chronic inflammatory skin diseases, first of all psoriasis, thanks to their high efficacy and the reduced number of side effects. However, the use of a single biologic drug does not always provide complete control of the disease or associated comorbidities over time. The first biological drugs used for the treatment of psoriasis, tumor necrosis factor alpha inhibitors, have long been used in combination with traditional topical and systemic therapies to induce a complete remission of the disease that could not be achieved with innovative drug alone. Even with the advent of new biological therapies with more precise molecular targets, the challenge of using combination therapies remained. Psoriatic patients often have major comorbidities, such as arthritis, inflammatory bowel disease, uveitis or have other concomitant conditions such as chronic spontaneous urticaria and atopic dermatitis, which may require different biologic treatments than those indicated in psoriasis. The objective of this article is, through a comprehensive revision of the literature, to analyze in which cases the use of the combination of the latest therapies for psoriasis may be useful.

IL-31: State of the Art for an Inflammation-Oriented Interleukin.

Interleukin 31 belongs to the IL-6 superfamily, and it is an itch mediator already studied in several diseases, comprising atopic dermatitis, allergic pathologies, and onco-hematological conditions. This research aims to assess the role of this cytokine in the pathogenesis of these conditions and its potential therapeutic role. The research has been conducted on articles, excluding reviews and meta-analysis, both on animals and humans. The results showed that IL-31 plays a crucial role in the pathogenesis of systemic skin manifestations, prognosis, and itch severity. Traditional therapies target this interleukin indirectly, but monoclonal antibodies (Mab) directed against it have shown efficacy and safety profiles comparable with biological drugs that are already available. Future perspectives could include the development of new antibodies against IL-31 both for humans and animals, thus adding a new approach to the therapy, which often has proven to be prolonged and specific for each patient.

Co-spray Drying Drugs with Aqueous Polymer Dispersions (APDs)-a Systematic Review.

Aqueous colloidal dispersions of water-insoluble polymers (APDs) avoid hassles associated with the use of organic solvents and offer processing advantages related to their low viscosity and short processing times. Therefore, they became the main vehicle for pharmaceutical coating of tablets and multiparticulates, a process commonly employed using pan and fluidized-bed machinery. Another interesting although less common processing approach is co-spray drying APDs with drugs in aqueous systems. It enables the manufacture of capsule- and matrix-type microspheres with controllable size and improved processing characteristics in a single step. These microspheres can be further formulated into different dosage forms. This systematic review is based on published research articles and aims to highlight the applicability and opportunities of co-spray drying drugs with APDs in drug delivery.

Unravelling the broader complexity of IL-6 involvement in health and disease.

The classification of interleukin-6 (IL-6) as a pro-inflammatory cytokine undervalues the biological impact of this cytokine in health and disease. With broad activities affecting the immune system, tissue homeostasis and metabolic processes, IL-6 displays complex biology. The significance of these involvements has become increasingly important in clinical settings where IL-6 is identified as a prominent target for therapy. Here, clinical experience with IL-6 antagonists emphasises the need to understand the context-dependent properties of IL-6 within an inflammatory environment and the anticipated or unexpected consequences of IL-6 blockade. In this review, we will describe the immunobiology of IL-6 and explore the gamut of IL-6 bioactivity affecting the clinical response to biological drugs targeting this cytokine pathway.

Evaluation of Hypersensitivity Reactions in Pediatric Patients Using Biological Drugs.

INTRODUCTION: Biological drugs are currently used for the treatment of chronic inflammatory, autoimmune, and neoplastic diseases. With their expanding indication spectrum and increasing use, hypersensitivity reactions to these drugs are also becoming more frequent. The present study aimed to report the incidence and the features of such reactions in pediatric patients using biologicals for the treatment of various diseases. METHODS: The medical records of pediatric patients treated with biological agents between October 1, 2011 and August 31, 2019 were reviewed and adverse reactions were evaluated retrospectively. RESULTS: During the study period, 211 patients (116 boys, 55%) used 21 different biological drugs for the treatment of various diseases. Their median age at the time of the first treatment was 139.9 (IQR: 92.2-187.8) months. Hematologic-oncologic diseases were the most common indication for biological therapy (97/211; 46.0%), followed by rheumatologic diseases (82/211; 38.9%). Of the 211 patients, 14 (6.64%) experienced reactions to biological drugs. The most common culprit agent was rituximab (57.1%). Most of the patients (85.7%) had a history of reactions either during the infusion or within 1 h after taking the drug. Five patients underwent desensitization to the culprit drug, while 7 other patients continued treatment with a reduced dose/infusion rate or premedication. Also 1 patient continued to take the drug without any additional treatment. CONCLUSION: It was reported that 6.64% of the patients who received biologic drug therapy for various reasons in our hospital had hypersensitivity. The most common culprit agent was rituximab, and most of the reactions were immediate reactions.