Drug-induced scleroderma-like lesion is a condition in which administration of a drug induces skin sclerotic lesions similar to systemic sclerosis or morphea. The clinical manifestations of drug-induced scleroderma-like lesion can be divided into two types: scleroderma-like lesions and morphea-like plaques. A wide variety of drugs can cause drug-induced scleroderma-like lesion. Bleomycin, _L-tryptophan, vinyl chloride, and phytonadione (vitamin K₁) have been reported, but in recent years, cases due to chemotherapeutic agents, such as taxane-based agents, gemcitabine, and tegafur-uracil, and immune checkpoint inhibitors have increased. Drug-induced scleroderma-like lesion differs from systemic sclerosis in that it does not include Raynaud's phenomenon, nail-fold capillary abnormality, organ involvement, such as reflux esophagitis, interstitial pneumonia, renal crisis, or anti-nuclear Abs. On the other hand, there are reports of cases in which Raynaud's phenomenon, positive conversion of anti-nuclear Abs, and development of skin sclerosis from the fingers developed after initiation of the drug. Whether the skin sclerosis improves after discontinuation of the drug depends on the patient. In patients with severe skin sclerosis, functional impairment, such as flexion contracture of the fingers, may occur, and systemic therapy, such as steroids, may be necessary. When treating patients with skin sclerosis, it is important to keep in mind the possibility that the sclerotic lesion may be induced by a drug.

Current cancer immunotherapies target immune checkpoint molecules such as the inhibitory receptor programmed cell death-1 (PD-1), one of its ligands, programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), a competitive ligand for CD28 binding to stimulatory receptors CD80 and CD86. Multiple biological drugs use monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 as cancer immunotherapies. These are termed immune checkpoint inhibitors (ICIs). However, activation of the immune system by ICIs can induce the development of immune-related adverse events (irAEs), which can affect multiple organ systems. The most frequent irAEs are cutaneous and mimic various types of spontaneous skin disorders. Most irAEs are classified as autoimmune conditions mediated by ICI-activated CD8⁺ cytotoxic T cells, some of which are also related to activated B cells and production of pathogenic antibodies. Interestingly, blockade of CTLA-4 mainly induces activation of T cells and inhibition of T_reg cells. On the other hand, the mechanisms underlying anti-PD-1/PD-L1 ICI-induced irAEs are more complicated. PD-1 is a receptor expressed on T and B cells, which binds not only PD-L1, but also PD-L2. The role of PD-L1 is dominant in Th1 and Th17 immunity, while PD-L2 works mainly in Th2 immunity. Better understanding of the mechanisms underlying irAEs will allow for better management of irAEs and improve outcomes and quality of life in cancer patients.

Systemic autoimmune diseases are reportedly associated with a high frequency of drug allergies. In particular, systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and adult-onset Still's disease (AOSD) have recently drawn attention. Based on previous reports, drug allergies have been reported in 17.1-63%, 7-40.1%, and 17.6-54% of patients with SS, SLE, and AOSD patients, respectively. Antimicrobial agents, including sulfa drugs and nonsteroidal anti-inflammatory drugs, are the most common causative agents of drug allergies. However, few studies have examined in detail the relationship between drug eruptions, a major symptom of drug allergy, and systemic autoimmune diseases, and their actual status remains unclear. These autoimmune diseases commonly exhibit a diverse range of skin manifestations in the course of these diseases, rendering it may be difficult to determine whether it is a true drug eruption.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), a fatal, severe drug eruption, has also been associated with autoimmune diseases. The development of SS-like symptoms after SJS/TEN onset and high prevalence of anti-SS-A antibodies in SJS/TEN are intriguing observations. Although the presence of SLE is known to be a risk factor for SJS/TEN, common pathological conditions, such as excessive immune status, abnormal function of regulatory T cells, and neutrophil extracellular traps in autoimmune diseases such as SS and SLE, are potentially involved in the development of drug eruptions.

Non-HIV immune reconstitution inflammatory syndrome (non-HIV IRIS) is associated with the recovery from an immunocompromised condition. It is defined as inflammatory disorders caused by antigens, including drugs or pathogenic microorganisms present prior to immune recovery, or by the exacerbation of an inflammatory disorder that was already present. Drug-induced hypersensitivity syndrome is a prototype of IRIS, and the pathophysiology of non-HIV IRIS can be recognized in several disorders treated with corticosteroids, immunosuppressants, molecular-targeted drugs, TNF-α antibody drugs, immune checkpoint inhibitors, and dipeptidyl peptidase-4 inhibitors. This review focuses on the relationship between the immune mechanism of non-HIV IRIS and drug allergies, especially severe drug eruption. The antigen recognition mechanism in drug allergy varies depending on the clinical type and the causative drug. The p-i concept is the main mechanism in severe drug eruption such as Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Lymphocytes activated by an antigen other than a drug, such as a virus, can also develop drug allergy by the loose binding of drugs with immune receptors of T cells or human leukocyte antigen. Therefore, fluctuations in the immune environment affect the onset of severe drug eruption. Novel agents that cause major changes in immunity have been marketed mainly for autoimmune diseases and malignant tumors; therefore, it is necessary to consider their effects when treating severe drug eruptions. Moreover, although a list of diagnostic criteria for this syndrome has been drafted, predictive and diagnostic biomarkers for this syndrome needs to be urgently developed.

Background: Airway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans.

Methods: In this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays.

Results: Sputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = -0.33, p = 0.004).

Conclusions: Sputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma.

Background: Wheezing may lead to asthma and reduced pulmonary function in later life. The study aims to identify wheezing trajectories and investigate their relation with pulmonary function and asthma-related outcomes at 22 years of age.

Methods: Individuals from a population-based cohort in Brazil (1993 Pelotas Birth Cohort) with post-bronchodilator pulmonary function data at 22 years (3350) were included in the study. From parentally reported (4 and 11 years) and self-reported (15, 18 and 22 years) history of wheezing in the last 12 months, we used a group-based trajectory modelling approach to derive wheezing trajectories.

Results: Four trajectories were identified: never/infrequent, transient-early, late-onset and persistent wheeze. After adjustments, wheezing trajectories remained associated with lower post-bronchodilator values of pulmonary function. Individuals in the persistent wheeze trajectory had a markedly poorer pulmonary function and also showed greater odds of asthma-related outcomes compared to other trajectories groups. Those following this trajectory had on average -109 ml (95% CI: -188; -35), -1.80 percentage points (95% CI: -2.73; -0.87) and -316 ml/s (95% CI: -482; -150) lower FEV₁, FEV₁/FVC ratio and FEF_25-75% respectively; higher odds of self-reported medical diagnosis of allergy (OR 6.18; 95% CI: 3.59; 10.61) and asthma (OR 12.88; 95% CI: 8.91; 18.61) and asthma medication use (OR 9.42; 95% CI: 5.27; 16.87) compared to the never/infrequent group.

Conclusions: Wheezing trajectories, especially the persistent wheeze trajectory, were related to lower pulmonary function values and increased risk of asthma and allergy diagnosis in early adulthood.

Background: The total naso-ocular symptom score (TSS) is widely used as an endpoint to evaluate the severity of seasonal allergic rhinitis. However, it is not a generic preference-based measure. We sought to develop an algorithm for mapping between the TSS and health utility in Japanese cedar pollinosis (JCP). We also performed a cost-utility analysis of sublingual immunotherapy (SLIT) for JCP by using this algorithm.

Methods: Patients with JCP filled out the TSS questionnaire and EQ-5D-5L simultaneously during the pollen season in 2019 and in 2020. We estimated a direct utility mapping model by regressing responses to individual TSS questions directly onto utility. The incremental cost-effectiveness ratio (ICER) of active SLIT to a placebo was determined by examining the drug expense and the estimated quality-adjusted life year (QALY) using a dataset from a double-blind placebo-controlled clinical trial.

Results: A total of 238 records were included for analysis. The estimated utility decreased with increasing severity of rhinitis. Patients with comorbid asthma showed lower utility. A negative and significant correlation was seen between the TSS and utility in both 2019 and 2020. The estimated equations were: Y(utility) = -0.0161∗X(TSS) + 1.005 in non-asthmatic JCP patients. The ICER of active SLIT to the placebo was estimated to be 4,049,720 and 6,011,218 JPY/QALY in the first and second year, respectively.

Conclusions: It is possible to reasonably predict utility from the total naso-ocular symptom score by using regression models. In the estimated algorithm, pre-seasonal SLIT for JCP is cost-effective.

Background: Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known.

Methods: After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events.

Results: Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%).

Conclusions: This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.

Background: IgE-mediated egg allergy is a common food allergy worldwide. Patients with egg allergy are known to easily achieve tolerance compared to other allergens such as nuts. Oral food challenge (OFC) is often performed on patients diagnosed with or suspected of having IgE-mediated food allergy, but whether hen's egg OFC is useful in IgE-dependent egg allergy patients to avoid complete elimination remains unknown.

Methods: We identified articles in which OFCs were performed in Japanese patients diagnosed with or suspected of having IgE-mediated egg allergy. We evaluated whether the OFCs were useful to avoid the complete elimination of eggs by assessing the following: (1) the number of patients who could avoid complete elimination; (2) the number of patients who experienced serious adverse events (SAEs); or (3) adverse events (AEs); (4) improvement in quality of life (QOL); and (5) immunological changes.

Results: Fifty-nine articles were selected in the study; all the references were case series or case studies in which OFC was compared to pre-challenge conditions. The overall negative ratio against egg OFC was 62.7%, but an additional 71.9% of OFC-positive patients could take eggs when expanded to partial elimination. Of the 4182 cases, 1146 showed AEs in the OFC, and two cases reached an SAE. Two reports showed an improvement in QOL and immunological changes, although the evidence was weak.

Conclusions: OFCs against eggs may be useful to avoid complete elimination, but medical professionals should proceed with the test safely and carefully.

Background: The interval between antigen ingestion may influence the safety of oral food challenge tests (OFCs), especially in patients with severe food allergies.

Methods: This retrospective chart review of OFCs eliciting objective reactions to wheat, egg, and milk that were performed between April 2012 and January 2021 evaluated an equivalent number of low-dose OFCs performed at 30-, 40-, or 60-min intervals. To avoid the influence of the potential allergy severity of the patients, the prediction scores of all intervals were matched. We evaluated the total symptom score (TS), total ingested dose, and the proportions of severe reactions (TS ≥ 30) and adrenaline use.

Results: We analyzed 945 OFCs (wheat, n = 186; egg, n = 561; milk, n = 198). The 60-min OFC had significantly lower TS than the 30- and 40-min OFC methods in wheat (p < 0.001 and p = 0.003, respectively), egg (p < 0.001 for both), and milk (p < 0.001 and p = 0.018, respectively). The total dose in the 60-min method was significantly lower than in the 30-min method (p < 0.001 for all). The proportion of severe reaction (TS ≥ 30) in the 60-min method was significantly lower than that in the 30-min method for the egg and milk OFCs (p = 0.001 and p < 0.001, respectively). There was no difference in the rates of adrenaline injection.

Conclusions: The 60-min interval is safer than 30- or 40-min intervals in wheat, egg, and milk OFCs in patients with a low threshold dose for food allergy.

Background: In tree nut (TN) allergy, singleplex tests showed the diagnostic utility of rAna o 3, rCor a 14/nCor a 9, and nJug r 1/nJug r 4 for cashew/pistachio, hazelnut, and walnut allergies, respectively. However, disadvantages of the tests include high costs and excessive blood sampling in multi-sensitized patients, and a limited number of components. We investigated the utility of a multiplex macroarray (i.e., the ALEX² test) in TN allergy.

Methods: In 169 children, skin prick test, the component- and extract-specific IgEs of TNs were investigated for clinical reactivity and tolerance.

Results: The predictors (AUC = 0.962-0.749) of clinical reactivity to cashew, pistachio, hazelnut, and walnut were rPis v 1/rAna o 3, rPis v 1/rAna o 3/nPis v 2/nPis v 3, rCor a 14/nCor a 11/nCor a 9, and nJug r 1/nJug r 2/nJug r 6/nJug r 4, respectively. More than 93% of the patients with clinical reactivity to pistachio/cashew, hazelnut and walnut had positivity of (≥0.3 kU_A/L) rPis v 1/rAna o 3, rCor a 14 and nJug r 1/nJug r 2, respectively. The highest accuracies of clinical reactivity to culprit nut were obtained with combination of rPis v 1, sIgE and SPT positivities for cashew/pistachio, rPis v 1 ≥ 1.0 kU_A/L for pistachio, rCor a 14 ≥ 1.0 kU_A/L for hazelnut and combination of nJug r 1 and nJug r 2 positivities for walnut, respectively. Also, higher concentrations of rPis v 1 (≥15.0 kU_A/L), rCor a 14 (≥5.0 kU_A/L) and nJug r 1/nJug r 2 (≥15.0 kU_A/L) had %100 specificity and PPV in predicting clinical reactivity to cashew, hazelnut and walnut, respectively.

Conclusions: Multiplex macroarray test is useful and reliable in the diagnosis of TN allergy in children, confirms and expands existing knowledge, and can be used as a stand-alone tool in the bottom-up diagnostic approach.