Double-negative T cells in pediatric rheumatic diseases.

Double-negative (CD4-CD8-) T (DNT) cells have been implicated in Autoimmune Lymphoproliferative Syndrome (ALPS), where their expansion inside the circulating pool of T cells represents a diagnostic criterion. Recent experimental evidence has supported the immunomodulatory roles of DNT cells, and studies in adult patients have suggested that they may be altered in some immune-mediated conditions. This study aimed to retrieve available data on circulating DNT cells in pediatric rheumatic disorders that do not arise in the context of ALPS through a systematic literature review of three scientific databases (PubMed, Scopus, and Web of Science). The final output of the systematic literature search consisted of eight manuscripts, including cross-sectional (n=6) and longitudinal (n=2) studies. Overall, the pooled population of patients includes children affected with pediatric Systemic Lupus Erythematosus (n=104), Juvenile Idiopathic Arthritis (n=92), Behçet's disease (n=15), mixed connective tissue disease (n=8), Juvenile Dermatomyositis (n=6), and Kawasaki disease/multisystem inflammatory disease in children (n=1 and n=14, respectively); moreover, one study also included 11 children with a high titer of antinuclear antibody but no diagnosis of rheumatic disease. All studies except one included a control group. The number of DNT cells were increased in most studies of children with rheumatic diseases. Even if such a limited number of studies and their great heterogeneity in several methodological aspects do not allow for reliable conclusions about the relevance of DNT cells in specific rheumatic conditions in children, this cell population deserves further investigation in this pathological setting through well-designed clinical studies.

Pediatric erythema ab igne: clinical aspects and diagnostic issues.

Erythema ab igne is a dermatological condition resulting from repeated low-grade heat exposure (below the burning point), which can variably manifest with reticulated erythema and skin hyperpigmentation. Not infrequently, the cause of such a skin disorder is not immediately evident or reported by patients, especially if these are children. Compared to adults, erythema ab igne is rare in children and, if the general practitioners and pediatricians are not aware of this disorder, pediatric patients are often addressed to rheumatologists and/or undergo useless immunological investigations. Here, we performed a systematic case-based review, which finally included 32 cases of pediatric erythema ab igne (in addition to our new clinical report), and discussed the main clinical aspects and issues of this clinical entity in children. In detail, similarities of erythema ab igne with livedo reticularis and/or vasculitis-related rashes sometimes can lead to perform a panel of immunological investigations, which could be avoided. Indeed, our analysis emphasizes the importance of a careful and complete patient's anamnesis, including active questioning about the potential exposure to any physical agents (including heat sources) that may cause dermatological lesions. We also highlight some peculiarities in terms of location and heat injury in children developing erythema ab igne, based on the presence or absence of comorbidities. CONCLUSION: The occurrence of erythema ab igne in children (and especially in adolescents) is likely to increase in the next years because of the greater and sometimes inappropriate use of technological devices. Physicians should be aware of this condition in order to prevent patients from useless investigations, especially in the differential diagnosis of rheumatic disorders. A careful and complete patient's history with active questioning about the potential exposure to heating source is often decisive to diagnose erythema ab igne. WHAT IS KNOWN: • Erythema ab igne is a dermatological condition which is mainly described in adults exposed to heating source at the workplace. WHAT IS NEW: • The occurrence of erythema ab igne in children is likely to increase in the next years because of the greater and sometimes inappropriate use of technological devices. • Erythema ab igne in children can be classified in two main categories, based on the presence or absence of comorbidity. • A careful and complete anamnesis (including the active questioning about potential exposure to any heating source) is the mainstay for diagnosing erythema ab igne in children.

Serum immunoglobulin A (IgA) levels in children affected with Juvenile Idiopathic Arthritis.

Background and objective: Immunoglobulin A (IgA) is the most abundant antibody isotype in the human body, considering its presence on the mucosal surfaces, in addition to the amount circulating in the bloodstream. Serum IgA levels can be variably altered in several pathological settings. However, very few studies specifically investigated serum IgA in Juvenile Idiopathic Arthritis (JIA). In the present study, we specifically assessed serum IgA levels in our cohort of patients affected with JIA. Methods: In this cross-sectional study, serum IgA levels were measured in patients with JIA (and age-matched controls) and analyzed according to age class. The correlation of serum IgA levels with hematological, inflammatory, and disease activity parameters was assessed. Results: No significant difference in the frequency of low IgA levels (according to the definition of complete and partial IgA deficiency) was observed between JIA patients and controls, overall. This pediatric study population showed a progressive increase of total serum IgA concentrations with age, as expected; however, in JIA patients aged 10-17 years, total IgA serum levels resulted to be significantly higher than in age-matched control subjects. No clear correlation between IgA levels and the examined inflammatory, hematological, and disease activity parameters was observed in JIA patients, except for the erythrocyte sedimentation rate (ESR) in oligoarticular JIA patients: here, serum IgA levels showed a positive and moderate covariation with ESR, which was also observed for disease activity (JADAS-10) in selected oJIA patients without biological therapy. Conclusions: In our cohort of JIA patients, total serum IgA levels were not reduced and were actually increased in adolescents compared to controls. Larger studies are needed to confirm this finding, which cannot be certainly explained based on the available data in this study, even though JIA disease control and/or chronic inflammation may be implicated to some extent.

Analysis of Peripheral Blood Basophils in Pediatric Systemic Lupus Erythematosus.

Basophils are the least abundant circulating leukocytes, and their immunological role has not yet been completely elucidated. There is evidence supporting their immunomodulatory role in several pathological settings; recently, studies in both experimental models and humans suggested that basophil homeostasis may be altered in systemic lupus erythematosus (SLE). Here, we first assessed circulating basophils in children affected with pediatric SLE (pSLE). In this cross-sectional study, circulating basophils were enumerated by fluorescence-based flow cytometry analysis in children affected with pSLE, in addition to children suffering from juvenile idiopathic arthritis (JIA) or non-inflammatory/non-rheumatic conditions. This study included 52 pediatric patients distributed in these three groups. We observed a statistically significant reduction of peripherally circulating basophils in children with pSLE compared to the other two groups of patients. This preliminary study is consistent with the available studies in adult patients with SLE showing a reduced number of circulating basophils. However, further research is needed to draw final conclusions on basophils' homeostasis in pSLE, in addition to their correlation with the disease activity and concomitant therapies.

Mycoplasma pneumoniae Seroprevalence and Total IgE Levels in Patients with Juvenile Idiopathic Arthritis.

BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is implicated in several immune-mediated extrapulmonary manifestations, including reactive arthritis. Recently, increased total serum IgE were reported in children developing M. pneumoniae-related extrapulmonary diseases (MpEPDs). Here, we aimed at analyzing these aspects in children affected with rheumatic disorders and, in detail, Juvenile Idiopathic Arthritis (JIA). METHODS: M. pneumoniae serology (IgG and IgM) and total serum IgE were concomitantly analyzed in 139 pediatric patients diagnosed with: JIA (Group 1, n = 85), or any rheumatic disease other than JIA (Group 2, n = 27), or non-inflammatory endocrinological disorders (Group 3, n = 27). RESULTS: Overall, 19.4% M. pneumoniae seroprevalence was observed in this hospitalized pediatric population, without signicant differences among the three groups. No significant differences in total serum IgE levels were noted among these groups; however, a second analysis excluding children with very high (and clearly abnormal) IgE levels suggested that JIA patients and, in detail, those with oligopolyarticular forms may have higher serum IgE concentrations. This relative difference among groups in serum IgE level seems to be more pronounced in M. pneumoniae seropositive children. CONCLUSIONS: M. pneumoniae infection should be actively sought in children developing immune-mediated diseases, including patients affected with JIA and, especially, in oligopolyarticular forms. There is some evidence that total serum IgE levels may tend to be increased in patients with oligopolyarticular JIA subtype and especially in those resulting as M. pneumoniae seropositive. However, further and focused research is needed to confirm these preliminary results and to clarify the relation between M. pneumoniae infection, atopic status, and immune-mediated arthritis.

Macrophage Activation Syndrome in Pediatric Systemic Lupus Erythematosus: A Systematic Review of the Diagnostic Aspects.

Macrophage Activation Syndrome (MAS) is a very severe complication of different rheumatic diseases, including pediatric Systemic Lupus Erythematosus (pSLE). MAS is not considered as a frequent complication of pSLE; however, its occurrence could be under-estimated and the diagnosis can be challenging. In order to address this issue, we performed a systematic review of the available medical literature, aiming to retrieve all those papers providing diagnostic (clinical/laboratory) data on patients with pSLE-related MAS, in individual or aggregated form. The selected case reports and series provided a pool of 46 patients, accounting for 48 episodes of MAS in total. We re-analyzed these patients in light of the diagnostic criteria for MAS validated in systemic Juvenile Idiopathic Arthritis (sJIA) patients and the preliminary diagnostic criteria for MAS in pSLE, respectively. Five clinical studies were also selected and used to support this analysis. This systematic review confirms that MAS diagnosis in pSLE patients is characterized by several diagnostic challenges, which could lead to delayed diagnosis and/or under-estimation of this complication. Specific criteria should be considered to diagnose MAS in different rheumatic diseases; as regards pSLE, the aforementioned preliminary criteria for MAS in pSLE seem to perform better than the sJIA-related MAS criteria, because of a lower ferritin cut-off.

HLA-B*51 allelic and carrier frequency in Kazakhstan: insights into Behçet's disease prevalence in Central Asia.

Behçet's disease (BD) is a systemic vasculitis whose prevalence varies according to the ethnicity. HLA-B*51 is a well-known genetic factor predisposing to BD: populations with higher HLA-B*51 allelic frequencies are also those with a greater disease prevalence, as occurs in the Silk Road countries. However, the BD prevalence is unknown in many countries, including Kazakhstan and, in general, Central Asia, despite the location on or near the Silk Road. Due to the lack of clinical studies from this area, we analyzed the bone marrow donors registry in Kazakhstan, in order to assess the HLA-B*51 allelic and carrier frequencies, which resulted to be 8.14 and 15.28%, respectively. Through a comparison with the same parameters in other countries (by performing a data search in the medical literature and in the Allele Frequency Net Database), we might speculate a BD prevalence in Kazakhstan of 10-15/100.000 at least. This result should prompt a greater clinical consideration of this disease in Central Asia, as well as the publication of clinical data from this geographic area.

Pruritus in patients with amyopathic dermatomyositis.

Amyopathic dermatomyositis has been associated with the exposure to several drugs: the article by Jeimy et al. described the onset of this uncommon disease in a patient treated with omalizumab. Paradoxically, this patient complained of an intense pruritus and this finding has been reported by several authors observing patients with amyopathic dermatomyositis.

Adalimumab in the treatment of pediatric Behçet's disease: case-based review.

Behçet's disease (BD) is a systemic vasculitis affecting prominently the veins, which is usually diagnosed in adulthood, but can occur in children younger than 16 years in about 4-26% of cases. The therapy is based on several immune-suppressive drugs; in case of inadequate control and/or complications, the biologic therapy with anti-TNF drugs has been successfully used in adults. Here, we reported one pediatric case of BD with systemic (persistent/recurrent high fever), skin and mucosal manifestations (recurrent aphthous stomatitis, anal/penile ulcers, erythema nodosum and papulo-pustules), that were unresponsive to the conventional treatment with steroids and colchicine; however, he was successfully treated with adalimumab. Compared to adult patients, the experience with adalimumab in the treatment of pediatric BD is very limited. Indeed, through a systematic search in the medical literature, we retrieved 4 case reports and 2 case series, describing BD pediatric patients treated with adalimumab, in addition to three clinical studies including some BD children. The analysis and discussion of these available clinical experiences may indicate adalimumab as an effective and safe option to treat several forms of BD, in addition to BD-related chronic uveitis.