Aicardi-Gouteres syndrome (AGS) is a monogenic interferonopathy characterized by early onset, dysregulation of skin (chilblain lesions), brain, and immune systems (fever, hepatomegaly, glaucoma, ...arthritis, myositis, and autoimmune activity). The disease looks like TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infection with early-onset encephalopathy resulting in severe neuropsychological disability.
A six-year-old girl has been suffering from generalized seizures, fever episodes, severe psychomotor development delay, and spastic tetraparesis since the first year of her life. Her two elder brothers died at a young age from suspected infantile cerebral palsy (ICP). Other siblings (younger brother and two elder sisters) are as healthy as their parents. The girl was diagnosed with juvenile dermatomyositis at 5.5 years. Basal ganglia, periventricular, and cerebellum calcifications; hypoplasia of the corpus callosum; and leukodystrophy were detected on CT. The IFN-I score was 12 times higher than normal. The previously not described nucleotide variant c.434G > C (chr 20:36935104C > G; NM_015474) was detected in exon 4 of the SAMHD1 gene in the homozygous state, leading to amino acid substitution p.R145P. Aicardi-Goutières syndrome 5 was diagnosed. Her treatment included corticosteroids, methotrexate, and tofacitinib 5 mg twice a day and it contributed to health improvements. The following brain CT depicted the previously discovered changes without the sign of calcification spreading.
Early diagnosis of AGS is highly important as it allows starting treatment in a timely manner. Timely treatment, in return, can help avoid the development/progression of end-organ damage, including severe neurological complications and early death. It is necessary to spread information about AGS among neurologists, neonatologists, infectious disease specialists, and pediatricians. A multidisciplinary team approach is required.
There are hundreds of twin adult patients with systemic lupus erythematosus (SLE), but male children with SLE are rarely affected. Two monozygotic twin brothers developed SLE at the age of 11 years ...during 1 month. The index brother manifested with Henoch-Shonlein purpura, accompanied by ANA positivity, and later developed critical left femoral arterial stenosis with high levels of anti-dsDNA, antiphospholipid antibodies, hypocomplementemia, and Coombs-positive hemolytic anemia. At that time his twin brother had only identical autoimmune findings and developed clinical manifestation (myositis and fasciitis) a month later. Both twins had increased IFN-score and shared a heterozygous variant in the RNASEL gene. Index patients developed scalp rash and nephritis 6 months after their parents refused the treatment which has been lasted for 1 year after disease diagnostics.
Conclusion
The simultaneous onset of the pediatric SLE in the male twin is a very rare situation suspected monogenic origin of the disease. Further functional studies are required to confirm the causative role of the mutation.
Introduction: Interferon I (IFN I) signaling hyperactivation is considered one of the most important pathogenetic mechanisms in systemic lupus erythematosus (SLE). Early manifestation and more severe ...SLE courses in children suggest a stronger genetic influence in childhood-onset SLE (cSLE). Aim: To evaluate IFN-I score and SLE-associated genetic variants in cSLE. Material and Methods: 80 patients with cSLE were included in the study. IFN I-score was assessed by real-time PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1) in 60 patients. Clinical exome sequencing (CES) was performed in 51 patients. Whole-exome sequencing was performed in 32 patients with negative results of CES. Results: 46/60 patients (77%) had elevated IFN-I scores. Leucopenia and skin involvement were associated with over-expression of IFI44 and IFI44L, while hypocomplementemia—with hyperactivation of IFIT3, LY6E, and MX1. No correlation of IFN-I score with disease activity was found. At least one rare genetic variant, potentially associated with SLE, was found in 29 (56.9%) patients. The frequency of any SLE-genetic variants in patients with increased IFN scores was 84%, in patients with normal IFN scores—33%, and in the group whose IFN score was not assessed was 65% (p = 0.040). The majority of genetic variants (74%) are functionally related to nucleic acid sensing and IFN-signaling. The highest frequency of genetic variants was observed in Sakha patients (9/14; 64.3%); three and two unrelated patients had identical variants in PTPN22 and TREX1 genes, respectively. Conclusions: More than half of patients with childhood-onset SLE have rare variants in SLE-associated genes. The IFN-I score could be considered a tool for the selection of patients for further genetic assessment in whom monogenic lupus is suspected.
Objectives:
To describe the clinical characteristics of hip involvement in juvenile idiopathic arthritis (JIA) from arthritis to hip osteoarthritis (HOA) and total hip arthroplasty (THA).
Study ...Design:
Seven hundred fifty-three patients aged 2–17 years with JIA were included in the study. The comparison analysis was performed between the following subgroups: (i) JIA without hip involvement (
n
= 600; 79.7%) vs. JIA with hip involvement without HOA (
n
= 105; 13.9%), (ii) JIA with hip involvement with HOA, but without THA (
n
= 32; 4.3%) and JIA with hip involvement with HOA and with THA (
n
= 16; 2.1%). Clinical, laboratory characteristics and treatment regimens compared.
Results:
Hip involvement was present in 20.3% of patients. HOA was present in 6.4% (12
*
1,000 patient-years) of the entire JIA group and 31.4% of patients with hip involvement. Sixteen patients (2.1%; 4.0
*
1,000 patient-years) required THA. The following factors were associated with HOA: sJIA (OR = 3.6,
p
= 0.008; HR = 3.0,
p
= 0.002), delayed remission (OR = 4.2,
p
= 0.004; HR = 1.4,
p
= 0.538), delay in biologic therapy initiation (OR = 7.5,
p
= 0.00001; HR = 6.7,
p
= 0.002), alkaline phosphatase <165 U\l (OR = 4.1,
p
= 0.0003; HR = 5.2,
p
= 0.000004), treatment with corticosteroids (CS) (OR = 2.6,
p
= 0.008; HR = 1.2,
p
= 0.670), cumulative corticosteroids >2,700 mg (OR = 4.3,
p
= 0.032; HR = 1.4,
p
= 0.527). The following factors were associated with THA: delay in biologic treatment initiation (OR = 1.04,
p
= 0.0001; HR = 9.1,
p
= 0.034), delayed hip involvement (OR = 5.2,
p
= 0.002; HR = 3.0,
p
= 0.044), and methylprednisolone pulse therapy (OR = 10.8,
p
= 0.0000001; HR = 5.6,
p
= 0.002).
Conclusion:
Both sJIA and systemic CS, impaired calcium-phosphorus metabolism, and delayed hip arthritis are associated with HOA development in JIA. HOA is considered to be a severe adverse event of CS treatment, especially delayed hip involvement.
JAK-inhibitors are small molecules blocking the JAK-STAT pathway that have proven effective in the treatment of different immune-mediated diseases in adults and juvenile idiopathic arthritis (JIA).
...To evaluate the safety and efficacy of tofacitinib in children with different rheumatic diseases.
We extracted information from 24 children with the following diagnosis: JIA (
= 15), undifferentiated systemic autoinflammatory diseases (SAIDs) (
= 7), and juvenile dermatomyositis (JDM) (
= 2) who have been treated with tofacitinib for a period of longer than 6 months. The treatment outcomes were classified according to the opinion of the attending physicians as having a complete response (CR), i.e., the absence of disease activity, or a partial response (PR)-a significant improvement of symptoms and disease activity, or no response (NR)-no changes in disease activity.
CR was achieved in 10/24 patients; 7/15 among JIA patients, 1/2 among JDM patients, 4/7 among SAID patients, and PR in 5/15 of JIA, 1/2 of JDM, and 3/7 of SAID patients. Three non-responders with JIA discontinued tofacitinib. Corticosteroids were successfully tapered off in 11/14 patients and discontinued in 2/14 patients. Four patients had side effects not requiring treatment discontinuation: liver enzyme elevation (
= 2), hypercholesterolemia (
= 1), lymphadenitis (
= 1).
JAK-inhibitors are effective new therapies for the treatment of multiple immune-mediated diseases. Our experience has shown the best results in patients with JIA and JIA-associated alopecia, and type I interferonopathies. More data from randomized controlled clinical trials are needed to use JAK-inhibitors safely in pediatric rheumatic diseases.
Juvenile localized scleroderma (JLS) is a group of childhood diseases with the main symptom — skin and subcutaneous structures lesions, without any organ involvement. There is active (inflammatory) ...and fibrotic phase in development of JLS. The JLS treatment during active phase (when skin lesions are reversible) is the most effective. The management is determined by the area and depth of skin lesions, appearance and spread of new lesions, presence of extracutaneous signs of the disease. Topical and systemic immunosuppressants are the basic therapy for JLS. The use of antibiotics is not suggested. Clinical scores (LoSCAT), ultrasound, thermography and magnetic resonance imaging are recommended to estimate the treatment efficacy.
The localized scleroderma (morphea) is the clinical option of the juvenile scleroderma, the third in prevalence rheumatic condition in pediatrics. The article summarizes all the data on the ...classification, diagnostics, and differential diagnosis of juvenile localized scleroderma. The recent international guidelines on the localized scleroderma in pediatrics (the European consensus of pediatric rheumatologists, the German and Japanese national guidelines) are presented in the article.
Background. Patients with juvenile idiopathic arthritis (JIA) can have low levels of antibodies to vaccine antigens due to immunologic features of the main disease, disruptions in vaccination ...schedule and immunosuppressive drugs administrationObjective. The aim of the study was to examine the status of postvaccinal immunity and determine the factors associated with preservation of protective level of antibodies in patients with JIA.Methods. This cross-sectional study included patients with JIA at the age from 2 to 17 years old vaccinated under the age of two (before JIA) against measles, rubella, parotitis, hepatitis B and diphtheria. Levels of IgG to vaccine antigens were measured by enzyme immunoassay. The minimum protective level of anti-measles IgG was esteemed as 0.18 IU/ml, antibodies to rubella — 10 IU/ml, for parotitis — COI > 1.0, for hepatitis B — 10 mIU/ml, antibodies to diphtheria — 0.09 IU/ml.Results. The study included 90 patients with JIA (71% of girls) at the age (median) 11.3 (7.5; 14.9) years. The age of JIA manifestation was 6.0 (4.0; 8.0) years, disease duration — 4.0 (2.0; 7.3) years. Glucocorticosteroids administration in anamnesis or at study entry was recorded in 24/88 (27%) patients, methotrexate — 81/88 (92%), genetically engineered biologic drugs — 54/89 (61%). Protective level of antibodies to measles virus was revealed in 45 (50%) children with JIA, to rubella virus — in 88 (98%), to parotitis — in 68 (76%), to hepatitis B — in 49 (54%), to diphtherial anatoxin — in 45 (50%). The decrease of postvaccinal immunity level was associated with JIA duration and glucocorticosteroids administration (against diphtheria) duration, as well as drop-out immunization (against measles).Conclusion. Major part of children with JIA have no protection against measles, parotitis, hepatitis B or diphtheria. High risk of progression of such vaccine-preventable diseases in these children demands development of individual programs of immunization.
BACKGROUND: Enthesitis-related arthritis is one of the subtypes of juvenile idiopathic arthritis and is characterized by the involvement of the joints, enthesitis, and axial skeleton (sacroiliitis ...and spondylitis). The clinical variability of enthesitis-related arthritis and similar manifestations with orthopedic diseases present difficulties in diagnosis.
AIM: To present the clinical features of enthesitis-related arthritis and issues of differential diagnosis based on literature analysis.
MATERIALS AND METHODS: A literature search was conducted in the open electronic databases of eLibrary, PubMed, and Cochrane Library. In total, 46 foreign and 4 Russian publications were analyzed, which were limited to 19812021. The keywords used in the literature search were as follows: enthesitis, enthesitis-related arthritis, juvenile spondyloarthritis, and SAPHO syndrome. Own archive data for instrumental investigations were used in the article.
RESULTS: The clinical manifestations can be variable, and laboratory tests do not always allow us to prove the inflammatory nature of the pain syndrome. The most priority diagnostic tests were imaging methods, namely, magnetic resonance imaging and ultrasonography. The greatest diagnostic difficulty was found in patients in whom enthesitis prevailed over arthritis, and in some cases, it was the only disease manifestation. The classification criteria used for the diagnosis of EAA were considered. The differential diagnosis of enthesitis included various orthopedic diseases. Ultrasound diagnostics of joints and enthesis should be performed in every patient with local pain musculoskeletal symptoms, which allows patients to be correctly routed.
CONCLUSIONS: The alertness of both orthopedists in relation to enthesitis-related arthritis and the awareness of rheumatologists of the most common orthopedic diseases that affect the entheses are necessary.
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