COVID-19 and what pediatric rheumatologists should know: a review from a highly affected country.

On March 11th, 2020 the World Health Organization declared COVID-19 a global pandemic. The infection, transmitted by 2019 novel coronavirus (2019-nCov), was first discovered in December 2019, in Wuhan, Hubei Province, and then rapidly spread worldwide. Italy was early and severely involved, with a critical spread of the infection and a very high number of victims. Person-to-person spread mainly occurs via respiratory droplets and contact. The median incubation period is 5 days. The spectrum of respiratory symptoms may range from mild to severe, strictly depending on the age of the patient and the underlying comorbidities.In children COVID-19 related disease is less frequent and less aggressive. In Italy 1% of positive cases are under 18 years of age, and no deaths have been recorded before 29 years of age. For patients affected by rheumatic disease, despite the concerns related to the imbalance of their immune response and the effect of immunosuppressive treatments, there are still few data to understand the real consequences of this infection. Major scientific societies have issued recommendations to help rheumatologists in caring their patients. Interestingly, some of the drugs mostly used by rheumatologists appear to be promising in critical COVID-19 infected patients, where the hyperinflammation and cytokine storm seem to drive to the multiorgan failure.Pediatric rheumatologists are expected to play a supporting role in this new front of COVID-19 pandemic, both as general pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs.

Evolución de pacientes con artritis idiopática juvenil en terapia biológica que cursan infección por virus varicela zoster: a propósito de 4 casos / Outcomes of patients with juvenile idiopathic arthritis on biological therapy and have a varicella-zoster virus infection

En niños inmunocomprometidos, la infección por virus varicela puede producir una enfermedad grave. Existen pocos casos publicados de varicela en pacientes con artritis idiopática juvenil (AIJ) y terapia biológica. OBJETIVO: Describir la evolución de pacientes con AIJ con terapia biológica que adquirieron el virus varicela. CASOS CLÍNICOS: Se describe la historia clínica de 4 pacientes con AIJ, de entre 3 y 12 años de edad, que presentaron infección por virus varicela zoster estando con distintas terapias biológicas: 2 con anti TNF, uno con anti IL-6 y uno con bloqueador de la coestimulación del linfocito T. Dos de ellos habían recibido la vacuna contra la varicela. Todos recibieron diferentes terapias y evolucionaron sin complicaciones, no encontrando diferencias importantes en relación con el tipo de terapia biológica ni con el antecedente de haber sido vacunados. En todos los pacientes se suspendió el tratamiento biológico por al menos 2 semanas y se reinició sin reactivación de la artritis. CONCLUSIONES: En esta serie de pacientes con AIJ tratados con terapia biológica que cursaron con infección por VVZ no se observaron complicaciones graves.

Varicella virus infection may develop into severe disease in immunocompromised children. There are few studies that describe the clinical presentation of varicella infection in patients with Juvenile Idiopathic Arthritis when on biological therapy. OBJECTIVE: Describe the outcomes of patients with a diagnosis of Juvenile Idiopathic Arthritis, who acquired a varicella virus infection during treatment with biological therapy. CLINICAL CASES: A description is presented on 4 cases of Juvenile Idiopathic Arthritis in children between 3 and 12 years old, who developed a varicella-zoster infection during treatment with different biological therapies. Two patients were taking anti-TNF agents, one an Anti IL-6 agent, and one patient a T cell costimulatory blockade agent. Two of them received varicella vaccination prior to the start of biological therapy. All of them received different therapies and had favourable outcome without developing complications. No significant differences were found as regards the type of biological therapy or history of previous vaccination. Biological therapy was suspended for at least 2 weeks in all patients, and was restarted without reactivation of arthritis. CONCLUSIONS: No serious complications were observed in this patient series of children with JIA treated with biological therapy associated with VZV infection.

Monitoring of Epstein-Barr virus load and killer T cells in patients with juvenile idiopathic arthritis treated with methotrexate or tocilizumab.

OBJECTIVES: Methotrexate (MTX) is used for the treatment of polyarticular juvenile idiopathic arthritis (JIA), and an anti-interleukin-6 receptor monoclonal antibody (tocilizumab: TCZ) is also used and added for the treatment of intractable JIA. It has been reported that MTX might induce Epstein-Barr virus (EBV)-associated lymphoma, but the discussion about the effect of MTX and/or TCZ against reactivation of EBV in pediatric patients has been incomplete. METHODS: The EBV loads in four polyarticular JIA and three systemic arthritis JIA patients treated with MTX and/or TCZ, and the percentage of EBV-specific killer T cells (EBV-CTLs) in some patients were prospectively monitored. RESULTS: No patients had EBV-associated symptoms during the observation period. EBV loads in all patients were not significantly increased, and the levels of EBV loads were the same as EBV-seropositive healthy children following the administration of MTX and/or TCZ. EBV-CTLs were detectable during the observation period, but some patients had slightly low levels of EBV-CTLs. CONCLUSION: Treatment with MTX and/or TCZ did not severely affect EBV load and prevent induction of EBV-CTLs in JIA patients.

[Outcomes of patients with juvenile idiopathic arthritis on biological therapy and have a varicella-zoster virus infection]. / Evolución de pacientes con artritis idiopática juvenil en terapia biológica que cursan infección por virus varicela zoster. A propósito de 4 casos.

Varicella virus infection may develop into severe disease in immunocompromised children. There are few studies that describe the clinical presentation of varicella infection in patients with Juvenile Idiopathic Arthritis when on biological therapy. OBJECTIVE: Describe the outcomes of patients with a diagnosis of Juvenile Idiopathic Arthritis, who acquired a varicella virus infection during treatment with biological therapy. CLINICAL CASES: A description is presented on 4 cases of Juvenile Idiopathic Arthritis in children between 3 and 12 years old, who developed a varicella-zoster infection during treatment with different biological therapies. Two patients were taking anti-TNF agents, one an Anti IL-6 agent, and one patient a T cell costimulatory blockade agent. Two of them received varicella vaccination prior to the start of biological therapy. All of them received different therapies and had favourable outcome without developing complications. No significant differences were found as regards the type of biological therapy or history of previous vaccination. Biological therapy was suspended for at least 2 weeks in all patients, and was restarted without reactivation of arthritis. CONCLUSIONS: No serious complications were observed in this patient series of children with JIA treated with biological therapy associated with VZV infection.

High prevalence of streptococcal or Epstein-Barr virus infections in children with acute non-septic monoarthritis.

To investigate associations between infections and acute monoarthritis, we performed a prospective study on 32 children consecutively hospitalized and 32 age-matched controls. Among 26 (81%) children having infections, the most frequent agents were Group A ?-hemolytic Streptococcus (GAS: 53%) and Epstein-Barr virus (EBV: 37.5%). Among controls, only 5 (16%) were infected with GAS and 2 (6%) with EBV (P<0.005). The most frequently involved joints were hip in 15 children and ankle in 10 children. Our study showed that acute monoarthritis in children may be frequently associated with streptococcal or EBV infections.

Prospective monitoring of Epstein-Barr virus and other herpesviruses in patients with juvenile idiopathic arthritis treated with methotrexate and tocilizumab.

Methotrexate (MTX) is widely used for the treatment of articular-type juvenile idiopathic arthritis (JIA), but patients receiving MTX for rheumatoid arthritis have been reported to be at increased risk of reactivation of Epstein-Barr virus (EBV) and the development of lymphoproliferative disorder. The association between MTX and reactivation of herpesviruses in pediatric patients is not yet understood. We prospectively monitored the viral load of EBV, cytomegalovirus (CMV), and herpesvirus 6 (HHV-6) in four JIA patients treated with MTX for 12-24 months. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, was added to the therapeutic regimen in three patients during the observation period. Prior to the administration of MTX, EBV and HHV-6 were detected by PCR in two patients. Significant increases in EBV and HHV-6 load were not observed following the administration of MTX or tocilizumab. In one patient, a relatively high EBV load remained detectable during 21 months of observation in the absence of clinical symptoms. CMV was not detected throughout the observation period in any patient. This is the first report monitoring the longitudinal DNA loads of EBV and other herpesviruses in JIA patients. EBV and HHV-6 were often detectable, but treatment with MTX and tocilizumab did not appear to influence the viral load.

Indications for a disturbed peripheral T-cell homeostasis in juvenile idiopathic arthritis (JIA): absent expansion of CD28 T-cells and no decrease of naive T-cells in cytomegalovirus-positive patients with JIA.

OBJECTIVE: To investigate the influence of latent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on CD28-expressing T-cell subpopulations and replicative senescence of naive T-cells as a marker for aging of the immune system in children with juvenile ideopathic arthritis (JIA). METHODS: T-cell subpopulations were analyzed from 24 patients with JIA and 61 healthy age-matched controls by fluorescence activated cell sorting. Relative telomere length (RTL) in CD4+CD28+CD45RA+ (naive) T-cells was measured by quantitative polymerase chain reaction. RESULTS: Although confirming known data of expansions of CD28- T-cells and tendency of decreasing naive T-cells in CMV-seropositive healthy individuals, our findings did not show a marked influence of latent EBV or CMV infection on CD28-expressing T-cells in patients with JIA. In contrast, CMV was an independent factor for loss of CD28, regardless of age, in healthy controls. Irrespective of serology results for CMV or EBV, patients with JIA showed signficantly decreased RTL compared to age-matched controls. Regression lines for RTL and age revealed decreased RTL with advancing age in CMV-positive and EBV-positive subjects. The evidence that findings for CMV-positive JIA patients did not resemble the findings of healthy CMV-positive controls, namely expansion of CD28- T-cells and decrease of naive T-cells, may support the theory of a disturbed peripheral T-cell homeostasis in JIA. CONCLUSION: Diminished mechanisms of T-cell homeostasis and premature aging of the immune system may play a role in the pathogenesis of JIA.

Hepatitis A-associated macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: report of 2 cases.

OBJECTIVE: We describe two 3-year-old patients with systemic juvenile idiopathic arthritis (SJIA) who developed hepatitis A-associated macrophage activation syndrome (MAS). One patient showed MAS as the presenting manifestation of SJIA, while MAS complicated SJIA during the second year of the disease course in the other child. Both girls presented with fever, jaundice, hepatosplenomegaly, neurological involvement, mucosal hemorrhage, and purpura. Cytopenias, hypofibrinogenemia, and hemophagocytosis confirmed the diagnosis. After aggressive treatment with high-dose corticosteroids and immunosuppressants one patient entered remission while the other one died. Hepatitis A virus may induce severe MAS in SJIA.

Different patterns of disease manifestations of parvovirus B19-associated reactive juvenile arthritis and the induction of antiphospholipid-antibodies.

Children with rheumatic oligo- and polyarthritis frequently establish persistent parvovirus B19 infections, which may be associated with the production of antiphospholipid antibodies. Reported in this paper are the data of five girls with polyarticular rheumatic diseases of different types and persistent parvovirus B19 infection associated in four cases with the presence of antibodies against phospholipids. Clinical parameters, virus load, and antiphospholipid-IgG levels were determined during an observation period up to 92 months. In two patients, erythema infectiosum preceded the development of arthritis and B19 viremia persisted. Two other girls showed antibodies against parvoviral structural proteins at time of the manifestation of the rheumatic disease. Subsequent samples also revealed persistent B19 infection. In the fifth patient, parvovirus B19-specific IgG antibodies were detected for the first time after 120 months of progressing disease at an age of 11 1/2 years. Five years later, quantitative polymerase chain reaction (PCR) revealed viral DNA. In a synovial tissue specimen subsequently obtained, parvovirus B19 structural proteins could be detected by immunohistochemistry. Three of five patients recovered completely without severe sequels. One patient is in remission under immunosuppressive therapy. The fifth patient suffers from progressive erosions despite intensive therapeutical efforts. In consequence, parvovirus B 19 should generally be taken into consideration as a trigger of various forms of juvenile arthritis and persistence of infection should be evaluated.

Seroprevalence of parvovirus B19 IgG in children affected by juvenile idiopathic arthritis.

Parvovirus (PV) B19 is the causative agent of the childhood disease erythema infectiosum. An association of PV B19 with chronic arthropathies, sometimes resembling rheumatoid arthritis or juvenile idiopathic arthritis (JIA), has repeatedly been described. Other studies, however, have failed to identify any such relationship. In order to study further whether there is a link between PV B19 and JIA, we determined the prevalence of PV B19 specific IgG antibodies in serum samples from children with rheumatoid diseases and compared it with the prevalence in unaffected children We reasoned that if there is an association between PV B19 and JIA, then the prevalence of PV B19 IgG in the children with JIA should be higher than in the control group. PV B19 IgG status was tested in 406 children with JIA and related diseases, and in 146 children constituting a control group. The percentage of PV B19 IgG positive children was not significantly elevated in the disease subgroups compared with age-matched control groups. In conclusion, our findings do not support the hypothesis that human parvovirus B19 is involved in the pathogenesis of JIA.

Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthritis.

OBJECTIVE: To determine the prevalence of human parvovirus B19 infection in patients with juvenile idiopathic arthritis (JIA) by detection of specific IgM, IgG, and viral DNA. METHODS: Serum samples of 50 patients with diagnosis of JIA and 39 healthy controls were analyzed by ELISA to detect IgG and IgM anti-B19-specific antibodies. The parvovirus B19 genome was detected by nested polymerase chain reaction (PCR). The average age of the patients was 9.6 years (2-14 yrs); 30 were female (60%) and 20 male (40%). The definitive diagnoses of these patients corresponded to 19 systemic forms (38%), 11 to the oligoarticular variety (22%) and 20 to the polyarticular (40%). The average age of the control group was 7.8 years (2-16 yrs); the distribution by sex was 25 females (64%) and 14 males (36%). RESULTS: IgM against parvovirus B19 was detected in 20% of the cases (10 patients) and B19 DNA genome by PCR in 48% (24 patients); in 10% of the cases (5 patients), both markers were detected. IgG was found in 32% (16 patients). In the control group neither IgM nor the viral genome was detected. However, 43.5% of the controls (17/39) had IgG against parvovirus B19, indicating past infection by the virus. CONCLUSION: Our study confirms recent observations regarding a high prevalence of viral DNA in JIA patients and a possible role of this viral infection in JIA pathogenesis.

Juvenile rheumatoid arthritis in children with Ebstein Barr virus infection.

Juvenile Rheumatoid Arthritis (JRA) is a disease of unknown etiology. A total of 50 patients with JRA who were hospitalized in the Pediatrics Rheumatology Ward of Imam Khomeini Hospital in Tehran during the years 2001-2002, were assessed serologically (IgM and IgG specific viral capsid antigens) for EBV infection and their response to therapy was studied. Minimum age of the patients was at least 6 months and mean age was 60.96 plus/minus 43.46 months. EBV infection was seen in 44 (88%) patients 24 of whom were girls and 20 boys. Ninety two percent of girls and 83% boys were infected with the virus. Ebstein barr virus (EBV) infection was seen in 33 cases, 6 cases, 4 cases and 1 case in the polyarticular, pauciarticular, systemic and spondylitis group, respectively. Fifty four percent of EBV-positive patients with JRA did not respond to the classic therapy. EBV virus is involved in the pathogenesis of JRA and patients with EBV are in greater risk of developing JRA.

Anakinra therapy in a child with systemic-onset juvenile rheumatoid arthritis after human herpesvirus 6 encephalitis.

A 3-year-old patient with biopsy-proven herpesvirus 6 (HHV-6) encephalitis developed a clinical condition consistent with systemic-onset juvenile idiopathic rheumatoid arthritis (SoJIA) and responsive to synthetic interleukin-1 (IL-1) receptor therapy. This suggested both a temporal relationship between HHV-6 infection and the development of SoJIA and the likely involvement of IL-1 in his disease. This case adds to the current experience of IL-1 receptor antagonist therapy in SoJIA. In addition, it suggests that future prospective studies in new-onset SoJIA should include an evaluation for HHV-6 infection.

[Role of parvovirus B19 as a causative agent for arthritis in children -- preliminary studies]. / Rola parvovirusa B19 jako czynnika etiologicznego artropatii u dzieci -- badania wstepne.

INTRODUCTION: Parvovirus B19 infection can be associated with arthritis in children and adults. The causative role of PB19 infection in arthritis and ulcerative synovitis would prove the etiology of juvenile idiopathic (jia) and reumatoid arthritis (ra). AIM: The aim of this study was the evaluation of the role of PB 19 infection in children's arthritis. MATERIAL AND METHODS: The group of 41 children with the diagnosis of jia, arthralgia, reactive arthritis and nodular erythema according to EULAR criteria was examined. In early stage of arthritis lasting less than 3 months, there were 22 and in prolonged period lasting more than 3 months there were 19 children. RESULTS: No evidence of PB19 genome was detected by PCR reaction in blood of the examined patients. The possible reasons of the obtained negative results in this study were discussed. CONCLUSIONS: PB19 research should be performed in more cases of children's arthritis, both using PCR and by serological methods.

Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein-Barr virus proteins in oligoarticular juvenile idiopathic arthritis.

OBJECTIVE: To evaluate whether abnormal T cell recognition may be generated by exposure to exogenous antigens presenting sequence homology with epitopes contained in self HLA alleles, and if such recognition may be part of the mechanisms that fuel inflammation in autoimmune diseases associated with certain HLA alleles. METHODS: Cytotoxic responses of peripheral blood mononuclear cells to 9-mer peptides derived from HLA molecules (DRB1*1101, DRB1*0801, or DPB1*0201) associated with oligoarticular juvenile idiopathic arthritis (JIA) or homologous peptides derived from Epstein-Barr virus (EBV) proteins (Bolf1 or Balf2) were analyzed in patients with oligoarticular JIA and in healthy controls matched for HLA-DRB1*1101, DRB1*0801, or DPB1*0201. Production of proinflammatory cytokines in culture supernatants was determined by enzyme-linked immunosorbent assay. RESULTS: T cell cytotoxic responses and production of proinflammatory cytokines in response to stimulation with self HLA-derived peptides were found only in patients with oligoarticular JIA, and not in controls. Patients with oligoarticular JIA, but none of the healthy controls, had EBV-self HLA cross-reactive T cells. CONCLUSION: Our data suggest a disease- and allele-specific mechanism of autoimmunity in oligoarticular JIA. This mechanism may be part of the pathogenesis of the disease, and could be the basis of one of the likely multiple candidates for antigen-specific immunotherapy approaches in the future.

Parvovirus B19 in the acute arthropathies and juvenile rheumatoid arthritis.

OBJECTIVE: To evaluate the prevalence of recent parvovirus B19 infection in a cohort of children presenting with acute arthropathy and to determine the prevalence of a subsequent diagnosis of juvenile rheumatoid arthritis in this cohort. METHOD: In this prospective study, parvovirus B19 IgM antibody was investigated in 75 patients who were referred to our clinic with acute joint complaints and also in 75 healthy controls. One patient in each group was excluded due to neuroblastoma and acute lymphoblastic leukaemia. The characteristics of parvovirus B19 IgM positive patients who were accepted as parvovirus B19 arthropathy were further evaluated. All the patients were followed up for at least 6 weeks and the patients with chronic progression of joint complaints were followed for at least 6 months to determine their progress. The cases of juvenile rheumatoid arthritis in this chronic group were identified. RESULTS: Parvovirus B19 IgM was detected in 16 of 74 patients (21.6%) with acute arthropathy compared with 3 of 74 (4.1%) in the healthy control group (chi(2) = 8.67; P = 0.003). The parvovirus B19 positive patients with arthropathy were more likely to become chronic (P = 3.7 x 10(-7)) and to be diagnosed as juvenile rheumatoid arthritis (P = 0.03) than the parvovirus B19 IgM negative group with arthropathy. Additional joint destruction developed in one case who was parvovirus B19 IgM positive in whom juvenile rheumatoid arthritis was diagnosed during follow up. CONCLUSION: These data support the hypothesis that parvovirus B19 infection may be associated with the onset of juvenile rheumatoid arthritis in a proportion of patients.

Remission of juvenile rheumatoid arthritis after infection with parvovirus B19.

A 22-year-old Caucasian woman with a 6 year history of persistently active, systemic onset juvenile rheumatoid arthritis (JRA) developed symptoms of headache, dry cough, nausea, vomiting, abdominal pain, diarrhea, and dehydration associated with a high fever, elevated liver enzymes, and lymphopenia. Subsequent investigation revealed acute infection with parvovirus B19. Following clinical improvement over 10-14 days solely with supportive care, her underlying disease remained in remission for about 7 months.

[A girl with systemic onset juvenile rheumatoid arthritis suspected to be due to human parvovirus B19 infection].

We encountered a case of a girl where Human Parvovirus B19 infection was considered to have been concerned with the development of systemic type juvenile rheumatoid arthritis (JRA). While the affected child did not show any evident infectious erythema-like findings, changes in the serum antibody titer by the EIA method presented the pattern of first infection. During the clinical course the condition of the disease as JRA was serious and hemophagocytic syndrome developed concurrently. Furthermore, the resistance to the treatment was also noted. So the patient was treated with prednisolone combined with low dose weekly MTX therapy. The possibility of Human parvovirus B19 being concerned with the development of rheumatoid arthritis in one form or another has been suggested in recent years. In the disease type with systemic angititis as main pathophysiology, which is called systemic JRA we encountered this time, it is not clear how Human Parvovirus B19 was concerned with the development of this disease, but it appeared to hold a key position in studying pathophysiology of the development.