Optimal biologics for juvenile idiopathic arthritis in an infection with SARS‐CoV‐2 α‐variant

To the Editor, The worldwide pandemic of coronavirus disease 2019 (COVID19) caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV2) is still raging and continues to have a serious impact on global health care and the economy across nations. The risk of severe COVID19 is of concern for patients with rheumatic diseases (RMDs) using diseasemodifying antirheumatic drugs (DMARDs) including biologics.1 COVID19 appears to show a milder clinical course in children than in adults, but multisystem inflammatory syndrome in children (MISC) occurs as a lifethreatening complication due to unknown causes.2 The emergence of newly identified mutant SARSCoV2 lineages, reported in the UK (B.1.1.7), South Africa (B.1.351), Brazil (P.1), and India (B.1.617.1– 3), is a grave menace, which is worsening the continued pandemic.3 However, limited information is available about the management of RMDs in childhood. We herein report a patient with juvenile idiopathic arthritis (JIA) who was infected by an αvariant of SARSCoV2 called lineage B.1.1.7 while under tocilizumab treatment. The patient was a 7 yearsold girl who was diagnosed as having systematic JIA at 2 years of age. She achieved remission without macrophage activation syndrome (MAS) for 5 years after the introduction of tocilizumab (8 mg/kg) every 4 weeks and methotrexate (MTX, 7 mg/m2) weekly. She developed fever and cough three days after her father was diagnosed to have SARSCoV2 lineage B.1.1.7 according to a reverse transcriptionpolymerase chain reaction (RTPCR) test. The patient presented with a fever of up to 38.0°C for two days, and then, a positive RTPCR result prompted the girl to be hospitalized at our institution for care and isolation. On admission, she was afebrile and free from respiratory symptoms or desaturation. Chest Xrays showed no abnormality. Laboratory tests were unremarkable as follows: leukocytes, 3.9 × 109/L (reference range [rr], 3.3– 8.6 × 109/L); neutrophils, 1.7 × 109/L (rr, 1.5– 8.0 × 109/L); lymphocytes, 1.6 × 109/L (rr, 1.5– 7.0 × 109/L); hemoglobin, 13.3 g/dl (rr, 11.5– 14.4 g/dl); platelet count, 22.3 × 109/L (rr, 18– 51 × 109/L); Creactive protein, 0.01 mg/dl (rr, <0.14 mg/dl); lactate dehydrogenase, 259 U/L (rr, 175– 320 U/L); fibrinogen, 218 mg/dl (rr, 200– 400 mg/dl); prothrombin time, 11.1 s (rr, 10.0– 13.5 s); Ddimer, <0.5 mg/L (rr, <0.5 mg/L); ferritin, 24.1 ng/ml (rr, 6.2– 138.0 ng/ml); and matrix metalloproteinase3, <10 ng/ml (rr, <10 ng/ml). The serum cytokine levels at the diagnosis of COVID19 showed slightly elevated levels of TNFα (26.4 pg/ml; rr, <10 pg/ml), IL6 (64.1 pg/ml; rr, <10 pg/ml), and IL8 (41.6 pg/ml; rr, <10 pg/ml). The patient was carefully observed while receiving concomitant oral MTX on scheduled days without antiviral drugs or oxygen therapy. Tocilizumab was postponed for 2 days from the scheduled day, and then administered for 5 days after the resolution of fever. She was uneventfully discharged from the hospital on Day 10 of illness under the sustained remission of JIA, CHAQDI of 0. A serum cytokine analysis at discharge showed undetectable levels of TNFα and IL8 (<10 pg/ ml) and a decreased level of IL6 (20.7 pg/ml). The activity of primary disease has been stably controlled during and after this episode of COVID19 without altering the management of JIA. Our review of all publications and sentinel sources using PubMed, and Google Scholar for citations published after the outbreak of COVID19 from December 2019 to July 2021, identified six JIA patients diagnosed with COVID19 during the treatment course of biologic DMARDs (Table 1).4– 6 They all received TNFα blockers or an antiIL1β antibody. This is the first report of infection of SARSCoV2 with the lineage B.1.1.7 in a JIA patient receiving tocilizumab therapy. Six of the seven patients including the present girl infected with B.1.1.7 under tocilizumab therapy had a favorable course without complications. Only one patient (case 3) who continued oral prednisolone during the early treatment phase of JIA under canakinumab therapy required oxygen therapy for pneumonia. Of the two patients (case 2: oligoarticular type and case 5: polyarticular type) who discontinued antiTNFα treatment, the former patient had a flareup of the primary disease. Our findings revealed that COVID19 was curable without serious complications in JIA controlled under biologics, but not steroid therapy. These results support the hypothesis that uncontrolled JIA and its baseline inflammatory state are a risk factor for severe COVID19, even in children, or that immunosuppression associated with prolonged corticosteroid treatment acts as another risk factor for severe disease. The current consensus on COVID19 in children is that immunosuppressive therapy does not significantly increase the risk in pediatric patients with RMDs.7 Several lines of cohort study indicated that adult or pediatric patients with RMDs under biologic DMARDs have no increased risk of severe COVID19. Demier et al.3 reported that 6 of 39 patients with RMDs under biologic therapies with corticosteroids contracted nonsevere COVID19. All of them received lowdose corticosteroids (<0.5 mg/kg/day). These findings support that patients in whom JIA is stably controlled by biologics without/with lowdose prednisolone show favorable outcomes. OpokaWiniarska et al.8