Sequential Tocilizumab and Tofacitinib Treatment for Systemic Juvenile Idiopathic Arthritis: a Case Report

In June 2020, a 4-year-old girl (height 110 cm, weight 20 kg) visited our hospital presenting with recurrent fever accompanied by multiple joint swelling and pain (Fig. 1).

Fig. 1figure 1

Timeline of the present case report

Eight months earlier, the patient had developed chills and fever, with a body temperature up to 39.5 °C. The initial diagnosis of the patient was not clear. She experienced fever which subsided after the administration of intermittent oral dexamethasone tablets but recurred on discontinuing the drug. Unfortunately, over the next 3 months, the patient attempted to discontinue dexamethasone, but her condition deteriorated rapidly, with persistent high fever and concurrent symmetric polyarticular swelling and pain involving almost all the joints of the body. Polyarticular swelling and pain were reported primarily in the bilateral proximal interphalangeal joints, bilateral metacarpophalangeal joints, bilateral wrists, bilateral elbows, bilateral knees, bilateral ankles and bilateral metatarsal toes, with morning stiffness lasting longer than 4 h. The patient’s daily life was severely affected; she was unable to walk, and required significant support from others. From February to May 2020, the patient visited several hospitals, all of which failed to diagnose the disease; she received various treatments from these hospitals, including ibuprofen suspension (3 ml three times per day, orally), dexamethasone injection (3 mg, intramuscularly, once), Chinese herbal medicine bath (the specific ingredients was unknown) and etanercept (12.5 mg, subcutaneously, twice). However, her fever and arthritis symptoms showed little improvement. In June 2020, the patient was referred to the Children’s Hospital of the Capital Institute of Pediatrics. Laboratory test results suggested a negative purified protein derivative test, T-cell spot test of tuberculosis infection, anti-cyclic citrullinated polypeptide and human leucocyte antigen B27. Enhanced magnetic resonance imaging of the left knee revealed effusion and synovitis of the left knee. Her family medical history was unremarkable. The patient did not undergo any further therapeutic intervention according to the physician’s advice.

As the symptoms continued, the patient presented to our hospital, where physical examination revealed swelling and tenderness in the interphalangeal joints, metacarpophalangeal joints, wrists, elbows, knees, ankles and metatarsophalangeal joints. She was uncooperative with Patrick’s test, and complete blood count revealed mild microcytic anaemia (haemoglobin 91.8 g/L, mean corpuscular volume 68.9 fL), increased white blood cells (15.3 × 109/L), neutrophils (7.9 × 109/L), lymphocytes (5.5 × 109/L), monocytes (1.7 × 109/L), eosinophilic granulocytes (0.1× 109/L), basophils (0.1× 109/L) and thrombocytosis (676.8 × 109/L) along with a serum ferritin level of 1,103.8 U/L, erythrocyte sedimentation rate (ESR) of 85.0 mm/h, C-reactive protein (CRP) level of 146.0 g/L, significantly elevated cytokine IL-6 level of 288.0 pg/ml, alanine transaminase level of 53.3 U/L and albumin level of 26.0 g/L. Test results for rheumatoid factor, anti-nuclear antibody, anti-cyclic citrullinated peptides and human leucocyte antigen B27 were negative. Ultrasound suggested effusion in both the wrist joints and knee joints, synovial hyperplasia and thickening of the articular cartilage in both the knee joints, as well as enlarged lymph nodes in the bilateral neck and groin regions. She was diagnosed with sJIA after exclusion of infections (including streptococci, tuberculosis, respiratory pathogens and Epstein–Barr virus infection) and other febrile illnesses (including Kawasaki disease and systemic lupus erythematosus), as well as after undergoing a haematological consultation to exclude haematologic neoplasms. The patient’s 27-joint Juvenile Arthritis Disease Activity Score (JADAS-27) was 56.5, indicating high disease activity. After obtaining parental consent, the patient was started on a regimen comprising TCZ (8.0 mg/kg every 2 weeks, intravenously), ibuprofen suspension (4 ml three times per day, orally) and methotrexate (7.5 mg per week, orally). After 1 day of treatment, the patient’s fever subsided and her arthritis symptoms improved.

Thereafter, the patient received TCZ once every 2 weeks, and her condition continued to improve, with no recurrence of fever and steady improvement in her arthritic symptoms. However, repeat laboratory test results obtained in September 2020 (after six infusions of TCZ) suggested the presence of certain cytokines at high levels (Table 1) and an elevated CRP level (14.1 mg/L, normal: < 6.0 mg/L). At this point, the patient was more resistant to repeated intravenous infusions, and her parents indicated that financial constraints may prevent them from continuing TCZ treatment. We considered JAK inhibitors, which function to inhibit multiple cytokines, including IL-6, and are effective in the treatment of adult rheumatoid arthritis (RA). Therefore, we chose the more economical and convenient drug, tofacitinib (2.5 mg twice per day), to replace TCZ, whereas the other treatment regimens remained unchanged. After 5 months, the patient’s arthritic symptoms disappeared, and the levels of acute phase reactants and cytokines decreased to normal ranges, indicating complete remission based on the JADAS-27 (Fig. 2A–C).

Table 1 Follow-up of cytokine levels before and after treatmentFig. 2figure 2

Follow-up of disease activity and acute-phase reactant levels. ESR and CRP levels before and after treatment (A); JADAS-27 before and after treatment (B); cytokine levels before and after treatment (C)

The patient subsequently presented with mild swelling and pain in some joints in May 2021 following an upper respiratory tract infection. Laboratory tests revealed increased levels of acute phase reactants (ESR 50.0 mm/h, CRP 127.0 mg/L) and increased cytokine levels [IL-6 39.3 pg/ml, soluble interleukin-2 receptor (sIL-2R) 1714.0 pg/ml]. However, the patient’s symptoms resolved rapidly after hospitalisation and a single intravenous dose of TCZ along with a switch to oral tofacitinib, and her condition has remained stable at follow-up as of March 2022. Overall, the efficacy of sequential tofacitinib treatment provided after the use of TCZ was remarkable in the present patient.

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