Clinical improvement of renal amyloidosis in a patient with systemic-onset juvenile idiopathic arthritis who received tocilizumab treatment: a case report and literature review

A 19-year-old female Thai patient had been diagnosed with SJIA 10 years previously and had been developing progressive proteinuria for 1 year. Her initial manifestations of SJIA were quotidian fever, polyarthritis, and pericardial effusion. Although she received pulse methylprednisolone, high-dose prednisolone, and multiple disease-modifying anti-rheumatic drugs from her previous hospital (including methotrexate, sulfasalazine, and cyclosporine A), her disease activity remained mostly active. At the age of 13 years, she was referred to Ramathibodi Hospital for proper management by a pediatric rheumatologist. Her blood samples were negative for antinuclear antibody, anti-double-stranded DNA, and HLA-B27 with normal levels of C3 (1550 μg/mL; reference range, 900–1800 μg/mL) and C4 (551 μg/mL; reference range, 100–600 μg/mL). No underlying disease was found in her family members. During the first year of follow-up at Ramathibodi Hospital, the patient was treated with 25 mg/week of etanercept [an anti-tumor necrosis factor (TNF) agent], 25 mg/week of methotrexate, 2 g/day of sulfasalazine, and 5 mg/day of prednisolone. After 6 months of treatment with etanercept, she still had severe polyarthritis. Therefore, the etanercept was discontinued, and tocilizumab, a humanized anti-interleukin (IL)-6 receptor antibody, was started at that time. However, we could not use a standard dose of tocilizumab for SJIA (8 mg/kg every 2 weeks) in the early treatment period because of the patient’s socioeconomic situation. Therefore, she received tocilizumab at a dose of 8 mg/kg every 4 weeks. She partially responded to the tocilizumab; her IL-6 level slightly declined from 1105.0 to 574.2 pg/mL 5 months after starting the treatment. Her disease course still waxed and waned. Her arthritis relapsed while receiving the tocilizumab. Therefore, pulse methylprednisolone at 1 g/month, leflunomide at 20 mg/dose, and hydroxychloroquine at 200 mg/day were gradually added to the tocilizumab regimen. The rheumatologist noticed her first episode of albuminuria when her urine albumin dipstick result was 2+. This proteinuria showed evidence of progression at her 1-year follow-up, when her urinary protein-to-creatinine ratio (UPCR) exhibited deterioration from 0.87 to 3.00 (normal ratio, <0.2). A nephrologist was then consulted to diagnose the cause of the progressive proteinuria on the background of refractory SJIA.

On physical examination, her vital signs were normal. She was cachectic (body weight, <3rd percentile) and had a short stature (height, <10th percentile). Her wrists, knees, and ankles were stiff and inflamed. There were no signs or symptoms of edema. Other physical findings were unremarkable. Her urinalysis showed an inactive sediment. Significant proteinuria was confirmed by a 24-h urine collection method, which showed a total urine protein of 1295 mg/day (1792 mg/1.73m²/day). Blood chemistry analysis showed hypoalbuminemia (2.68 g/dL), a normal serum cholesterol level (152 mg/dL), and a normal serum creatinine level (0.47 mg/dL). Infectious screenings were negative for hepatitis B, hepatitis C, and human immunodeficiency viral infection. Other diagnostic investigation results are listed in Table 1.

The renal tissue contained eight nonsclerotic glomeruli. The glomeruli were unremarkable. The mesangium showed focal expansion without hypercellularity. Depositions of acellular eosinophilic amorphous material were seen in the glomerular hilum, mesangium, arteriolar wall, and interstitium (Fig. 1a, b). The material demonstrated fuchsinophilic staining, and Congo red staining was positive (Fig. 1c, d) with apple green birefringence under polarized microscopy. Mild tubular atrophy and interstitial fibrosis were also seen. An immunofluorescence study was negative for IgG, IgM, IgA, C3, C1q, fibrinogen, kappa, and lambda. Electron microscopy revealed randomly oriented fibrils of 8 to 10 nm in diameter in the mesangium, interstitium, and arteries (Fig. 2a, b). The glomerular basement membrane was unremarkable, but the podocytes showed partial foot process effacement under electron microscopy. These biopsy findings confirmed renal amyloidosis.

Because the amyloidosis was secondary to uncontrolled SJIA, the tocilizumab was increased from a dose of 8 mg/kg every 4 weeks to a dose of 8 mg/kg every 2 weeks. We also started enalapril at 5 mg/day (0.12 mg/kg/day) for an additional antiproteinuric effect. The other drugs were continued at their same dosages. Two months later, the patient’s Childhood Health Assessment Questionnaire Disability Index score decreased. Her UPCR had also decreased from 3.00 to 0.92, and her arthritis improved 3 months after the tocilizumab increment. At the 1-year follow-up, her UPCR had decreased to 0.23 and renal function remained stable, with a serum creatinine concentration of around 0.42 to 0.52 mg/dL. Her C-reactive protein concentration had returned to normal and her IL-6 concentration had slightly decreased. Other follow-up investigation results are listed in Table 1.

A 3-mL venous blood sample was collected from the patient for DNA extraction. Next-generation sequencing was performed by SureSelect V5 using the Illumina HiSeq 4000 platform. Sanger sequencing was performed for variant verification. Variants of the MEFV gene (NM#000243, transcript ID: ENST00000219596) were analyzed. A heterozygous c.442G > C (pE148Q) mutation in the MEFV gene was identified.