Inebilizumab Monotherapy in Relapsing IgG4-Related Tubulointerstitial Nephritis

To the editor:

IgG4-related disease is a rare but clinically significant systemic fibroinflammatory disorder affecting multiple organs, characterized by IgG4 plasma cell infiltration and tissue fibrosis, with an estimated prevalence of 5.3 per 100,000 persons in the US.^1,2 Kidney involvement is reported in approximately 7%–24% of IgG4-related disease cases and represents considerable clinical heterogeneity.³ Although glucocorticoids have historically been used as the first-line therapy for IgG4-related disease, relapse after tapering is very common, creating a significant need for durable, steroid-sparing treatment in order to avoid long-term complication of prolonged steroid therapy.^3,4 Inebilizumab, a CD19-targeted B-cell–depleting monoclonal antibody therapy, is the first US Food and Drug Administration-approved therapy for IgG4-related disease.⁵ However, experience with its use in biopsy-proven IgG4-related kidney disease remains limited, because patients with kidney involvement represented only a small subgroup in the MITIGATE trial.⁵ We describe a patient with relapsing IgG4-related tubulointerstitial nephritis who achieved sustained steroid-free remission after treatment with inebilizumab.

A 63-year-old man with an established diagnosis of IgG4-related tubulointerstitial nephritis through kidney biopsy (Supplementary Figure S1) was started on prednisone 30 mg daily for 4 weeks, resulting in an improvement in kidney function (creatinine, 1.4 mg/dl), normalization of serum complements C3 and C4, a marked reduction in IgG4 levels, and resolution of lymphadenopathy. Prednisone was tapered over 3 months and discontinued. Several months later, he experienced a disease flare. Given his preference to avoid steroids, he was initiated on inebilizumab monotherapy. He received 2 300-mg intravenous infusions on days 1 and 15, with a planned maintenance dose at week 26. Following treatment, serum IgG4 levels decreased substantially from 523 mg/dl at relapse to 215 mg/dl by 4 months, remained low with minor fluctuations (222 mg/dl and 245 mg/dl) through 6 months, and further declined to 147 mg/dl after the 6-month maintenance infusion. This was accompanied by stabilization of kidney function (creatinine, 1.57 mg/dl, estimated glomerular filtration rate, 44 ml/min per 1.73 m²) and normalization of C3 (110 mg/dl) and C4 (19 mg/dl) levels. He remains off steroids with an improved metabolic profile and no recurrence of lymphadenopathy, showing a favorable early response to inebilizumab (Figure 1). A detailed description of the patient's clinical presentation, diagnostic evaluation, laboratory findings, and overall clinical course is provided in the Supplementary Case Description.

Figure 1.

Shows longitudinal trends in serum IgG4 levels and eGFR across key clinical time points, including presentation, initial treatment response, disease flare, and follow-up after initiation of inebilizumab, showing biochemical relapse and subsequent improvement with targeted B-cell therapy; the lower panel illustrates concurrent HbA1c and serum complements trends over the same period. eGFR, estimated glomerular filtration rate.

Although inebilizumab was generally well tolerated in the MITIGATE trial, CD19-directed B-cell depletion requires appropriate safety monitoring. Patients should be screened for chronic infections, including hepatitis B, before treatment, and serum Ig levels should be monitored during therapy, particularly in those receiving repeated dosing or with recurrent infections. In the phase 3 MITIGATE trial, serious adverse events occurred in 18% of patients receiving inebilizumab compared with 9% in the placebo group, highlighting the need for ongoing vigilance for infectious complications.⁵

Disclosure

NE has received grant from GlomCon and educational grant from Medtronic. She also serves as the social media editor for the Nephrology Dialysis Transplantation. RJG is a compensated consultant for Alexion, Alpine, Arrowhead, BioCryst, Chinook, Equillium, Horizon, Immunovant, Ionis, Mironid, Nkarta, Novartis, Omeros, Orange Grove Bio, RenaSight (Natera), River 3 Renal, Travere, Vera, Zydus, and ZyVersa. He receives a stipend from Wolters Kluwer and Karger for editorial services. AR has received research grant support from AbbVie, Alexion, AstraZeneca, Bayer, GlaxoSmithKline, Palladio, Protalix, Reata, Regulus, Sanofi, Takeda, Vera Therapeutics, and Vertex Pharmaceuticals. He has served as a consultant for Akebia, Amicus Therapeutics, Ardelyx, AstraZeneca, Chiesi, Chinook Therapeutics, Fresenius Medical Care, Novartis, Otsuka, Pfizer, Travere Therapeutics, and Vera Therapeutics. He has received speakers' bureau honoraria from Amgen, AstraZeneca, Aurinia, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly, Natera, Sanofi, Travere Therapeutics, Vantive, and Vifor. He has also served on advisory boards for Akebia, Natera, Novartis, and Vera Therapeutics. SN has received consulting fees and honoraria from Calliditas, Otsuka, Alexion, Travere Therapeutics, Novartis, Sanofi, Amgen, Vera Therapeutics, Vertex Pharmaceuticals, Boehringer Ingelheim, and Emerald Clinical Trials. She serves as a member of the Board of Directors of the IgA Nephropathy Foundation. She has also received grant support from GlomCon, the IgA Nephropathy Foundation, the American Society of Nephrology (ASN), and Otsuka. VH has no conflicts of interest to disclose.

Patient Consent

Informed consent was obtained from the patient described in this report.

Supplementary Material

Supplementary File (PDF)

Supplementary Background. Supplementary Case Description. Supplementary References. Figure S1. Kidney biopsy demonstrating the characteristic histopathologic findings of IgG4-related tubulointerstitial nephritis. Table S1. Clinical manifestations and major subtypes of IgG4-related kidney disease.