FOCAL SEGMENTAL GLOMERULOSCLEROSIS ASSOCIATED WITH THE USE OF THE IL-23 INHIBITOR

GUSELKUMAB

Marijke Stryckers1, Stefaan Van Oevelen1, Priyanka Koshy2, Ben Sprangers3,4

and Amaryllis H. Van Craenenbroeck5,6

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1
Division of Nephrology, HH Ziekenhuis Lier, Belgium
2
Department of Pathology, University Hospitals Leuven, Leuven, Belgium
3
Division of Nephrology, Ziekenhuis Oost-Limburg, Genk, Belgium
4

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Biomedical Research Institute, Department of Immunology and Infection, University Hasselt,
Diepenbeek, Belgium

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5
Microbiology and Immunology, Laboratory of Nephrology, KU Leuven, Leuven Belgium
6
Division of Nephrology, University Hospitals Leuven, Leuven, Belgium.

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Correspondence to: Marijke Stryckers; E-mail: marijke.stryckers@heilighartlier.be

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© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article
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 ABSTRACT
We report a case of a 38-year-old man who developed a nephrotic syndrome shortly after the start
of Guselkumab for the treatment of plaque psoriasis. Renal biopsy showed focal segmental
glomerulosclerosis (FSGS). The clinical course of our case is highly suspect for drug induced FSGS
since the nephrotic syndrome resolved after cessation of the drug without relapse (2 years of follow
up). To the best of our knowledge, this is the first case describing FSGS lesions associated with the

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use of an IL-23 inhibitor.
Keywords: focal and segmental glomerulosclerosis, guselkumab, IL-23

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BACKGROUND
Guselkumab is a human monoclonal antibody, FDA approved for the treatment of plaque psoriasis. It

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binds the p19 subunit of IL-23. IL-23 induces and maintains differentiation of Th17 and Th22 cells
which produce pro-inflammatory cytokines involved in the inflammation and epidermal hyperplasia

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of psoriasis [1]. Th17 cells are involved in a variety of autoimmune diseases, including those affecting
the kidney. Guselkumab is a highly efficacious targeted therapy for psoriasis with a favorable safety

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profile in its phase III trials [2]

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Focal segmental glomerulosclerosis (FSGS) describes a lesion on renal histology characterized by focal
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and segmental scarring in the glomerulus [3]. FSGS is divided in primary (or idiopathic), genetic and
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secondary FSGS. Secondary forms can be maladaptive, viral or drug-induced. The common
pathogenic mechanism of FSGS is podocyte injury and depletion leading to proteinuria. The
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characteristics of foot process effacement on electron microscopy are helpful in differentiating

between primary and secondary FSGS [4]. The clinical presentation of FSGS can vary from
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subnephrotic proteinuria to overt nephrotic syndrome. We describe a case of secondary FSGS

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following treatment of plaque psoriasis with Guselkumab.

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CASE REPORT
We describe a case of a 38-year-old man, who presented with new onset nephrotic syndrome shortly
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after starting Guselkumab for the treatment of therapy-resistant plaque psoriasis. He had no other
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medical history and was not taking any other medication. Serum creatinine and serum albumin
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before the start of Guselkumab were within the normal range, respectively 0.88mg/dL and 47g/L.
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Last urine analysis before the start of Guselkumab dated from more than 10 years ago. He was
referred to the outpatient nephrology clinic because of the development of peripheral pitting edema
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about fourteen days after the start of Guselkumab. Blood pressure at presentation was high (150/90
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mmHg). Spot urine analysis showed gross proteinuria (25g per liter, 10g/g creat), microscopic
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hematuria (117 RBC/µL) and discrete pyuria (30 WBC/µL). Serum creatinine was 0.96 mg/dL at
 presentation. The serum albumin was 20mg/L. Complement levels (C3-C4) were within the normal
range. Antineutrophil cytoplasmic antibodies (ANCA) were positive but anti-myeloperoxidase
antibodies (anti-MPO-Ab) and anti-proteinase 3 antibodies (anti-PR-3-Ab) were negative as well as
nuclear antibodies (ANA). A renal biopsy was performed. The results of the light microscopy revealed
the diagnosis of focal segmental glomerulosclerosis (FSGS) with FSGS lesions in 4 of the 22 viable
glomeruli (18.2%). The glomerular size was within the normal range. The cellularity of the mesangium

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was normal. There was no significant tubule-interstitial damage, no signs of vasculitis.
Immunofluorescence microscopy showed discrete depositions of IgA in the mesangium, however
there were no other signs of IgA nephropathy. The diagnosis of FSGS was confirmed by electron

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microscopy. On electron microscopy, 90.5% of the glomerular capillaries showed a foot process
effacement of < 80%, suggesting a secondary form of focal segmental glomerulosclerosis. Figure 1

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shows the results of the light and electron microscopy. Serologic tests for CMV (IgM and IgG) and HIV
(HIV -1 and 2 Ab and Ag) were all negative. EBV IgG was positive but IgM was negative. We promptly

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stopped the therapy with Guselkumab as the time course was very suspect. Low dose RAAS inhibition
(Ramipril 5mg) was started in the context of arterial hypertension and proteinuria. Soon after

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stopping Guselkumab, we saw a remission of the nephrotic syndrome with normalization of the

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serum albumin and spontaneously disappearance of edema. Proteïnuria diminished to < 3.5 g/day
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about 3 months after stopping Guselkumab. Psoriatic lesions reoccurred and increased in number
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and severity. Secukinumab, an IL17-inhibitor was started. Proteïnuria diminished further and became
negative. Complete remission remained (2 years of follow up). Results of genetic testing were all
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negative which confirms the assumed diagnosis of secondary FSGS.

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DISCUSSION
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To the best of our knowledge, this is the first case describing FSGS lesions associated with the use of
an IL-23 inhibitor. We searched the publicly available EMA and FDA database and found no reported
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renal adverse events with Guselkumab. A medline search neither did reveal a previous case of
nephrotic syndrome linked to the use of Guselkumab. Th17 cells are known as potent pro-
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inflammatory cells involved in a variety of autoimmune diseases including renal autoimmune

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diseases. Furthermore signs of disintegration of the podocyte cytoskeleton accompanied by

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increased apoptosis when cultured in the presence of IL-17, a pro-inflammatory cytokine produced
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by Th17 cells are recently described [5]. It is therefore surprisingly that a potent Th17 inhibitor could
cause an FSGS lesion. However, the clinical course of our case is highly suspect since the nephrotic
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syndrome resolved after cessation of the drug. There were no signs of auto-immune disease on the
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renal biopsy. As soon as proteinuria was subnephrotic, psoriatic plaques reappeared suggesting
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Guselkumab was not therapeutically active anymore.

 CONFLICT OF INTEREST STATEMENT
Ben Sprangers and Amaryllis H. Van Craenenbroeck are members of the CKJ Editorial Board.

REFERENCES

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1. Jeon C, Sekhon S, Yan D, Afifi L, Nakamura M, Bhutani T. Monoclonal antibodies inhibiting IL-
12, -23, and -17 for the treatment of psoriasis. Hum. Vaccin. Immunother. 2017; 13: 2247-
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2. Foley P, Gordon K, Griffiths CEM, Wasfi Y, Randazzo B, Song M, et al. Efficacy of Guselkumab

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Compared With Adalimumab and Placebo for Psoriasis in Specific Body Regions: A Secondary
Analysis of 2 Randomized Clinical Trials. JAMA Dermatol. 2018; 154: 676-683.
3. D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N. Engl. J. Med. 2011; 365:

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2398-2411.
4. De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC. Differentiating Primary, Genetic,

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and Secondary FSGS in Adults: A Clinicopathologic Approach. J. Am. Soc. Nephrol. 2018; 29:
759-774.
5. Dolff S, Witzke O, Wilde B. Th17 cells in renal inflammation and autoimmunity. Autoimmun.

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Rev. 2019; 18: 129-136.

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A) PAS (400X) – segmental glomerulosclerosis (black arrow); B) EM (3000X) – diffuse foot process effacement

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Figure 1
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