Elsevier

Autoimmunity Reviews

Volume 13, Issue 8, August 2014, Pages 873-879
Autoimmunity Reviews

Review
Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: Systematic literature review and analysis of a monocentric cohort

https://doi.org/10.1016/j.autrev.2014.05.005Get rights and content

Abstract

The use of biologic drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. The aim of this study was to describe the features of biologics-induced autoimmune renal disorders (AIRD) through a systematic review and a cohort study of 707 adult patients affected with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (SA) and Psoriatic Arthritis (PsA).

The literature search identified 2687 articles of which 21 were considered relevant for the present study, accounting for 26 case reports. The cohort analysis retrieved 3 cases. According to clinical manifestations and kidney histology the identified AIRD cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Twenty-two out of 29 cases with AIRD were reported in patients affected by RA, 5 in AS and 2 in PsA. The biologic drug most frequently associated with development of AIRD was Etanercept (15 cases, 51.7%), followed by Adalimumab (9 cases, 31.0%) and Infliximab (3 cases, 10.3%) while Tocilizumab and Abatacept were reported in 1 case (3.4%) for each. Thirteen out of 29 (44.8%) cases were classified as affected by IARD, 12 (41.3%) as GNSV and 4 (13.9%) as GNLS. Worse prognosis was associated with GNSV and lack of biologic withdrawal. Although rare, AIRD may be life-threatening and may lead to renal failure and death. If AIRD occurs, biologic drugs must be stopped and patient should be treated according to clinical manifestations and kidney biopsy findings.

Introduction

Biologic drugs are licensed for the treatment of chronic inflammatory rheumatic diseases (IRD) including Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS). The introduction of anti-TNF-alpha agents has changed the treatment of these inflammatory conditions [1], [2]. Afterwards, a better understanding of disease pathogenesis has led to the development of new-targeted biologic treatments for RA with different mechanisms of action. They act by inhibiting the effect of specific cytokines (IL1, IL6) or selectively targeting CD20-positive B cells or preventing antigen-presenting cells from delivering the co-stimulatory signal to T lymphocytes by binding to CD80 and CD86, thereby blocking interaction with CD28 [3]. Further treatment modalities are being investigated such as targeting IL-17 to modulate Th17/Treg balance and reduce inflammation [4].

Biologics are usually considered cost-effective in controlling disease activity, inhibiting the progression of structural damage and reduce the risk of co-morbidities such as osteoporosis in patients with chronic IRD [5], [6], [7]. On the other hand, all of these drugs have a range of shared adverse effects including the paradoxical development of autoimmune processes, ranging from asymptomatic immunologic alterations to life-threatening systemic autoimmune diseases [8]. The higher number of reports on the development of autoimmunity is related to the use of TNF-alpha-blocking agents, however other biologics have recently been associated with the development of systemic and organ specific autoimmune conditions [9]. Although unusual, biologics-induced autoimmune kidney damage has been reported in patients affected by chronic IRD as isolated disorder or as part of the spectrum of drug-induced Systemic Lupus Erythematosus (SLE) and drug-induced systemic vasculitis [8], [9]. However, the clinical characteristics and outcomes of autoimmune renal disorders (AIRD) triggered by biological therapy have not been specifically addressed. The purpose of this study is to describe the features of biologics-induced AIRD in adult patients with chronic IRD through a systematic review and the analysis of a monocentric cohort followed-up in an Italian third level center of rheumatology.

Section snippets

Systematic review

Two investigators (MP, EC) performed a systematic review of the literature, according to the PRISMA guidelines, searching for articles published between the 1st of January 1990 and the 31st of January 2014 reporting on the development of AIRD (Outcome) in adult patients with IRD (Population) receiving biologics (Intervention). The following search strategy through MEDLINE via PubMed was designed using a combination of Mesh terms: (“Arthritis, Rheumatoid”[Mesh]) OR (“Spondylitis,

Literature search

The literature search identified 2687 articles, from which 24 were initially considered relevant for the present study. The manual search retrieved 7 additional articles. Finally, 21 articles were included in the study (Fig. 1), accounting for 26 case reports. Reasons for exclusion were especially diseases of interest different from IRD and treatment different from biologics. Among the articles retrieved by PubMed search 8 were excluded because they did not report of descriptive features of

Discussion

Despite mesangial GN, membranous GN and minimal change nephropathy have been described as extra-articular manifestations of IRD, mainly in RA and rarely in AS and PsA, glomerular disease in these patients is more commonly related to secondary amyloidosis or complications of drug therapy [31]. Lupus nephritis may very rarely develop in a subset of RA patients who have overlap with SLE [32], while ANCA positivity in RA has been related to the development of NCGN [33]. Drug-induced nephropathy is

Take-home message

  • Biologics-induced AIRD are mostly, but not exclusively, associated with anti-TNF-alpha treatment.

  • Although rare, AIRD may be life-threatening and may lead to renal failure and death.

  • If AIRD occur the biologic drug must be stopped.

  • Treatment of AIRD should be tailored to clinical manifestations and kidney biopsy findings.

Acknowledgment

Matteo Piga gratefully acknowledges the Sardinian Regional Government for its financial support (P.O.R. Sardegna F.S.E. Operational Program of the Autonomous Region of Sardinia, European Social Fund 2007–2013 — Axis IV Human Resources, Objective l.3, Line of Activity l.3.1).

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