Biologics and Targeted Synthetic Drugs Can Induce Immune-Mediated Glomerular Disorders in Patients with Rheumatic Diseases: An Updated Systematic Literature Review

Abstract

Objective Our objective was to update the understanding of the development of paradoxical immune-mediated glomerular disorders (IGDs) in patients with rheumatic diseases treated with biologics and targeted synthetic drugs (ts-drugs). Methods A systematic literature review was performed by searching PubMed for articles published between 1 January 2014 and 1 January 2020 reporting on the development of IGD in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus (SLE) who were receiving biologics or ts-drugs. IGDs were classified on the basis of clinical, laboratory and histopathological data as (1) glomerulonephritis associated with systemic vasculitis (GNSV), (2) isolated autoimmune renal disorder (IARD) or (3) glomerulonephritis in SLE and in lupus-like syndrome (GNLS). The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment was applied to evaluate the causal relationship between IGD and specific drugs. The classification was based on a six-category scale, where the “certain” and “probable” categories were deemed clinically relevant relationships. Results The literature search retrieved 875 articles. Of these, 16 articles reported IGD data, for a total of 25 cases. According to the WHO-UMC assessment, the strength of the causal relationship between IGDs and investigated drugs was higher for anti-tumor necrosis factor-α agents (a clinically relevant relationship was found in four of six cases), abatacept (one of two cases), tocilizumab (two cases), ustekinumab (one case) and tofacitinib (one case) than for rituximab (nine cases), belimumab (three cases) or secukinumab (one case), which showed a weak causal relationship with these paradoxical events. No cases associated with apremilast or baricitinib were found. The retrieved cases were classified as 11 GNLS, seven IARD and seven GNSV. Conclusions Biologics and ts-drugs can cause IGDs. These events are rare, and the causative effect of a specific drug is hard to establish. When a patient is suspected of having an IGD, the drug should be discontinued, and treatment for the new-onset renal disorder should be promptly started.

Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies

“…It has been suggested that BAIRD might better fit an acronym for "Biologics Associated Immune-mediated Renal Disorders" which would be a more inclusive term (Piga's original paper only designated the acronym as "AIRD due to Biologics" and later authors added the "B" so the acronym is not yet established in stone). 4,6,11,38 This latter designation would then more closely fit with animal toxicity findings related to immunomodulatory therapies, where interstitial inflammation in the kidney has been identified with some of these new-generation alternative classes of medicine affecting STING and interferon pathways. 38 At present, these nonclinical immunomodulatory toxicities may only represent BAIRD-like lesions since BAIRD has not been accepted as a classification scheme in the nonclinical toxicology community.…”

“…7-10 BAIRD lesions in humans that are associated with vasculitis often do not involve ADA, and may lack immune complex formation at the site of injury. 6,11 Lupus-like glomerular syndromes are extremely rare as a drug- or chemical-related toxicity in animals, as are “isolated autoimmune renal disorders.” 10 Therefore, none of the three forms of classification for BAIRD have specifically been applicable in nonclinical DIKI. Hence, BAIRD has been considered a clinical syndrome, and one that has not been utilized in the veterinary or nonclinical toxicologic pathology literature.…”

“…As antibodies, recombinant peptides and multimeric complex biologics have become increasingly popular as therapeutic modalities, development of kidney-specific autoimmune conditions, termed "biologics-induced autoimmune renal disorders" (BAIRD) have been recognized with greater frequency in patients, but are still considered a rare clinical event. [4][5][6] BAIRD can occur in adult populations of any age, but it is more common in patients with pre-existing rheumatoid conditions. 6 According to the original definition, BAIRD cases are classified either as: a) glomerulonephritis associated with systemic vasculitis; (b) glomerulonephritis in lupus-like syndrome; or (c) isolated autoimmune renal disorders.…”

“…[4][5][6] BAIRD can occur in adult populations of any age, but it is more common in patients with pre-existing rheumatoid conditions. 6 According to the original definition, BAIRD cases are classified either as: a) glomerulonephritis associated with systemic vasculitis; (b) glomerulonephritis in lupus-like syndrome; or (c) isolated autoimmune renal disorders. [4][5][6] This terminology and classification fits some of the original autoimmune presentations in humans, but it is not as applicable in the case of nonclinical toxicities with biologic agents.…”

“…6 According to the original definition, BAIRD cases are classified either as: a) glomerulonephritis associated with systemic vasculitis; (b) glomerulonephritis in lupus-like syndrome; or (c) isolated autoimmune renal disorders. [4][5][6] This terminology and classification fits some of the original autoimmune presentations in humans, but it is not as applicable in the case of nonclinical toxicities with biologic agents. The relationship between the use of biologics and glomerular injury in laboratory animal (nonclinical) species is generally based on their immunogenicity and the development of immune complex formation related to antidrug antibodies (ADA).…”